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Home , Gamma camera, Nuclear chemistry, Nuclear medicine, Radiation therapy, Radioactive tracer, Radionuclide

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Basics of radiopharmacy

BUCK A. RHODES, Ph.D. Director of Radiopharmacy, University of New Mexico College of , Albuquerque, New Mexico

BARBARA Y. CROFT, Ph.D. Division of Nuclear , University of Virginia Medical Center, Charlottesville, Virginia

with 246 illustrations, including drawings by Mark Prouse

The C. V. Mosby Company SaintLouis 1978 Copyright @ 1978 by The C. V. Mosby Company

All rights reserved. No part of this book may bc rcproduced in any manner without written permission of the publisher. Printed in the United States of America

’Ihe C. V. Mosby Company 1 1x30 Westline Industrial Drive, St. Louis, Miswuri 63141

Library of Congress Cataloging in Publication Data

Rhodes, Buck A,, 1935- Basics of radiopharmacy. Includes bibliographies and index. 1. . 1. Croft, Barbara Y., 1940- jointauthor. 11. ‘litle.[DNLM: I. . 2. Radioisotopes--l)iagnostic use. 3. Radioisotopes-Therapeutic IISC. WNW R476bl RM825.R46615’.8424 77-26557 ISBN0-8016-4127-6

CW/M/M 9 X 7 6 5 4 3 2 I Foreword

The evolution of radiopharmacy as a special- Even as the discipline of radiopharmacy de- ty has been extremely rapid when compared to velops, its future will be molded by many in- other disciplines within pharmacy. Essentially ternal and external forces and pressures. These it has developed as aspecialty area within a pressures includefederal regulatory actions period of 20 ycars, and its route has been tor- concerningradiopharmaceuticals, actions of tuous. The preparation, dispensing, and clinical state boards of pharmacyconcerning radio- investigation of radioactive materials as drugs and radiopharmaceuticals, new di- started experimentally early in the 1950s with rections of research in imaging in nuclear medi- the use of I3'l and a2P.As the early use of these cine, new directions in de- and other evolved and as the impor- velopment, and the numbers and direction of tance of labeled compounds as imaging agents educational program in radiopharmacy by col- bccame recognized,primary development of leges of pharmacy. It is certain that these forces radiopharmaceuticals lay with the research ra- and pressures among others will dictate many diochemist and . In the late 1960s and dramatic changes and developments within ra- early 1970s, however, nuclear medicine devel- diopharmacy in the forseeable future. oped as a separate and began With their extensiveexperience in and to expand dramatically. With this development knowledge of the field of radiopharmacy, the came a whole regiment of new radiopharma- authors of Basics oj Radiopharmucy have ceuticals. The proliferation of these radioactive clearly defined the functions and types of pro- imaging agcntsrequired the parallel dcvelop- fessional activities that the radiopharmacist per- ment of specialists qualified to prepare, run forms. Thistextbook provides a current and quality control on, run clinicalstudies on, detaileddescription of the basics of radio- and dispense these agents. In short, by evolu- pharmacy and theessential knowledge base tion radiopharmacy and the radiopharmacist needed for the student intending to enter this emerged as an essentialdiscipline and asa field. It also will serve as an important refer- partner to nuclear medicine and the nuclear ence book for educators and others who wish medicine physician, to expand their knowledge of radiopharmacy Today radiopharmacy is viewed as a distinct but who may not be actively involved in prac- discipline. While constant interaction and close tice. 1 congratulate the authors on a very cow- cooperative ties between the nuclear rnedicinc plete text, well organized and well written. This physician andthe radiopharmacistare essen- text should be a valuable addition to the excit- tial, the functions of radiopharmacists are be- ing and interesting new specialty of radiophar- coming more defined, and their distinct role as macy . clinicians and as distributors of radiopharma- Carman A. Bliss, Ph.D. ceuticals is evolving rapidly. Dean, Universiry of New Mexico College of Pharmucy, Albuquerque, New Mexico

V Preface

Basics of Radiopharmacy was written to pro- . Although knowledge of these subjects vide afirst-course textbook in radiopharmacy is assumed, an outline of prerequisite knowl- for use by undergraduates in pharmacy and nu- edge is given in the Appendix. Our experience clear medicine technology. The text is planned in teaching this class over the past years is that as a comprehensive introductionto the prepara- a few review sessionsare sometimes neces- tion and clinicaluse of radioactivetracers. sary to prepare the students for this course. Tracer principles are combined with pharmacy The outline of material was developed from techniques to provide the student with the in- courses presented at the University of Virginia, formation needed to prepareradioactive sub- TheJohns Hopkins Medical Institutions,the stancesfor intravenous administration to pa- University of Kansas, and the University of tients. New Mexico. The text assumes that the student will have an understanding of and basic atomic Buck A. Rhodes Barbara Y. Croft

vii Contents

1 What is radiopharmacy? 1 Mechanisms of localization, 33 Definitions, 1 The magic bullet approach versus the tracer Radiopharmacy, 1 concept, 33 Radiopharmaceuticals, 3 Capillary blockage, 36 Radiopharmacists, 5 Phagocytosis, 40 Nuclear medicine, 6 sequestration, 42 History of radiopharmacy, 7 Active transport, 44 Radiopharmacy compared to pharmacy in Compartmental localization, 47 general, 1 1 Simple or exchange , 48 ‘Types of radiopharmacics, 14 Missing mechanisms, 48 Hospital radiopharmacics, 14 Blood flow and tracer localization, 50 Central radiopharmacies, 14 Training radiopharmacists, 14 of Design criteria, 52 Physical characteristics, 52 Chcmical and biologic characteristics, 56 2 Tracer techniques in Solubility, 58 medicine, 17 Tagging reactions, 58 In vivo stability, 59 ‘Tracer tcchniques: uses and advantages, 17 Clearance, h 1 Usc of tracers to dctermine Inass and space,19 Amount of tracer, 61 Law of conservation of matter, 19 Elements by groups in the pcriodic chart, 62 Group 1, 65 Red cell mass, 19 Groups 2 and 65 Volumes of distribution, 21 3, Groups 4 to 66 Use of traccrs to determinc ratcs and 6, Esscntial tracc elements and nonessential pathways, 23 transition metals, 66 Dynamic studies and nuclear Group 7, 68 , 24 Group 0: thc noble gases, 69 Tracer clearance as a measure of blood Row, 24 and rare earths, 70 Bifunctional compounds designed for use Indicator concentrations and transits as as radiopharnlaceuticals, as 73 ! measures of hlood flow, 26 Absorption, , and turnover studics, 27 Making radiopharmaceuticals!’ Use of tracers in quantitative microanalysis, safe and effective, 76 27 dilution analysis, 28 Preliminary hiodistribution sludies, 76 Substoichiomctric analysis, 29 Checking systcm for sterility and Isotopic equilibrium analysis, 3 I apyrogenicity , 77 Activation analysis, 32 Sterilization, 78 ix X Contents

Sterility testing, 78 9 Generatorsystems, 1 13 Pyrogens and the pyrogen response, 79 Pyrogen testing, 79 Generalcharacteristics, 113 Toxicity studies, 83 Construction, I 14 Introducing new radiopharmaceuticals, 86 Operation, 116 The IND, 86 99Mo/99mTc generator, 1 I7 Clinical trials, 87 Description, 117 Replacing old radiopharmaceuticals, 88 Evaluation of eluate, 119 Adverse reactions to radiopharmaceuticals, 113Sn/113mIn generator, 121 88 Description, 121 Overdosing and underdosing, 89 Evaluation of eluate, 121 Injection problems, 89 Generators for ultrashort-lived nuclides, 12 I Uses, 121 Examples:'31Cs/137mBa, 81Rb/M1mKr,and 6 Radiationtherapy with 8iSr/82Rb. 122 radiopharmaceuticals, 91 Design, 91 10 Production of radiochemical$, 123 1311, 91 Basic concepts, I23 32Psodium , 91 Radioiodination, 123 Colloids, 9 1 chemistry, 126 Handling patients, 92 Reduction, 126 Assurance of radioisotope dosage, 92 exchange, I27 safety considerations, 92 Chelation, 128 Talking with the patient, 93 F'rotein labeling, 130 -based reduction products, 130 7 Radiationdosimetry, 95 Chelation and complexation of other metals, 13 I Early observations of radiation effects, 95 Organic and biochemical synthesis, 132 Review of radiation , 95 Biologic synthesis, 133 Review of the properties of radioactive materials and absorption of radiation, 96 calculations, 98 11 Daily preparations and their Physical and biologic contributions, 98 quality control, 136 Sample calculation, 102 Summary, I03 Routine quality control, 136 General requirements, 136 8 Production of , Thin-layer , 136 Gel-columnscanning, 137 105 Sodium solution, 138 Activation of stable elements, 105 Elution volume, 139 Calculation of production rates and Assay of total radioactivity, 139 reactor production, 105 Assay of radionuclidic purity, 140 Separation techniques, 106 Assay of radiochemical purity, 141 Specificactivity, 107 , 141 Example: lSF from LiCO,, 107 Aluminumbreakthrough, 142 Linear accelerator and Labeling and record keeping, 142 production, 107 99mTccolloids, 142 "C, 13N, I5O, 11 1 99mTclung agents, 144 Halogens (1231 as an example), 1 1 1 99mTc agents, 144 Other cyclotron-produced nuclides, 11 1 99mT~DTPA, 145 Fission production, 11 1 99mTcHSA, 146 9rmT~RBCs, 146 YPmTcWCs, 147 Contents XI

12 Operating a radiopharmacy, 148 APPENDIXES Physical setup, 148 A Layout of a radiopharmacy, 155 Staffing, 148 Robert Adams, R.Ph. Dispensing of doses, 148 Economics,150 B Practicalgenerator kinetics, 163 Automation, 15 1 Mylerr Lamron 111, MS., Clifford E. Rules and regulations, 151 Hotte, Ph.D., and Rodney D. Ice, Ph,D. Record kceping, 152 Transportation of radioactive prescriptions, Problems, 173 153 System quality controls, 154 Glossary, 179 CHAPTER 1 What is radiopharmacy?

Definitions pensed drug is in the final dosage form appro- RADIOPHARMACY priate for administration to the patient. A radiopharmacy is the place where radioac- When a prescription is to be filled, the re- tivc drugs are prepared and dispensed. The ra- quired amount of the stock solution is appor- diopharmacy also serves asa depot for the stor- tioned. Usually this means withdrawing a tracer age of radioactive materials and nonradioactive solution from a -shielded vial into a syringe supplies. It is here that the inventory records of of the required size. The syringe must be fitted radioactive materials are recorded and stored. with the type and size of needle required for This latter function includes the maintenance of the injection. It or its carrier must be labeled prescription records. The radiopharmacy is also with the patient’s name and the dosage informa- likelyto be the correlation point for radioac- tion: radiopharmaceutical, radioactivity calibra- tive waste rnaterialsand their assignment to tion time, and date. As soon as the syringe is wastc disposal or waste storage units. filled with the and its radin- The radiopharmacy is usually a center for activity is measured, it is inserted into a syringe clinical investigations employing radioactive shield or syringe carrier so it can be transported tracers, as well as for education of radiophar- to the patient without exposing anyone to the macy students, students, emitted radiation. and nuclear medicine or residents. At othcr times, capsules arc counted out, or The radiopharmacymay also be a centerfor oral solutions are nleasurcd out, into dispos- rcscarch in the development of new radioactive able cups or other suitable containers. This also tracers. requires assay of the radioactivity, labeling the Wc often divide the work of the radiophar- dose, and housing itin radiation shicldsfor tnacy into two primary activities, dispensing transportation to the patient. In some instances and clinical. lhe dispensing function is consid- the patient is brought into the radiopharmacy ered first. This includes all activities required to so the tracer can be administered to the patient prepare and deliver to thc clinic the radioactive by the radiopharmacist ortechnologist. Often tracers necdcd for patient studies. Usually, this is the safest way to administer oral solu- multidose amounts of several tracers are pre- tions of radioiodine used for therapy. Fig. 1-1 pared each morning. Calculations to correct for shows examples of doses of radiopharmaceu- are used to determine how ticals as they are issuedby a radiopharmacy. much of a tracer is to be measured out for an Radiopharmacies also may issue some non- individual patient. Not only mustthe amount radioactive drugs,such as perchlorate, atro- of the tracer, in terms of millicuries (mCi) or pine, iodide solution, or intrinsic factor. These micmcuries (pCi) of radioactivity, be consid- ancillary drugs arc used to enhance the uptake, ered, butthe amount in terms of both milli- alter the biodistribution, or otherwise aid in grams and milliliters must also be considered. controlling thc biorouting of the radioactivity. A check system is used to assure that the dis- Standards used in the calibration and quality 1 2 Basics of rudiopharmacy A

Syringe carrier

Fig. 1-2. Field flood test source that can be loaded with MvmToO;solution. In backgroundis a bar CAUTION phantom. These testing devices are used for routine e quality control testing of an Anger camera. (From Rhodes, B.A., editor:Quality control in nuclear medicine:radiophatrnaceuticals, instrumentation,

MATERIAL and in vitroassays, St. Louis, 1977, The C. V. Mosby Co.)

Vial holder (PIG) pounds can be tested in a matter of minutes to determine percent of radioactivity in the desired Flg. 1-1. Radiopharmaceuticals are dispensed either chemical state (often called percent tug). The as unit doses (top) or as multidoses (bottom). Unit effective clinical use of radiopharmaceuticals doses are usually dispensed as precalibrated ready- to-injectintravenous preparations. Multidose solu- often requires understanding and communica- tions usually contain a day's supply of radiopharma- tion of the quality control data. This us ceutical, which may be as many as ten or more doses into a discussion of the clinical activities of a for a busy nuclear medicine clinic. radiopharmacy . The clinical activities of a ra- diopharmacy are not really distinct from the dispensing activities: however, for simplicity of control testing of nuclear detection instrumen- discussion the clinical activities are considered tation are often stored in the radiopharmacy separately. and issued periodically for instrument testing. When the biodistribution" of a tracer is dis- For example, a field flood test source(Fig. tributed in the patient in a manner that is un- 1-2), used to measure the uniformity of re- explained by the patient's or differs sponse of an Anger camera to radiation, may significantly from whatis normally expected, be loaded daily with several millicuries of per- then the performance of the tracer becomes sus- technetate (QgmT~O;)solution and issued on re- pect. In order to proceed with the diagnosis, quest. the nuclear medicine physician frequently re- The radiopharmacy is responsible for quality quires additional information obtained from control of the radiopharmaceuticals. The rou- quality control or other types of performance tine preparation procedures often incorporate tests. Sometimes this may involve talking with quality control tests for radiochemical purity. For instance, most technetium-labeled com- "Terms in boldface are defined in the Glossary. What is radiopharmucy? 3

the patient to determinedrug history, check- Table 1-1. Classification of radioactive ing the results of other patients who have been drugs given the sametracer, and may even require doing tissuedistribution studies in animals. Type Examples These troubleshooting activities make up a part Multidose-corn- la'l Rose Bengal,technetium of what is called clinical radiopharmacy. mercially sup- YYrn solution, U.S.P. In summary, a radiopharmacy is dispcnsarya plied where orders for radioactive drugs to be used Generators ggMo/~'BmT~generator in patientsare filled. Supply of radioactive Reagentkits Kit for preparing 99mT~pyro- drugs and troubleshooting of radioactive tracer phosphate studies are major radiopharrnucy functions. these broadcasts we can infer the concentrations RADIOPHARMACEUTICALS of the tracer material in different organs. Using What isa radiopharmaceuticul? The term the signals, we can even obtain low-resolution that is legally defined in the Federul Register images of the organs. By monitoring these of the U.S.A. is radioactive drug. This is any broadcasts as a function of time, we can study substance defined as adrug" in the federal the kinetics and metabolism of the drug within Food, Drug, and Cosmetic Act that exhibits the body. The monitoring device is usually a spontaneousdisintegration of unstable nuclei collimated external gamma-ray detector. Thus, with the emission of nuclear or pho- diagnosticradiopharmaceuticals are adminis- tons and includes any nonradioactive reagent tered to patients to differentiate normal from kit or generator that is intended to be abnormal ,physiology, or anat- used in the preparation of any such substance. omy. The term radioactive drug includes radiour- Unfortunately, not all diagnostic radioactive tive biologic product. - and - tracers are gamma emitters that permit their in containing compounds with naturally occurring situ determination with noninvasiveexternal 14C and 40K are excluded from this definition. radiation detectors. A few diagnostic radiophar- Basically,radiopharmaceuticals are usually maceuticals are prepared using , carbon classified asdiagnostic ( DJ, therapeutic 14, or 32. Since these do (rad R,), orresearch radiopharmaceuticals. not emit gamma rays, it is impossible to moni- They can also be classified by reference to the tor their position within the body using external categories that stem from the legal definition detectors. They can be used, however, in tracer of aradioactive drug. Thesc classes and ex- diagnosis by taking samples for analysis. One amples arc listed in Table I - I. example of thisis to administerglucose 14C Diagnostic radiopharmuceuticals. These are and then monitor the excretion of carbon diox- radioactive drugs used for diagnostic purposes ide 'IC inthe breath as an indicator of the as radioactive tracers in patients. These drugs absorption of thecompound, its subsequent broadcast theirpositions within the body by metabolism, and its elimination in the breath as their gamma-rayemissions. By monitoring the metabolic end product, 14C02. Other body fluids that can be sampled and counted are *The term drug means (I) any of the articles recognized in blood,urine, and, in someinstances, biopsy the official United Stares Pharmacopda, official Homeo- samples. pathic Phurmacopeia ($the United States, official National Formuluty, or any supplement to any of them; (2) an ar- Therapeutic radiopharmaceuticals. Radioac- ticleintended for use in the diagnosis, cure, mitigation, tive substances can be administered to a patient treatment, or prevention of diseasein man or other ani- for the purpose of delivering radiation to body mals; (3) an article (othcr than food) intended to affect the tissues internally. The best example of this is structureof any function of thebody of man or other the administration of iodide I3 I for the purpose animals; and (4)an article intended for use as a component of any articles specified in clause I, 2, or 3; the term does of ablation in patients who are hyper- notinclude devices or their components, parts, or ac- thyroid. The thyroid is internally irradiated by cessories. the radioactive that it concentrates. 4 Busics of rudiophurmacy

Fig. 1-3. Radiopharmacist answers tclephone, taking prescription for radiopharmaccutical. Pre- scriprion is typed from information rcceived over telephone.

Fig. 1-4. Dose of radiopharlnaoeutical is withdrawnfrom vialin leadcontainer into syringe. Radiophartnacist works behind lead shicld and observes work through leaded glass window shield. Whar is rrrrlillphnrmary;’ 5

Othcr radiopharmaceuticals that arc used for Live tracers and for the clinical aspects of radio- therapeutic purposes are those administered in pharmacy. In order to carry out these functions, the treatment of certain . radiopharmacists nccd to be trained in (1) ra- Regular drugs labeled with a mdioartive dioactive tracer techniques, (2) safe handling of tracer. Another typc of radiopharmaceutical is radioactive materials, and (3) preparation and a regular drug labelcd with a small quantity of quality control of drugs preparcd for adminis- radioactive substances. Thew are administered tration to humans. These individualsare also to the patients, not for diagnostic p~~rposes,but required to understand the basic principles of to study the metabolism and kinctics (i.e., the nuclear medicine so that they can function ef- biodistrihution) of a drug that may eventually ficiently whcn troublcshooting clinical prob- be used in a nonradioactive form. This type of lems involving performancefailure of the radiopharmaceutical is used primarily for rc- radioactive tracer in an individual patient (Figs. search purposcs. 1-3 to 1-5). The first radiopharmacists usually wcrenot RADIOPHARMACISTS pharmacists, but individuals who wcre involved Radiopharmacists are responsible forthe fill- in the creation of the specialty of nuclear medi- ing and dispensing of prescriptions for radioac- cine. individuals whowcre interested in the

Fig. 1-5. Eachprescription is numbcred serially and recorded in mastcr log. Each patient dose must be traceable to vial from which dose was drawn, to quality control test data, and to supply of radioactive material used in its fnrmularion. 6 Basics of radiopharmacy application of tracer techniques to the diagnosis in medicine. The supply of radioactive isotopes and management of patients. Many of these rapidly expanded with the development of individuals came from related areas of science nuclear reactors that followed WorldWar 11. such aschemistry, , physics, Programs were instituted both nationally and chemical engineering, and biology. Their train- internationally to promote the peaceful uses of ing usually included few formal courses, with atomic . Many of the early studies were most of the training being on the job. This encouraged and funded by theseprograms. trainingdealt primarily with the handling Since that time, nuclear medicine has become a of radioactivematerials and the application vital part of the diagnostic and therapeutic man- of tracertechniques to diagnosticproblems. agement of patients. Since 197 1, the Joint Com- Theseindividuals were forced to learn asep- mission for Accreditation of Hospitals has re- tic techniques in order to be able to prepare quired that a nuclear medicine service be pres- these new tracersfor administration to pa- ent or at least that formal arrangements be made tients. to provide these services to patientsin order for Currently, it is widely appreciated that some ahospital to receiveaccreditation. By 1975, of the best candidatesfor becoming a radio- approximately 50% of thenation’s hospitals pharmacistare persons trained in pharmacy, had some type of nuclear medicine facility. It then trained in the special techniques of rddio- is projected that some 20 million studies will labeling drugs. Some states require that radio- be conducted annually by 1980. active drugsbe dispensed by a licensed pharma- Nuclear proceduresare useful for a broad cist.Other states recognize individuals called rangc of diseasestates. At least 15% ofall radiopharmaceuticalspecialists who may or patients admitted to a hospital will have a nu- may not be graduates of a school of pharmacy. clear medicine procedure as partof their routine In many institutions the individual who pre- diagnostic workup. The spectrum of diagnostic pares the radiopharmaceuticals works under the procedures includes (1) static imaging of or- direct supervision of a nuclear medicine physi- gans and compartments,(2) sequential or cian, who may assume the primarylegal re- of physiologic processes, sponsibility for the safety and efficacy of the (3) in vivo tracer studies(Fig. 1-6), and (4) drugs that are administed to patients, thus ob- in vitro studies. viating the requirement to havca registered In1971 the American Board of Nuclear pharmacistdispensing the radiopharmaceu- Medicine was approved by the American Medi- ticals. cal Association Council on and the American Board of Medical Special- NUCLEAR MEDICINE ties. A physician, after fulfilling one of several Nuclear medicine is aspecialty devoted to accepted combinations of training and experi- the diagnostic and therapeutic use of radioac- ence, can become qualified for examination by tive compounds. The application of radioactive the specialty board. On satisfactory completion tracer technqiues in the study of human biology of the examination he is admitted into the spe- began in the early 1920s. ’s cialty asa board-certified nuclear medicine classical volume, Radioactive Indicators, set physician. Beginning in 1977, a physician must forth many of thebasic principles that were have completed an approved program laterincorporated into the nuclear diagnostic to become eligible to apply to take the certify- techniques. Herrman Blumgart was one of the ing examination. first individuals to apply naturalradioactive Nuclear medicine is interdisciplinary in na- isotopes in the study of circulation in man. ture and relies heavily on interactions with all Artificial radioactive isotopes were introduced medical specialties. Input into the development at first by E. 0. Lawrencearound 1932. In of this field comes from continuingadvances 1946 the Atomic Energy Commission was es- in electronics, computer science, physics, an- tablished by Congress;a significant area of alyticalchemistry, , and ra- focus was the peaceful use of atomic energy diopharmacy . What is radiophurmacy.? 7 TI Right atrium h Right ventricle Pulmonary artery

0 10 20 30 0 10 20 30 0 10 20 30

Seconds Seconds ~ Seconds I ventricle Left Aorta I

4 T 1 I I I I I I I I I I' 0 10 20 30 0 10 20 30 0 10 20 30 Seconds Seconds Seconds

Fig. 1-6. This in vivo tracer study is a angiocardiogram. Strip-charl recordings show passage of radioactive tracer through six areas of intercst in central circulation. Arrows indicate anatamic structure selected for each recording. (From Van Dyke, D, C., Anger, H. O., Sullivan, R. W., Vetter, W. R.. Yano, Y., and Parker, H. G.: J. Nucl. Med. 13585-592, 1972.)

History of radiopharmacy much of thc basic data needed to develop the Before radiopharmacy there was bionucle- tracer techniques. onics. This term was used as a catchall title for Of major importance was the work done at courses taught in colleges about the biologic Oak Ridge, Tennessee. In 1946 the Oak Ridge application of radioactivematerials. In these National Laboratory began to produce radio- courses, the use of radioactivetracers inthe nuclides for biologic and medicalpurposes. study of physiology,chemistry, and biology These were made in an air-ct~oledgraphite was discussed.The courses also dealt with . Many and biomedi- , nuclear instrumentation, radio- cal who have contributed the founda- chernistr4, and radiation safety. As the use of tions to this field began by training and work- radioactive indicators as diagnostic agents be- ing at Oak Ridge. came more widespread,the courscs were ex- National laboratories in othernations also panded to include a bit of pharmacy, particu- began to supply reactor-produced nuclides for larly instruction in the use of aseptic proce- biomedical purposes and toconduct training dures and other techniques associated with the programs. preparation of intravenous solutions. The InternationalAtomic Energy Agency has Programs were initiated by sevcral national beenan active forcc in the formalization and laboratories, which made majorcontributions evolution of the field of radiopharmacy. In to the development of the clinical use of radio- 1966 the agency published the Manual of Ru- active materials. As these laboratories began to dioisotopc Production. Theagency sponsored produce radioisotopes, they developed both several study groups and international sympo- training programs in their medical applications siums, published several monographs, andin and undertook basic research that provided 197 I revised their originalmanual and published rose bcngal,an indicator of function. Iodine can be tagged to almost any protein. One of the mostwidely used is human serumal- bumin; radioiodinated human serum albumin can be used as a tracer of plasma proteins. It can be microaggregated toform a colloidal , which can be used to visualize the reticuloendothelia1 system, and macruaggre- gated toprnducc an indicator of relative re- gional to the . Iodine 131, whichis a satisfactory isotope fortherapy, is far from ideal for use as a diagnostic tracer bccause ofits long half-lifc, its high-energy beta radiation (has high-), and the possibility of the radioactive eletnent concentrating in normal thyroid tissue and caus- ing long-term radiation damagc to thegland. Iodine 13 1 has been popularfor manyyears because it is cheap and widely available. It can be used to prepare radioactive tracers with long shelf-lives; thus, the materia1 can be prepared in one area and shipped for use in distant hos- pitals. The radiochemistry of iodine became well understood, and radiochemists have be- comequite adept at incorporating this tracer into a wide varicty of . Probably the greatest impetus to the develop-

Fig. 1-7. Paticnt is receivingdose of 13'1 iodide ment uf radiopharmacy was thc introduction of solution,which is administeredto ablate thyroid. the !'LJml'cgenerator. Powell Richards, working Treatment is used for and thyroid at Brookhaven National Laboratory, realized . thc potential of the parent-daughter pair of ra- dionuclides, molybdenum99 and technetium 99m, in the early 1960s. In I966 he reportcd the basic reference book,Rudioisotope Produc- the details of a gencrator system thatwould tion and Quality Control. permit the short-lived gYnlT~radioisotope to he The clinical applications of radioisotopes made available at laboratories located great dis- began to gain popularity with the realization tances from the source ofthe parent nuclide, that a drink of a solution of radioiodine could "Mo (Fig. 1-8). Soon after this, otherinvcstiga- be used in place of the related complicated tors bcgan to appreciate the potential of s!JmTc and sometimes dangerous thyroid (Fig. and to evaluate it as a tracer in biologic sys- 1-7). tems. Since that time, a great variety of coni- Iodine 13 I was initially uscd for the study of pounds have been prepared that are labeled by iodine metabolismand for the evaluation of complex formation with reduced gymTc.The thyroid function, as well as for radiation ther- radionuclide, as itis obtained from the gen- apyof the thyroid. Iodine 131 eventually be- erator, canbe used directly as a radioactive came the most popular radionuclide for the tracer. Fortunately, the generator system preparation of radiopharmaceuticals. It was can be eluted with sterilc, pyrogen-free saline used to label sodium iodohippurate, a substance to obtain directly a drug of pharmaceutical secreted by the kidneys, thus giving us an in- quality. dication of renal function. It was used to label Why is this radioisotope so important to the What is rudiopharmacy? 9

Since radiation exposureto the patient is minimized by using shorter- and shorter-lived radionuclides, the problems of obtaining the indicator and converting it into a suitable tracer become increasingly important. The radiophar- macist of the future must not only be adcpt at the rapid formulation of YumTccornpounds but must also become involved in the preparation of even shorter-lived compounds prepared from such radionuclides as carhon 11 (20.4 minutes) or 18 (109.8 minutes). A major event that helped to begin the for- malization of the basic concepts of radiophar- macywas a 1966 symposium on radioactive pharmaceuticals at Oak Ridge, Tennessce. This symposium and the subsequent publication of its proceedings" documented many of the basic principles of radiopharmacy. Atthis time the word radiopharmaceutical hadnot yet been widely used. The more common terms inthe early days were atomic cocktails, radioindica- tors, and radioactive pharmaceuticals. After considerable debate, Wagner, in his classic text Principles qf Nuclew Medicine, agreed to use the word radiopharmaceutical, establishing this Fig. 1-8. Powell Richards of Brookhaven National Ihoratory. In 1977 Richardsreceived thc Paul C. term once and for all. AebersoldAward for his contributions to nuclcar Another major event contributing to the for- medicinc,which include development of gHMo/ rnation of this ficltl was the First National Sym- :j9"'Tc gcnerator. posium onRadiopharmaccuticals held in At- lanta, Georgia, in February, 1974. This meet- development of radiopharmacy? It has a physi- ing was cosponsored by the Society of Nuclear cal half-life of 6 hours. Thus, in order to use it, Medicine, Tnc., and the U.S. Food and Drug a "'"Tc generator is eluted daily. Compounding Administration. The purposc of this symposium of the tracer drug must occur the same day that was to generate comprehensive reviews of the the patient is to be studied. Either the eluate is major radiopharmaceutical categories, to pre- directly used for administration to the patient, sent developments in radiopharmaceutical tech- or it is subjected to radiochemical manipulation nology,to provide a forum forexchange of to prepare one of several other possible radio- ideas, and to publish a comprehensive review indicators. Thus, in ordcr to run a modern of the field. The review book, published by the nuclear medicine clinic, the daily job of ob- Society of Nuclear Medicine, Tnc., in 1975;/' taining the radioactive isotope and preparing provided an updated overview of the develop- it for injection into patients has becornc very ment and use of radiopharmaccuticals. important. Atthe present time approximately Only recently have colleges of pharmacy be- 85% of the 10 million or more diagnostic tracer gun to develop training programs in radiophar- studies performed each year in the United States require !3YmTc asthe basic radionuclide. *Andrews, G. A,. Knisclcy, R. M., and Wagner, H. N., The demand for high-quality drugs made with Jr., editors: Radioactive phamlaccuticals, Springfield, Va., 1966, U.S.Department of Commerce. YynlTchas in turn created a demand for spccial- tsubratnanian, G., Rhodes, B. A,, Cooper, J. F., and ists in the handling and chemical manipulation Scdd, V. J., editors:Radiclphartnaceuticals, Ncw York, of this radionuclide. 197.5, Society of Nuclear Mcdicine, Inc. I 10 Basics of radiopharmacy

Fig. 1-9. Each formulation is tested to dctermine percentage of radionuclide that is in appropriate radiochemical state.

Fig. 1-10. Most radioactive tracers are administered through antecubital vein in arm. What is rudiopharmucy? 11

macy. The programs that have provided most of amine the similarities and the differences be- thefirst radiopharmacists with formal college tween pharmacy and radiopharmacy. educations in this field are the master of sci- The pharmacist deals primarily withthera- ence program in radiopharmacy at the Univer- peutic drugs. A radiopharmacist deals primarily sity of Southern , developed by with diagnostic drugs. Actually, for a tracer to Walter Wolf and Manuel Tubis, and the bach- be a true tracer, itmust have no pharmaco- elor of science program (Fifth-Year Option logic effect whatsoever. Thus, whereas a phar- in Radiopharmacy) at theUniversity ofNew macist is concerned that his drugs are produc- Mexico, developed by Richard Keesee and ing the desired pharmacologic effect, the tadio- Carman Bliss. pharmacist is concerned ifhis drugs are pro- ducing any effects. Both are concerned with Radiopharmacy compared to drug performance, but the tools used to mea- pharmacy in general sure performance of an R, are quite different When a pharmacy student first looks at radio- from those used to measure the performance of pharmacy, it seems to be almost a foreign sub- a DX.Both are concerned with drug interac- ject; however, after studying and working in the tions; one involves changes in the therapeutic field for a while, its similarities to other areas process, and the other involves change in bio- of pharmacy begin to become apparent. To help distribution that influences the diagnostic pro- bring about this integration itis useful to ex- cess.

Fig. 1-11. Radiopharmacist is taking drug history of patient who will receive dose of lS1I iodide. Histories are also taken from patients who are suspected of having an adverse reaction to a radio- pharmaceutical. $”*

Fig. 1-12. Radioactive prescriptions are packaged in lead-carrying shields according to U.S. De- partment of ‘Transportation regulations and surveyed prior to leaving central radiopharmacy.

Most pharmacists compound only a few of A radiopharmacist also is rnuch more involved the drugs thcy dispense; a radiopharmacist will in troubleshooting activities. When the biodis- probably compound at least 85% of the doses. tribution of a radioactive tracer is other than Most pharmacists rely on the manufacturer to expected, it bccomesthe responsibility ofthe carry out the quality control testing. A T‘ddio- radiopharmacist to determine thc cause of the pharmacist often does quality control testing problem. The biodistribution of thc radiophar- daily on many products (Fig. 1-9). Mostra- maceutical isusually cvident.Thc image ob- diopharmaceuticals areadministered intrave- tained in the nuclear clinic provides immediate nously; thus aseptic technique and control of evidcnce of thc performance of the tracer. pyrugens is of as much concern to thc radio- Thus, biodistribution is a daily concern of the pharmacist as itis to the hospital pharmacist radiopharmacist. who prepares parenteral injections (Fig. 1- 10). Onearea inwhich radiopharmacy is quitc What is radiop,pharmac.y? 13

Fig. 1-13. Radioaotivcprescriptions are delivered in special vchiclcs to neighboringhospitals. Special carrying cases arc used to assure safe handlingof drugs. similar to otherarcas of pharmacy is in the syringes, needles, and othcr injection parapher- clinic.The radiopharmacist is also a clinical nalia are radioactive wastcs. Usually, these are pharmacist. He is conccrncd with drug intcr- returned to thcradiopharmacy for disposal or actions andwith adverse reactions. He is in- storage.Thus, a radiopharmacy is a two-way volved with consulting the physicians on thc street. The volume of wastes received may be performance of the tracer and in recommending greater than the volume of materials dispensed. which tracers can be used in concert with other The greatest area of diffcrence between a drugs that have been given to the patient. The radiopharmacy and otherpharmacies is the radiopharmacist consults mostly with physi- control of radioactive materials and the con- cians and nuclear medical technologists rather cern for radiation safety. The control of radio- thanwith patients. Most patient contact will active materials is basically similar tothat of involve only the taking of drug histories and other controllcd substances, such as narcotics. the extraction of other data that can influence The practice of radiation safety is basically the bindistribution of the tracer (Fig. 1-11). similar to the control of microbiologic con- A regular pharmacyis basically a one-way tamination. Aseptic techniques can thus be street, accepting prescriptions primarily from readily augmented toinclude radiation safety patients and dispensing most drugs directly to techniques (Fig. I- 12). the patient. Only rarely will radiopharmacists The regulatory problems of a radiopharmacy dispense directly to a patient. Usually, the are more complex than those of other pharma- drugs are dispensed to nuclear medicine physi- cies.Essentially, all regulations that apply to cians who administer the drugs intravenously to pharmacies or pharmacists apply to radiophar- the patient in the nuclear medicine clinic. The macies and radiopharmacists. Notall state 14 Basics of radiopharmacy

boards of pharmacy have become involved in cal~.The laboratory also carries on a vigorous radiopharmacy;however, the trend indicates research and developmentprogram. The Na- that those currently not involved soon will be. tional Radiopharmacy of Denmark is more in- Theadditional agencies that regulate radio- volved in the control and performance of radio- pharmaciesare the Nuclear Regulatory Com- pharmaceuticals than itis in the actual manu- mission (NRC)(or the state equivalent, in facturing of drugs. National radiopharmacies agreement states) and the Department of Trans- provide a central focus for the control,intro- portation (DOT). NRC controls the possession duction, and development of radiopharmaceuti- and use of radioactive materials;. DOT controls cal~within the country.The national radio- the transportation of radioactive materials (Fig. pharmacies have also played a very important 1-13). role in providing inputinto the International Atomic Energy Agency for the development of Types of radiopharmacies recommendations and qualitycontrol proce- HOSPITAL RADIOPHARMACIES dures, Often a hospital that has a nuclear medicine In the United Statesthere are several uni- service will prefer to have its own hospital ra- versity radiopharmacies that supply radiophar- diopharmacy located within thedepartment. maceuticals to a region, often to an entire state. This radiopharmacy is usually a subdivision of These university or statewide radiopharmacies the nuclear medicine clinic. In many cases, the provide training laboratories for students of ra- person in charge of the radiopharmacy may diopharmacy, as well as central depots for the have little involvementwith the regular hospital elution of Y”Tc from large generator systems pharmacy. In some hospitals theradiopharmacy and for the preparation of unit doses of radio- is under the joint administrative controlof both pharmaceuticals that can be distributed on pre- the hospital pharmacy and the nuclear medicine scription to physicians and hospitals throughout clinic. This has the advantage of keeping the the territory serviced (Fig. 1- 14). The advan- radiopharmacy working directly in nuclear tage of this type of operation is that the cost can medicine but allowing it to take advantage of be reduced by greater and more rapid use of the personnelavailable in thehospital pharmacy inventory of radiopharmaceuticals.The faster and to use some of the services and facilities radiopharmaceuticalsare used, the less radio- availablefrom the hospital pharmacy. When active tracer is lost by radioactive decay. thehospital radiopharmacy is located in the Commercialradiopharmacies are currently nuclear medicine clinic, it usually comes under being developedacross the United States. the direct supervision of the nuclear medicine These radiopharmacies are usually managed by physician or a nuclear medical . a licensed pharmacist who must also obtain When the hospitalradiopharmacy is under authority fromstate or national regulatory the supervision of a residentnuclear medical agencies to handle radioactive materials. These scientist or nuclearmedicine physician, the central radiopharmacies can provide the same day-to-day work is usually done on a rotational economic advantages to theindividual physi- basis among the nuclearmedicine technolo- cian as the state or university operations. Cen- gists.Thus, it is important that the technolo- tral radiopharmacies and commercial radio- gists be trained in the various radiopharmacy pharmacies can provide a large numberof small techniques. hospitals with radiopharmaceuticals more eco- nomically than the clinic can purchase the drugs CENTRAL RADIOPHARMACIES directly. In thismanner, one radiopharmacist National radiopharmacies have grown up in can serve a dozen or more nuclear medical several countries.One example is Australia, clinics. where a national radiopharmacy synthesizes or Training of radiopharmacists importsradionuclides, manufactures reagent kits for use throughout the country, and super- It is only in the last few years that the train- vises the quality control of radiopharmaceuti- ing of radiopharmacists has becomeformal- What is radiopharmacy? 15

Fig. 1-14. Map of New Mexico showing distribution of radiopharmaceuticalsthroughout state from two nuclear pharmacies, one located in Albuquerque, and the other in El Paso, Texas. Cen- tral radiopharmacies that servicc multiple nuclear medicine clinics are called nuclrar pharmacies. ized.Survey courses are currently being in- try and , dispensing radio- troduced into most undergraduate programs in pharmacy, and clinical radiopharmacy. Courses colleges of pharmacies. Undergraduate special- in hospital pharmacy and in sterile techniques ization in radiopharmacy is available in a few are also of importance to the person who wants colleges of pharmacy.Short courses and ex- to practice radiopharmacy, It takesabout a year tended training periods or residencies in radio- of additional training beyond the 4 years of col- pharmacy are also available at a few colleges. lege to prepare oneself for the routine work Graduate credit coursesand programs are being of both dispensing and clinical radiopharmacy. introduced in several colleges of pharmacy. This can be accomplished by on-the-job wain- Toprepare oneself to go into the fieldof ing; however, participation in a year-long resi- radiopharmacy, a bachelor of science degree in dency program or the completion of a master’s pharmacy or certification as a nuclear medicine or doctoral program in radiopharmacy is pre- technologist is a good beginning. This can be ferred. followed by a year of specializedtraining in Suggssted readings radiopharmacy that includes the safe handling Andrews, G. A,: History of radiopharmacy. In Tubis, M., of radioactivematerials, principles of tracer and Wolf, W., editors: Radiopharmacy, New York, 1976, techniques and nuclear medicine, radiochemis- John Wiley Lk Sons, Tnc. 16 Busics of mdinpharmacy

Briner, W. H.: New dimensions for pharmacy, Hosp. Top. pharmaceuticals, New York, 1975, Socicty of Nuclear 43:79-90, June, 1965. Mcdicine, Inc. Briner, W. H.:Radiopharnlacy: the emerging young spe- Phartlracists for the future-the report of the Study Com- cialty. Drug lntcll. Clin. Pharm. 2:8-13, Jan., 1968. missionon Pharmacy (commissioned by theAmerican Charlton, J. C.: Problems characteristic of radioactive phar- Association of 2ullegcs of Pharmacy), Ann Arbor, maceuticals. In Andrcws, C. A,, Kniselcy, R. M., and Mich., 1975. Health Administration Press. Wagner. H. N,, editors:Radioactive pharmaceuticals. Quinn, J. L., IJl: Thc role of the hospital radiopharmacy. CONF. 651 1 I I, National Technical Information Service, In Yearbook of nuclear medicine, Chicago, 1970, YCN- Springfield, Va., 1966, U.S. Department of Commerce. hook Medical Publishers. Diskfano, R. M., and Hernandez, L.: Clinicalradio- Radioisotope production and quality control, Technical Re- pharmacy, Drug Intell. Clin. Pharm. 4209-212, Aug., ports Scries No. 12X, Vienna, 1971, International 1970. Atomic Energy Agency. Ice, R. D., Shaw, S. M., Born, G. S., et al.: Nuclear Selected papers on nuclcar pharmacy, Washington, D.C., pharmacyeducation, Am. J. Phartn. Ed. 38:420-425, 1974, American Pharmaceutical Association. Aug., 1974. Subramanian, G.: The role of the radiochemist in nuclear Kawada, 'I., Wolf, W.. andMachizuki, D.: ,Semin. Nucl. Mal. 4219.228, 1974. radiophannacy training program, Am. J. Hosp. Pharm. Wagner, H. N., Jr., and Rhodes, B. A.: The radiophar- 32:587-589, 1975. maceutical. In Wagner, H. N., Jr., editor: Principlcs of McAfec, J. G.: Radioactivcdiagnostic agents: current nuclearmedicine, Philadelphia, 19668, W. B. Sauntiers problems and limitations. In Subramanian, G., Rhodes. Co . B. A.. Cooper, J. F.. and Sodd, V. J., editors: Radio- Wolf, W.: Radiopharmacy: a new profession, Hospitals 47ff-68, Sept. 16, 1973. Tracer techniques in medicine

Tracer techniques: uses and using thcse methods. For instance, the presence advantages of dyc in the river indicates where the What do we mean when we talk of a tracer'? spring from inside the cave flows into the river. What is the tracer technique? One of the oldest The actual concentration of the dye is a quanti- tracer techniques is to put a colored cork in a tative indicator of how much dilution has oc- rivcr and watch the cork move along tracing the carred in the watcr as it went from the cave into river's current. In this situation the cork is not the main surface water supply. an exact tracer of the current: its properties arc Isotopes are the truest of thetracers. The different fromthe water,and itmoves at a The term isn/upP is used to denote an atom of a slightly different rate, since itis affectcd dif- different mass of the sameelement. For ex- ferently by variables such as wind than are the ample, iodinc 129 is an isotope of iodine and water molecules themselves. A water-soluble differs in mass by 2 from the most comn1on iso- dye is a better tracer than the cork. However,to tope of iodinc, iodine 127. Chcmically, the be- trace most accurately the current of the river, it havior of the two isotopes are idcntical except is necessary to use actual molecules ofwater whcn atomic mass is a reaction parameter. Even that are going to have exactly the same proper- in this case, the reaction rates of the 129 isotope ties as all the Inolccules of water in the river. chernically approximates that of other of Thesemolecules can be used as truetracers iodine because its mass differs from the mean only ifthey also have some property such as mass by lcss than 2%). In general, an isotopc is radioactivity thatwill allowus to distinguish a true tracer exccpt in situations where there is a them from the mnleculcs of water that we are significant isotope effect. An isotope effect is tracing. most frequently observed whcnusing tritium Several different kinds of tracers can be used (3H) to trace ('H) in reactions where that approximate truc tracers. The first of these the kinetic rate is a function of the atomic mass are the dyes. Ink, poured into the water, can be of the hydrogen. Practically, the isotope effect observed as the color traces the current. This is rarely encountered in biologic tracer studics. technique is actually used to trace water flowing When atoms of different mass are used as a inside caves to determine where the under- tracer, one detectorthat can be used is the mass ground streamsurfaces. ln this example, the spectrometer. The actual measurement em- human eye is the detector. There are, however, ployed is the tnass ratio or changes in mass ra- more sensitive optical detectors thanthe hu- tio. In some instances, nuclear magnetic res- man eye.These detectors are spertromrtcrs. onance spectrometry or neutronactivation The use of spectrometry expands the range of analysis can be usedto detectthe isotopic dyes that can be used. In addition to dyes that tracer. can be seen in the , dyes which With so many kinds of tracers available to us, emit in the or the rcgion of why do we choose to use the radioactive ones? the spectrum can also be employed. Both quali- The reasonis that analytical methods forde- tative and quantitative studiescan be done tecting radinactivily are among the most sensi- 17 18 Basics of radiophurmacy

Flg. 2-1, Patient has just received intravenous dose of 99mTcsulfur colloid that is being trapped in liver. Nuclear medicine technologist positions patient so that accumulation of radioactive tracer in patient’s liver is visualized by Anger camera. Oscilloscope in background displays image of liver. tive in the world. Most other measuring systems The disadvantage of theradioactive tracer depend on colligative properties of the mole- technique is that we exposethe individual to cules. For example, ifwe measure something radiation. Fortunately, the amount of radiation using weight, volume, or intensity of color, we that is given is not largeenough to produce are required to have a large collectionof atoms detrimental biologic consequences in a signifi- with the same property all in the same placeand cant portion of thepopulation under study. at the same timein order to elicit the colligative However, since the possibility of radiation property. With the radioactive method we have damage is greater than zero, it is always neces- thepossibility of detectingasingle atomic sary to design the radioactive tracers so that ra- event.Thus, whenwe aremeasuring radio- diation exposure is minimized while detection activity, the mass of tracer atoms required to sensitivity is maximized. This is accomplished conduct the tracer experiment can be diminish- by using isotopes(radionuclides) with radia- ingly small. So small, in fact, that we do not tions energetic enough to permit their detection alter the system at all by adding the tracer. The outside the body. We try to maximize useful secondtremendous advantage of theradioac- and minimizeuseless or harmful tive tracer method over the other methods that is radiations.Radionuclides with a short half- the detecting device can be placed some dis- life and with radiation suitable for detection are tance from the system in which the tracer atoms selected as biologic tracers. The best nuclides are being used. The tracers are administered in- emit a single penetrating gammaray (80 to 400 travenously, and thedetector is outside the kev) and little nonpenetrating beta and betalike body (Fig. 2-1). In the jargon of the field, we radiations(Fig. 2-2). Itshalf-life is just long say that these tracer techniques arenoninvasive. enough toget the job done. Thus, whenwe This allows us to see what is going on inside want to trace something for an hour, an isotope the body without interfering with the subject’s with a half-life of an hour or two is superior to biochemistry, physiology, or anatomy. one with a half-life of a week or a month. With Tracer techniques in medicine 19

Fig. 2-2. Radioactive element undergoes radioactive decay inside patient. Gamma rays emitted dur- ing decay can be detected with Anger camera. Beta and betalike radiations do not emerge from body; they thus irradiate paticnt without providing usable signals that can be registered or used for imaging. isotopes of longer half-lives, unnecessary radia- where A = totalradioactivity, usually in units of tion exposurecontinues after we are finished FCi with our measurements, V = volume.usually in units of milliliters (ml) Use of tracers to determine C = concentration,usually in units of pCi/ mass and space ml LAW OF CONSERVATION OF MATTER Since by our first principle, this statement The first tracer principle follows fromthe law (equation 2) is true both before and after dilu- of conservation of matter.Simply stated, the tion, we are allowed to write the third equation: amount of radioactivity is not changed by dilu- (v x C)hefurt.dilution = (v x C)afterdllution tion. For instance, if 1 have 1 mCi of sgmTc,and (3) I pour this millicurie into the Atlantic Ocean, You may notice that this is the same equation the Atlantic Ocean now will have 1 mCi of used for calculating the dilutions of regular ysmTcin it. By expressing this concept mathe- chemical solutions, which is shown here: matically, we derive the first and simplest form (ml X Njhefuredilution = (ml X Wanzr dilution (4) of the dilution equation. This is expressed in equation I and illustrated in Fig. 2-3. where N denotes normality, the concentration term, and ml is thc volume term Amfort. diluliun = Aattrr dliutlon (11 Thus, equation 3 is actually equation 4 with ra- where A is used to denote radioactivity diochemical units substituted for the usual chemical units. The total amount of radioactivity, A, is equal to the activity per unit volume, that is. the con- RED CELL MASS centration, C, times the volume, V. An example in which the principles of iso- A = VC (or V = A/C) (2) tope dilution areused routinely in nuclear medi- 20 l3asiL.s c~j’radiopharmacy

Fig. 2-3. Law of conscrvation of matter states that total radioactivity is not changed by dilution. Thus, it’ 50 pCi dosc is given to paticnt, patient contains SO KCi. Only the conccntrationof radio- activity is changed. When changes in concentration are measured, volumc of distribution can he calculated from equations dcrivcd from law of conservation of matter. cine is to measurc a patient’s total mass of red ticnt into which the tracer has been diluted (the blood cells (RBCs). A sample of the patient’s unknown), the patient’svolume, that is, the blood is collected andincubated with a solution volume of dilution, can be established. of sodium chromate. The used is the The blood volume is calculated using isotope isotope,chromium 5 I. The radioactive chro- dilution equations derived from the principle of mate diffuse into the red cells, where they conservation of matter.These cquations have are reduced to chromic ions. Thc chromic ions to be modified somewhat to account for other then bind to structural proteins inside the cell or factors: (I) thc hematocrit and (2) the percent onto the cell walls or internal membranes. Be- of the radioactivity that actually is taggcd to thc tween 50 and 100 PCi of radiochrornium arc cells. If, after the tagging reaction, the cells are tagged to the RBCs. An exact volume of the washed three times to rcmove unbound radio- chromiurn-tagged blood, usually 10 ml, is in- chromium and then administered back to the pa- jected into a peripheral vein of the patient in tient,and if the cells that are collected after such a way that complete delivery of the radio- dilution are separated from plasma, equation 3 active solution is assured. When the tracer has can be used directly. In practice, however, it is had time to mix completely and equilibrate with easier to carry out the more complicated mathc- the rest of the patient’s blood ( IS to 20 minutes rnatjcs and avoid thc moretirne-consuming cell- after injection), a second sample ofblood is washing procedures.These mathematical withdrawn. A different venipuncture site is manipulations allow for the correction for the used to make surc no cross- oc- two points just mentioned. Equation 5, which curs. By rncasuring and comparing the radio- results from the measurements and dctermina- activity in an aliquot of the tagged blood (the tions shown on p. 2 I, is used to calculate red standard) to an aliquot of the blood of the pa- cell mass. Truc'er techniques in rnedirine 21

I Denotations ~~ Measurements Standard, value before dilution Patient, value after dllution

cpn1/ ml, whole blood A\\)", A \1 I?! cpm/rnl, plasma A 1'1 A,,, Hernatocrit Hct, Hct2

values Determination Denotation Determination Key values

Known injectedVolume blood of tagged VI Unknown VolumeUnknown patientof KBCs in v,nc

Intermediate calculations

Concentration of radioactivity in RBCs dtcr dilution

Volumes of distribution do not nccessarily correspond to well-dcfined spaccs withinthc VI [Awn, - AI,, (I - Hct,)] Hctz body. For example, thc hematocrit is not con- Awn2 - Ap, (I - Hct,) stant throughout the body.This mans that, VOLUMES OF DISTRIBUTION even after uniform mixing of tagged RBCs with the rest of the blood, the concentration of tracer Ifwe administer a small volume of radio- cells is not the same everywhere in the blood labeled human serum albumin to a patient, fol- pool. The tracer cells arc uniformly mixedin lowthis by taking a series of serum samples the RBC compartment; theRBCs, however, are frorn the patient as a function of time after ad- not uniformly dilutcd in the whole blood. The ministration, and measure the conccntration of volume of distribution is therefore the volume the tracer in the serum, we can plot a curve as that the tracer wouldoccupy if it were uni- shown in Fig. 2-4. The radioactivity decrcnses formly diluted throughout thc compartment into in cach sequential sample. The decrease is grad- which it was initially in,jectcd. ual and linear; this permits extrapolation of the Youcan see from Fig. 2-4 that the volume curve back to the time of administration (t,)). of distribution increases with time after admin- The extrapolated concentration at t,, is a func- istration. Several factors contribute to this. tion of the initial volume of distribution (V,). Some of the tracer can leak or be transported Since the volume of the tracer (the radinphar- into another compartment. Some of the tracer maccutical) is so small, its effect on thetotal can be metabolized or excreted. Some of the serum volume of the patient is nil. Thus, we can tracer can bc chemically degraded. Thcse fac- rearrange equation 3 to calculate the initial vol- tors makethe extrapolation back to t = 0 ume of distribution: necessary to get reproducible data. Theabsolute radioactivity also decreases with time bccause of radioactivedecay. We where A = totalradioactivity injected usually avoid the complicated calculations Ct,>= extrapolated concentration at t,, needed to correct for decay by counting all 22 Basics of radiopharmacy

Time in Net counts minutes minute !per 0 (2,970)

11 2,907

30 I 2,813

1.000 ! 1 1 I I I I 1 0 10 20 30 40 50 60 70 Time in minutes Fig. 2-4. Dose of radiolabeled red blood cells (tagged RBCs) is administered to patient. Concen- tration of radioactivity in blood is measured 10 and 30 minutes after injection. Data are plotted on graph paper and curve extrapolated back to time of injection (to). This allows for calculation of initial volume of distribution.

Table 2-1. Relationships of cpm and pCi to counting efficiencies for the purpose of calculating volumes of dilution

~ ~~ Counting Arbitrary efficiency LLci Net cpm Net cpm PC1 units of Sample cpm/dpm* t=O t=O t=6 t = 6 radioactlvity Standard 0.50 (50%) 0.10 1 I1,OOo 55,500 0.050 I .oo Unknown O.SO(SO%) 0.03 33,300 16,650 0.015 0.33

*dpm is disintegrations per minute. I FCi = 2,220,000 dpm. samplesalong with the standards at approxi- mately the same time. On a practical basis, we measure concentration in units of cpm/ml It is not even necessary to know the true radio- (counts per minute per millilirer). Counting ef- activity of the standard, since the ratioof radio- ficiency is the ratio of detected cpm/pCi. The activity of the standard to that used as a tracer data in Table 2- 1 illustrate this point. You can isfixed by the experimenter. For example, if noticefrom these data that both the standard one arbitrary unit of radioactivity is used as a and the unknown radioactivity(either pCi or standard and a duplicate amount is used as the cpm) are decreasing with time.However, tracer, the ratio of cpm of the unknown to the counting efficiency and the ratio of radioactiv- cpm of the standardmeasures the fractionof the ity between the standard and the unknown are standard that is in the sample. The simplified constant with time. Therefore, when the stan- calculation of the volume of distribution thus dard and the unknown are measured at approxi- becomes mately the same time,neither efficiency nor de- cay correction has to be made; that is, the fol- lowing relationship holds: Tracer techniques inmedicine 23

Table 2-2. Dynamic studies with radioactive tracers

~ ~ ~ ~~ Study Tracer Reglon imaged Lesions or pathology detected

Cistemography ll1In DTPA Head and neck Blockage or slowed cerebral spinal fluid flow Cerebral blood flow R9mTcDTPA Head and neck Blockagc of carotidarteries, arteriovenous malformations, or other arterial blood flow abnormalities Dynamic thyroid 123 1- Throat Abnormaltotal or regionalthyroidal iodine uptake rates Nuclear cardio- 89mT~HSA Chest Congenitalheart defects, aneurysms, myo- angiography cardial dyskinesia, cardiomegaly Dynamic livcr 99mTcSC Chest and upper Detection of hypervascular or hypovascular abdomen hepatic lesions and abnormal colloid clear- ance rates snmTc HlDA Upper abdomen Obstructivc biliary Gastric cmptying I 13rnIn Upper abdomen Abnormal gastric cmptying rates, gastric re- gurgitation Pulmonary ventilation 133Xe Upper back Obstructive airways Renogram l3ll Hippuran Back Renal dysfunction Dynamic 99m~~DTPA Back Obstructiverenal or ob- structed urine flow Cistogram !+WITcO; Lower abdomen Reflux of urine Isotope venogram """Tc microspheres Lcgs Thrombosis Adrenal uptake 1311 NP 59 Back Adrenal dysfunction Rose bengal uptake l3Il rose bengal Upper abdomen Polygonalcell dysfunction and obstructive biliary disease

when I ml of tracer is administered. Often the of patients with suspected electrolyte im- standard is "too hot to count," that is, it con- balances. Usually, simple ionic tracers such as tains so much radioactivity that it is above the radiopotassium,sodium, halide, or tritiated linear range of the detector. In such cases, the water serve as the radiopharmaceutical. standard will be diluted, andan aliquot taken for counting. Frequently, 1 ml of radioactivity Use of tracers to determine will be injected into the test subject, 1 ml will rates and pathways be diluted to I liter, then a I ml aliquot of the diluted standard willbe used as the counting Tracers are used to evaluate the dynamics of standard. In such a case, the equation to be used physiology and biochemistry. Eventhe most for the calculation is static structures of living organisms experience turnover. Bonemineral, for example, under- goes continual deposition and reabsorption. The determination of the rates and pathways of dy- where D = the dilution factor, whichwas namic processes relies on the kinetic analysis 1,000 in the example just cited.If the unknown of tracer studies. Pathology can often be de- counted 100 cpm andthe standard counted tected from altered absorption, excretion, stor- 1,100 cpm, thevolume of distribution would age, or turnover rates of vital substances. The be 1,000/100 X 1,000, or 10,000 ml. study of the rates and pathways of movement The volume of dilution of a tracer is some- of foodstuffs,urine, blood, lymph, air, and times used directly as adiagnostic indicator. spinal fluids forms the basis for such important An example of this is its use in the management diagnostic tests as nuclear cardioangiography, 24 Basics of rudiophurmucy isotopic lymphangiogr~tphy,and cistcrnography TRACERCLEARANCEASAMEASURE (Table 2-2 gives a more complete listing). OF BLOOD FLOW A traccr is cleared from thc bloodstream at a DYNAMIC STUDIES AND NUCLEAR rate proportional to the blood flow to the organ ANGIOGRAPHY wherc clearance occurs and to the efficiency of It has become common practice in nuclear the clearancemechanism. Thc liver normally medicine to administer the tracer as a bolus and has agreater than 85% efficiency for the re- to take sequential gamma-camera itnages asthc moval of radioactive particles from the blood. tracer moves from the site of injection through This is so efficient, in fact, that the rate of clear- downstream flow channels. Table 2-2 lists sev- ance of such particles can be used to estimate eral of thewdiagnostic techniques. You will liver blood flow. note as you read through Table 2-2 that both the Blood flow can also be studied using washout rates and the pathways are of diagnostic signifi- iechnjques. A tracer deposited in a tissue is re- cance in the dynamicimaging procedures. rnovcd by diffusioninto the local blood or Often the visual imagcs denoted with the time lymph supply, which washcs the tracer away. If of imaging are suffcicntly quantitativeto arrive the tracer freely diffusesinto the capillaries, at the diagnosis(Fig. 2-5). Solnctimcs it be- thenthe washout rate is totally dependent on comes helpful to quantitate more precisely thc the blood flow. This technique, which might be flow or clearance rates; thcse rates can be dis- called the tracer depot method, has bcen used played ;is an array of relativcintensities that to dctermine local skin or muscle bloodflow form a map of the function beingevaluated. (Fig. 2-7). lhis type of image, which is gerlcrated frcm a Thegeneral equation for calculating blood computer analysis of aseries of images as a flow by thc blood clearancc or the tracer wash- function of time, is referred to as a functional out technique is image. Fig. 2-6 is such an image. A, =” A,,e (10)

Fig. 2-5.Sequential Anger-camera imagcs of neck after injcction of (99n’Tc). Noticc that carotid arteries are seen in initial images and that thyroid and parotid glands are visual- ized by 1 minute. Tracer techniques in medicine 25

Fig. 2-6. A, Sequential images ofpaticnt’s chest after having lungs ventilated by xenon133. Areas of lungs with poor ventilation due to chronic obstructive lung disease such as emphysema are slow at “washing out,” that is, clearing radioactive traccr gas. B, Functional image composed of re- gional washout constants calculated from data used to rnakc up images shown in A. (From Strauss, H. W., Pitt, B., and Jarncs, A. E.: Cardiovascular nuclear medicine, St. Louis, 1974. Thc C. V. Mosby Co.) 26 Basics of radiopharmacy

t=O t = 25

Fig. 2-7. Gamma scintigram of ten intradermal injections of microdroplets of Na 99mTcO; in skin flap on back of pig. Pictures were taken at time of injection and 25 minutes after injection. Upper part of graft (above openarrow) is viable, and lowerpart of graft (below solid arrow)is dead. When there is skin blood flow (i.e., viable tissue), tracer is washed out (clearance constant was 0.026 min"). When there is no flow because tissue has died, tracer does not wash out (clearance constant was 0.002 min"). (From Munderloh, S. H., Damron, J. R., Orgel, M., and Knight, R. L.: Pre- dicting skin flap survival by radioisotope washout. Unpublished.)

where A, = the radioactivity at any time, t, in such aresuggested, and thestudent is referred to units as cpm more comprehensive textssuch as Sheppard's.* A,, = the initial radioactivity in thesame units The clearance constant, k, is the fraction of k = the clearance constant, in units of rnin- the tracer removed per unit of time. If the blood Utes", for example volume is also determined, the actual clearance t = time in units such as minutes can be estimated:

In cases where a single organ is responsible Clearance = k X bloodvolume (11) for clearance,then the uptake rate and the blood clearance rates are identical. Thus, the rate of Relative clearance is sufficient for some applications. To give percentage cleared per unitof time, k is mul- accumulation of ggmTcHIDA can be measured tiplied by 100. over the liver, or the rate of sgmTcHTDA clear- ance over the head (cerebral) blood pool can be INDICATOR CONCENTRATIONS AND measured. The rates should be identical. These TRANSITS AS MEASURES OF BLOOD FLOW rates aredetermined using thesame mathe- Blood flow can also be determined frommea- matical techniques that we use to determine ra- surements of indicator concentrations overtime dioactive decay rates.Fig. 2-8 demonstrates downstream froma bolus injection. Alterna- clearance and uptake curves. When the data are tively, mean transit times can be measured. plotted on semilog paper, as shownin the lower The mean time is equal to volume divided by parts of the figure, a straight-line relationship flow. The studentis referred to basic tracertext- occurs.The rate constant is directly obtained as the slope of the line. If the data do not fall *Sheppard, C. W.: Basic principles of the tracer method, on a straight line, then more complex kinetics New York, 1962, John Wiley & Sons, Inc. Trucer techniques in medicine 27

aJ cz .-c E

1 5 10 15 20 Time in minutes

""1""""

5,000 - 0 cz .-c E

vLo C 2 1,000

500 I I I I I 5 10 15 20 Time in minutes Fig. 2-8. A, Clearance of radioactive tracer from blood measured with detector focused at temple (to measure radioactivity in cerebral blood pool). 8, Uptake of same tracer by liver. books for a completedevelopment of these tant diagnostic tracer tests are listed in Table tracer concepts. 2-3.

ABSORPTION, METABOLISM, AND Use of tracers in quantitative TURNOVER STUDIES microanalysis Radioactivetracers often provide the sim- In theprevious section, we discussed the plest, the tnost accurate, and the most sensitive methods of tracer kinetics. Alternatively, tracer means for measuring absorption, metabolism, statistics are alsodiagnostically useful. From or turnover of substances. Diagnosis can often tracer statistics come a large group of methods be made from measurements which reveal that for the analyticaldetermination of minute these rates are altered. Someof the more impor- amounts of importantbiologic substances in Table 2-3.Nonimaging, in vivo tracer kinetic studies

S tudy Tracer Study Samples detected Defects

Gastrointestinal protein loss "'Cr albumin Feces Gastrointcstinal protein enteropathy Gastrointestinal blood loss "Cr RBCs Feces Gastrointestinal bleeding Red cell survival "Cr RBCs Blood Iron turnover 5upet3 Whole body Abnormal ferrokinetics :7c0 Vitamin B,, absorption p) 12 Urine Pernicious (Schilling test) I4COzbreath test 14C Breath Glucosc intolerance Radioiodinc uptake 123- Urine or, external Abnormal thyroidal iodine uptake rates count over thyroid (hypothyroid or hyperthyroid function) Renogram Hippuran Exterrlal counting Renal disease over kidneys O cular uptakeOcular 32p0-3 External counting Mclanotna over eyes Fdt absorption studies '''I I triolein Feccs of fats Protein absorption studies l3I1 albumin Feces Malabsorption of proteins Platelet jlCr platelets Blood Abnormal platelet loss Splenic sequestration "Cr RBCs External counting Hypersplenism over spleen 1251-fibrinogen uptake lzsI fibrinogen External counting Fibrin deposition (thrombosis in legs) over legs '"'I-fibrinogen uptake I3II fibrinogen External counting Fibrin deposition (kidncy rejxtion) over kidneys

small samples. Here the tracer method is used tivity before and after adding the tracer is con- as a substitutcfor chemical methodsof analysis. stant. Thus:

ISOTOPE DILUTION ANALYSIS A = (W X SjbPfurt.dilutiurl (13) (W X SJaner nilutiurl (wo + Wx)Sx The basic principle of isotope dilution was developed on pp. 19 to 23. The same concepts where Wo = the weight of the tracer used to measure red cell mass or plasma volume W, = the weight of thc unknown So = thespecific activity bcfore dilution, can bc used to make quantitativc determinations that is, of the tracer of chemicals. In the examples of red cell mass S, = the specific activity after dilution, that and plasma volume, the key measurement was is, of the sarnplc with tracer added concentration of radioactivity. In the use of iso- tope dilution to measure amounts of chemical If we solve for the weight of theunknown, substance, the key measurement is specific ac- equation 14 is obtained.

tivity, that is, radioactivity per unit of mass, w, = W,,(So/S, - I) (1 4) such as pCi/gram. The basic equation isthe same as equation 2, except weight, W, is sub- These equations are consjstcnt with the deri- stituted for volume, and specific activity, S, is vations of Tiilgyessy and Varga, who explained substituted for concentration: several illustrativc examples from the biologic litcrature andwho alsodcrived many other A WS (or W = AIS) (12) equations that arc used in calculations of the Often in this determination, the weight of thc many variations on this basic principle. These added tracer cannot be ignored as in the pre- include reverse isotopc dilution, double isotope vious examples. Again, according to the law of dilution, and derivative dilution. In addition to conservation of matter, the amount of radioac- the advantage of great sensitivity, thcse rncth- Trucw rechniques in medicine 29 0 0 0 a0 0 0 + 0 0 0 0

Fig. 2-9. A, Antigcn and antihodies combine, with antibodies being limiting or substoichiometric rcagent. B, Radiolabeled antigen is mixed with or uscd to dilute original antigen. C, After dilution, substoichiometric reagent removes same amount of antigen. D, Aftcr reaction with antigen, mix- turc is scparated so amount of radioactivity hound to antigen can be tneasurcd. ods often allow for analysis of substances that acids; however, significant and unavoidable cannot be achicvcd by othermeans. Often a losses had occurred during the multiple separa- tracer can be uscd to measure yields from in- tions. The recovery of the 13'1 was then used efficient separation tcchniques. Forexamplc, to measure the overall yieldof the separation thc determination of thyroxine in the plasma of procedures andto correct the final analytical a rat on a low-iodine diet was achieved by first result to givc the total thyroxine in the original adding '"'I-labeled thyroid hormone to the plas- sample. rna, then separating the iodoamino acids by ex- traction and doublc-paper chromatographicpro- SUBSTOICHIOMETRIC ANALYSIS cedures. The final thyroxine preparation was Stoichiometry is the part of chemistry which highly purified and free from other iodoamino deals with the relative amounts of substances 30 Basics oj' rudiophurmucy that combine in a . One mole determine. The amount of thyroid hormone in a of hydrogen ions combines, stoichiometrically, small sample of serum is easily determined by with one mole of hydroxyl ions to yield one this method.Some l3'1-labeled thyroid hor- mole of water, If one reagent is in limited sup- mone is added to the serum, then all the thyroid ply relative to the other,then the reagent in lim- hormone, both native and the added tracer, is ited supply (i.e., the substoichiometric reagent) extracted and reacted with a substoichiometric will determine howmuch reaction product is amount of thyroid hormone antibody. Thereac- formed.Thus, if only 0.5 mole of hydrogen tion product, antibody-bound thyroxine, is lim- ions was available in thepreceding example, ited, so not all the tracer becomes bound. The then only 0.5 mole of water could be pro- antibody-bound hormone is separated from the duced. Substoichiometric analysis takes advan- unbound hormone by one of several available tage of using one reagentas the limiting, or sub- techniques. One way is to absorb the unreacted stoichiometric, reagent to divide the radioactive hormone ontoactivated charcoal. Thus, the tracer into two chemical species, one combined radioactivity on the charcoal is measured rela- and one uncombined. As such, the two forms of tive to that which remains in solution (i.e., the the tracer can be separated from each other by bound). The more native hormone in the origi- some simple chemical procedure. The ratio of nal sample, the morenative (nonradioactive) combined to uncombined radioactivity is mea- hormone combines with the substoichiometric sured. This measurementis used as an indicator reagent, and the lessradioactivity combines of the amount of the substance that we want to with the antibodies. The amount of hormone in

Fig. 2-10. Automatic sample processing scintillation detector equipped with dedicated computer for automated RIA. This is Squibb Gamma FloHsystem introduced in 1977. Trucer techniques in medicine 31

the original sample is therefore inverselyrelated sicfactor is aprotein that reacts specifically to the amount of radioactivity on the charcoal with vitamin B,, and thusis used asa sub- and directly related to the amount of radioactiv- stoichiometric reagent in the BIZassay. Thy- ity that remains in solution(Fig. 2-9). Many roid-binding globulin can be used as a reagent variations on this concept have been developed for the thyroid hormone assay; conversely, thy- for the measurement of thyroid hormone levels roid hormone can be used as a reagent for deter- in serum. A variety of reagent kits can be pur- serum levels of thyroid-binding globu- chased commercially that permit this type of lin. Another general term seen in the literature microanalysis to be readily performed in clini- is assay. The radioligand would be cal laboratories (Fig. 2-10). I3lI thyroxine or 57C0B,, in the examples just Radioimmunoassay (RIA) is the major type given. of substoichiometricanalysis used clinically because the sensitivity and specificity of the ISOTOPIC EQUILIBRIUM ANALYSIS antigen-antibody reaction is so great. Anti- If a biologic system, like a living rat, is fed bodies to many biologically active molecules only iodine that comes from a source of uni- canbe produced using immunologic tech- formly labeled iodine, the specificactivity of niques. Often the substoichiometric reagent is the iodine in the rat will approach, in time, that an unpurified antiserum from a rabbit, goat, or of the iodine source (Fig. 2- 1 I). When equilib- other laboratory animal.One animal can pro- rium is reached, the specific activity becomes duce enough reagent for thousands upon thou- known as it was originally determined by the sands of microanalytical tests. experimenter. At this time, a measure of radio- Competitive protein binding is a somewhat activity becomes a direct measureof the amount more general term that includes RIA as well as of iodine in the rat or in tissue samples obtained other specific protein-binding reactions. Intrin- from the rat. If the rat contains 1 pCi of 1251 of

Specific @ activity

Time in days

Fig. 2-1 1. Isotopic equilibrium is achieved when specific activity of test subject is same as that of diet or environment. At isotopic eqilibrium, measurement of radioactivity can be used to determine mass. 32 Basics of radiophurmacy

NaCl n

Fig. 2-12, Specific activity of potassium in is same as that of environment or diet. Since potassium is primarily associated with muscle tissues, a tneasure of total-body 40Kcan be used as indicator of lcan body mass. In this drawing, both individuals have same lean body mass (shat-irdnr~a)and thus about same amountof 40K,even though total body massis greatly different. This is an cxamplc of how principles of isotopic equilibrium can be used to determine mass for mcdically uscful purpose.

specific activity of 0.1 pCiIpg, then the rat ing its radioactivity. 'This method offers the ad- contains a total of 10 pg of iodine. vantage of extreme sensitivity of the radioiso- A clinical test that employs this principle is topic tracer method without the necessity of ad- the totalbody potassium measuremcnt. A ministering a radionuclide to the subject. whole-body count determines 40K in the sub- Suggested readings jcct. The specific activity of potassium in thc Chase, C. D., and Rabinowitz, J. L.: Principles of radio- body is the same as that in thc cnvirnnment; it isotope methodology, Minneapolis, 1967, Burgess Pub- is 0.0 I 18%. Once the pCiof 40K in the body is lishing Co. Comar, C. L.: Radioisotopes in biologyand agriculture, measured, total body potassium is determined. New York, 1955, McGraw-Hill Book Co. The total body potassium is related to lean body Hevesy, G. de: Radiwactive indicators: thcir application in mass, so it is used to cstimate ratios of lean to biochcmistry,animal physiology, and pathology, Ncw fatty tissues (Fig. 2-12). York, 1948, Interscience Publishers, Inc. Mohr, J. W., editor:Prospectives in clinicalradioassay, ACTIVATION ANALYSIS New York, 1975, United Busincss Publications, Inc. Sheppard, C. W.: Introduction to mathematical tracer ki- Nonradioisotopic tracers, that is, enrich- netics. In Basicprinciples of thetraccr tncthcd, New ments of stable isotopes, can be employedin York, 1962, John Wilcy & Sons, Inc. the tests just described. The radioactivity is in- Tiilgyessy, J., andVarga, S.: Radioactiveindicators in duced in the final stage of thc analysis by plac- chemical analysis. In Nuclear analytical chemistry, vol. ing the sample in a beam or ficld of nuclear par- 2, Baltimore, 1972, Univcrsity Park Press. Welch, T. J. C., Potchcn, E. J., and Welch, M. J.: Funda- ticles. 'The nuclear particles activate the tracer mentals ol the tracer method, Philadclphia, 1972, W. B. isotope, permitting its quantitation by measur- Saundcrs Co. CHAPTER 3 Mechanisms of localization

The magic bullet approach versus The quantities usedmust be chosen by refer- the tracer concept ence tothe system under study and to the For many years in medicine there has existed amount of thc nonlabeled tnaterial already pres- the concept that a particular medicine should ent. The use of tracer techniques implies a cer- be used to cure or alleviate a particular condi- tain amount of knowledge about the system, tion. We call this the magic bullet upprouc'h. since one cannot very successfully incorporate This idea was prcvalent in folk medicine and tracer techniyucs into the shotgun method of has persisted to the present. As medicine be- research.Tracer techniques seek to discover comes more scientific and particular organisms normal and abnormal pathways for the move- are associatcd with particular , the idea ment of a particular matcrial in a particular sys- has gained yetmore credence.This approach ternand to relate these pathwaysto disease to therapeutic medicine leads to a similar ap- states whenever possible. proach to diagnostic medicine, that is, a specif- The first nuclear medicine studics capitalized ictest and a specific answer for each disease on application of the tracer technique to solve and each organ. Eachof us can thinkof ap- diagnostic questions. Soon, however, the em- propriate counterexamples, such as theuse of phasis switched to the magic bullet approach. penicillin to trcat a number of diseases.This This is illustrated bythe history of the tracer is not really a counterexatnplc, since we know diagnosis of . The first methods ofmany diseases for which penicillin isnot for evaluating the thyroid rclied on hand-hcld useful at all. X-ray contrast media are indeed collimated radiation detectors to measure the useful under several different circumstances, uptake of a tracer dose of radioiodine. It was but one does take careto giveIVP (intravenous soon appreciated that more information could pyclogram) dyes for renal studies and gall- he obtained by measuring and recording the bladder dyes for cholccystograms. The magic spatial distribution of the tracer. For instance, bullet approach makes use of B specific mech- clinicians could determine if the nodule felt on anistic connection between a drug and a dis- the gland had a greater or lesser affinity for ease or organ. the radioiodine thanthe surroundingtissues, In direct contrast to this approach is the usc Thus,some physicians began to record thy- of the tracer concept as described in the prc- roidal uptake values on maps they drew to rep- vious chapter. George de Hevcsey, one of the resent the gland. Cassen appreciated the value fathers of nuclear mcdicine, applied radioactive of such spatially correlateddata but did not tracer methodsto the study of chemical and like to spend so much of his time getting the biologic systems. In using tracer methodology data. Hc solvcd the problem by inventing the itis irnperative thatwe use an infinitesimally (Fig. 3-1). Thisis a CUI- small amount of labeled material, that is, that limated scintillation probe that moves back we use high specific activities or materials con- and forth over the area of interest automat- taining little or none of the nonradioactive ically recording the count rate data as a map fonn.This is necessary in order to perform of the distribution of the accumulated radio- physiologic studies without altering the system. activity. 33 34 Basics of radiopharmacy

Fig. 3-1. Dual-head rectilinear scanner. Patient is positioned between two detector heads. Two rec- tilinear scans are made simultaneously. (From Rhodes, B. A., editor: Quality control in nuclear medicine: radiopharmaceuticals, instrumentation, and in vitro assays, St. Louis, 1977, The C. V. Mosby Co.; courtesy Elscint, Inc.)

This type of nuclear medical technique a reemphasis of the tracer principles in nuclear greatly appealed to radiologists because it pro- diagnosis began. For example, OgrnTcDTPA is vided a way of making pictures of organs they no magic bullet for the kidneys, yet it is very had not been previously able to visualize with useful for visualizing the movement of a sub- other methods. The magic bullet approach be- stance into and out of the kidneys. Our nuclear came dominant during this next period of the medicine procedures are now capable of pro- history of nuclear medicine. It began withan viding a blend of anatomic and physiologic extensive search forspecific tracers and specific data. mechanisms that would provide means for lo- Thus, as we trace the development of in vivo calizing radioactivity in organs that clinicians tracer studies of the thyroid, we see the role of wanted to visualize. Clinicians, accustomed to both concepts in the development af the meth- the diagnostic value of x-ray images, readily odology. Early thyroid studies, as well as our appreciated the importance of this new type of current techniques,really stem fromboth ideas. image.Radioisotope imaging was rapidly ex- Radioactiveiodine is administered to the pa- panded to include visualization of lungs, liver, tient by mouth. The thyroid is counted at 6 and spleen, heart, kidneys, and brain. 24 hours, following the idea for determiningthe The first radioisotope imaging devices were function of the thyroid by use of the tracer con- incapable of viewing more than one point at a cept.However, the iodineconcentration after time. Thus, tracers were sought chat would rap- 24 hours remains quite stable and can be used idly accumulate in or around the areas of clini- to make a picture of the thyroid, following the cal interest and stay there while the rectilinear magic bullet approachfor thyroid scanning. scans of these areas were being made. With this The best of nuclear medicine really does com- approach nuclear medicine, like diagnostic ra- binethe two ideas,allowing us to simulta- diology, primarily provided anatomicdata to neously picture the functionand anatomy of the thediagnostician. With the development of gland. Both can then be compared both to nor- radioisotopeimaging devices like the Anger mal pictures and to normal functional data to camera (Fig. 3-2), which is capable of viewing provide motediagnostic data than eitherap- an extended area of interest repeatedly in time, proach alone provides. Mechanisms oj localization 35

Fig. 3-2.Scintillation camera with whole-body imaging table. (From Early, P. J., Razzak, M. A,, and Sodee, D. B.: Textbook of nuclear medicine technology, ed. 2, St. Louis, 1975, The C. V. Moshy Cn.; courtesy Ohio Nuclear, Inc.)

In consideration of the mechanisms used for all the examinations were not performed at the localization of radioactive materials, this chap- same time. The reason, of course, is that dif- ter will follow a scheme proposed by Wagner ferent YtlmTc tracers are given for different or- some years ago. These mechanisms, however, gan scans and that the radioactivity of one or- willbe considered from both viewpoints just gan often interferes with the study of another discussed. organ. It is the carrier substancethat determines The term mechanisms of localizution is used the biodistribution of agiven radionuclide. to describe the various ways in which radio- Thus, by tagging a tracer nuclide like ggmT~to active materials are concentrated in specific re- an appropriate carrier, it can be directed to one gions of the body. This differential concentra- of several specific target organs. tion allows us to study the function of the par- ticular tissue or organ in which the concentra- Capillary blockage tion occurs. To outsiders,nuclear medicine Capillariesare the small blood vessels, up must appear to be a trick. The patient sees the to about 7 microns (p)in size, that are the con- technologist inject something into his arm and nection between the arterial and venous blood then aim an instrument at a particular area of supplies. In the capillaries,the membranes the body. All the material seems to comeout of allow transfer of materials in both directions: identical bottles. On successive days, a single from the blood to the tissue, as for nourishing patient may have liver, brain, and bone scans, the cells, and from the tissue to the blood to all obtained after a dose of 89mT~was injected. remove waste materials. In the lungs, the capil- Thestudies thus appearextremely similar; it laries allow the blood to come within a mem- may even occur to the patient to wonder why brane of the air we breathe so that and 36 Basics of rdioyhumwy other things in the air can be transferred into corporates !’!lrnTc. The use of this rrlaterial has the blood,and CO, and othergases may be been limited becausc of problems of adverse passed into the gaseous phasc and eliminated. rcactions. Patients sometimesflush when they The lung capillaries separate returning venous are injected. The inorganic iron particles are blood of theright heart circulation from the more difficult for thc body to remove than arc oxygenated arterial blood of the left heart cir- the albumin particles. Of course, anyparticle culation. Lung capillaries thus are a filter be- ofthc correct size thatcan bc labeled with tween the venousand the arterial blood sup- radioactivity can bc used for capillary blockadc plies . studies, but in the human body we are limited In order to study the relative regional per- to materials that are nonantigenic and hiode- fusion of blood to a particular area and to obtain gradable. In animal research studies, other ma- a picture that will represent average rather than terials such as carbonized plastic microspheres instantaneous perfusion, as isshown by the orstarch gel microspheres maybe preferred transit of a bit of contrast agcnt or a bolus of becausethey are not readily metabolized and radioactivity, a few of themany capillaries carried away from the point where they initially in that area can be plugged or embolizecl with lodge. This gives the investigator greater flexi- a radioactive plug.The microembolization bility in experimental design. occurs in proportion tothe location and the Most often the area being studied is the lung amount of the blood flow. ‘1’0 do this, radio- (Fig. 3-3), so the particles may be injected in active particles larger than the capillaries (10 the peripheral venous system, where thc parti- to 90 p) are injected so that the direction of cles will be carried to the right heart and mixed blood flow will take them to the capillary bed well with the blood flowing into the lungs. The whose blood flow is under study. The injection usual injection site is an ann vein. Howcver, technique must also provide for uniform mixing when the legs are suspected as the site of throm- of the particles with the blood that will be per- bosis, anisotope venogram is often done just fusing the region of interest. priorto the lung scan. In these instances thc The injected particles will plug a small num- tracer is injcctcd into veins of the feet. ber of capillaries. Only about onc in IO5 capil- Lung scanning wasfirst discovered when larics in the lungs is plugged; thus, the pul- attempts to make colloidal particles of albumin monary circulation is not compromised. So that failed. The investigators observed thatwhen this embolization willnot be permanent, the the colloidal particles aggregated, the radio- particles are made of biodegradable materials. activity was localized in the lungs rather than Human serum albumin (HSA) is often used as the liver, as theyhad intended. They quickly the starting material for preparing the radio- realized that thcy had inadvertently discovcred labeled particlcs. The albumin is either macro- a wayto visualizc pulmonary perfusion and aggregated ormade into microspheres. The that the procedure would allow far the detection bodycan phagocytize these particles andre- of perfusion defects caused by pulmonary em- move them from the capillary beds. The HSA bolism. Thus, l3lI HSA was macroaggregated must be converted into particles of the required andintroduced as a radiopharmaceutical for size, either by cooking it into feathery particles lung scanning. called macroaggregated albumin (MAA) or by Bothparticle size andnumber are critical Forming it into spherical balls and cooking the considerations in the preparation of lung-scan- balls, called microspheres. The balls canbe ning agents. The particles must be largc enough sorted quite accurately for the correct size. to be trapped quantitatively in the microcircula- Besides albumin, cither as MAA or as micro- tion; that is, all particles should be larger than spheres, which once were labcled with l3lI and the largest capillaries. Theymust bc small are nowusually labcled with gBmTc,feathery enough so as notto be dangerous andnot to particles (called flocs) of ferrous hydroxide be trapped too far upstream from the capil- labeledwith oomTchave also been used. This laries. Almost all particles greater than 15 p are material forms a flocculated precipitate that in- trapped in the lungs. Particles greater than 100 Mrchurzisms of localization 37

A

Fig. 3-3. Rcctilinear scans of lungs after intravenous dose of 13’1 rnacroaggrcgatcd albumin. Dis- tribution of radioactivity within lungs is proportional to regional perfusion, Arcas of dccrcascd dot density on film oorrcspond to regions of lung where perfusion is blocked by pulmonary emboli. A, Antcrior and left lateral views. B, Posterior and right latcral vicws.

p can cause vasoconstrictive rcsponses on in]- statistical variations in the distribution of the paction in a small artery or arteriole. Thus, radioactivity. It is generally accepted that larger particles may alter perfusion patterns and I - 1 .S X 105 is probably the best balance by in large numbcrs cause pulmonary hyperten- having enough particles toalso assure a truc sion. Ideally, particlc sizes should all be great- representative sampling of the distribution er than IS p with thc mean size as near 15 as without excessively embolizing thc pulmonary possible. Macroaggregatedalbumin with par- circulation. ticles up to 90 p is accepted for lung scanning. Lung scanning is usually performed to aid Albumin microspheres are available, with 35 p in the diagnosis of pulmonary emboli. These the upper limit of particle size. Particlc numbcr mobilized blood clots (thrombi) very often is related to the number of particles per milli- originate in thc wins of the legs or , They gram. The number of particles is inversely pro- can block off perfusion to segments of the lungs portional to the cube of the radius; that is, if the and sometimeseven blockoff a wholc lung. particle size is doubled, the number of particles The nonperfused areas show up on thc scan as per milligram decreases by a factor of eight. nonradioactivc rcgions, while the rest of the When toofew particles areused, statistical lung tissuc is radioactive. Of course, everything parameters may lead to false positive results. that causes a perfusion deficit causes a defect to When lcss than 4 X lo4 particlcs arc injected, be visualized on the lung scan, Other causes a patchy scan may result from the expected for perfusion dcficits arcpneumonia, fluidin 30 Basics of radiopharmacy the pleural space, chronic obstructive lung dis- dose may be injected in a leg or foot vein in ease, and acute asthma. order to see if there are areas in the leg where In addition to capillary blockade, radioactive the particles appear to collect (Fig. 3-4). These particlesare employed to viewstructures in may be areas that arepartially closed off by other parts of the body, usually asan adjunct thrombi or where fibrin is forming on the inner to a lung-scanning procedure. A lung-scanning surface of a vein. Occasionally one sees such

Fig. 3-4. Isotope venogram taken immediately after injection of 99mTcmacroaggregated human serum albumin into vein in right font. Movement OF radioactivity up venous system and its appear- ance in lungs is seen in image. Mechanisms of localization 39 an area of particle accumulation in the arm be ischemic or infarcted. Theinjections are veins during a routine injection. These are fre- usually carried out when a is inserted quently associated with indwelling venous cath- into the coronary arteries for the purpose of eters, which can cause irritation of the venous obtaining a coronary arteriogram. Of course, epithclium, followed by fibrin deposition and the distribution seen may be a result of catheter particle entrapment.The mechanism of ac- placement or of the injection technique if either cumulation isnot capillary blockage;rather, result in the particles not being well mixed with it appears to bc an adhesion of the particles to the blood prior to their reaching the capillaries. thrombogenic elements. The arterial flow to the extremities or the head Particles may be injected to observe the flow may also be studied by this sametechnique, of blood in the coronary arteries and used to that is,injecting radioactive particles through help diagnose the areas that are not receiving a catheter directly into an artery. blood at the time of injection. These areas may Rather than looking at specificareas for

Fig. 3-5. Rectilinear scan, posterior view, performed on young adult after intravenous administra- tion of ssmTcHSA microspheres. Appearance of radioactive tracer in kidneys is due to right-to-left shunting of particles throughheart so that some microspheresbypass pulmonary capillary bed. (From Deland, F. H., and Wagner, H. N.: Atlas of nuclear medicine, vol. 2, Lung and heart, Phila- delphia, 1970, W. B. Saunders Co.) 40 Basics oj radiopharmacy

pictorial information, one may use particle pared by heating thiosulfate in the presence of techniques to get quantitative information, The acid and pertechnetate. This forms a sulfur col- lungscan can be quantitated to give the per- loid of 300 to 1,500 p that tends to increase cent of the total perfusion that occurs in a par- in averagc particle size with timc. Stannous ticular area. If the patientis shunting blood reductioncan also be used to repair a 99111Tc around the lungs into the arterial side of the colloid. In the past, ISHAucolloid and ':$'I HSA circulation, either throughan arterial venous colloid (microaggregated albumin) wcrc uscd anastomosis or via a hole in the septum of the for scanning. colloid is a rosy-red solution hcart, thematerial intended for thelungs will containing both radioactive and stable gold iso- go elsewhere. Since the kidneys receive much topes. The '311-micro~tggrcgated albumin has of the cardiac output, thcy will be visualized in the conceptual advantage of being made from a cases of significant right-to-left shunting. The human product and as suchis biodegradable amount ofradioactivity not localized in the and nonantigenic, but it has the distinct disad- lungs can be counted and compared to the lungs vantage, along with lYHAucolloid, of conferring in order to quantitate the amount of shunting far too large a radiation dose compared to the (Fig. 3-5). This same idea can be used to quan- number of usable counts for scanning. In ad- titate nutritional and shunted blood flow to any dition to those already mentioned, phos- region. The region of interest determines the phate or hydroxide can be formed in colloidal- point of injection. sized particles. These particles can be labeled with 113m1n or "'In. YY1nTc-labeledphytatc is a Phagocytosis solution that when injected forms a colloid with When certaintypes of albumin macroag- the eaf2 ionin the blood. The "InTc colloid gregates are broken downby the cells inthe formcd in theblood is thenpicked up in the lung, they become smaller than red blood cells RE cells. and can fit through the smallest capillaries and Functioning liver, spleen, and

thus escape back into the circulation. 'I'o the can be imaged minutes after the intravenous body thcy appear to be foreign material, much injection of radioactive colloid (Fig. 3-6). Once as pieces of red cells might after the red cell thematerial is sequestered, Ihephysical loca- had died and begun to break up. These foreign tion of the radioactivity usually remains con- particles are coated by a plasma protein called stant. It has been suggcsted that the size of the an opsonin. Opsonized particles are recognized injectedparticles determines to some extent by the reticuloendotheliul cells (RE or Kupffer which of the three organs will bc the primary cells)and are engulfed.These RE cells are site of sequestration, with small particles going ,found primarily in liver, spleen, and bone mar- more to the bone marrow, medium-sized par- row. They function by grabbing onto materials ticles more to the liver, and larger particles i of size range of about 50 to 4,00q p and in- more to the spleen. The differences in electro- 5 1. >., .-.-- gesting or phagocytizing the foreigi particles, chemical properties of the different sizes may I I" thereby removing them from the circulation. also account for differences in biodistribution. Ifthe cell can digest the material, as in the Experimentalverification of this idea hasnot case of albumin, it will; if it cannot, it simply been presented. holds onto it. Although these phagocytic RE The RE cells are evenly distributed in the cells exist normally in thc liver,spleen, and liver and spleen, spatially associated withthe bone marrow, they may be present and active other cells found in these organs. One can study in other organs in certain abnormal conditions. morphology (size and shape) of the organs, RE function allows us to use radiolabeled par- evenness of the distribution of the material, and ticles as tracers to study phagocytosis and to the apparcnt relative amounts accunlulated in localize and visualize the organs where phago- each of the primary organs of RE function. A cytosis is taking place. poorly functioning cirrhotic liver may have an The liver-scanning agent thatis most com- unevcn distribution of radiocolloid uptake; in monly used today is 99111Tcsulfur colloid, pre- addition, thespleen will usually collect more Mechanisms of localizaiiort 41

Fig. 3-6.Scintigram showing distribution of rrD1l’T~sulfur colloid in liver and spleen. Upper image is anterior view; lowcr image is posterior vicw.

than its normal share of the dose, and the bonc liver is challenged with larger and larger doses marrowwill appear more prominently in the of nonradioactive colloid alternating with tracer image than usual. This results from bone mar- amounts of the radiolabeled colloid. The rate of row expansion and its relatively increased avid- disappcarancc of each dose of tracer ismea- ity for the radioactive tracer, which in turn sured. There are data to suggest that RE system results in more radioactivity (counts) coming capacity may be incrcascd in bactcriologic from the marrow as compared to the liver. and decreascd in viralinfection As an indicator of liver blood flow, with (Wagner and lio). everything else remaining constant,one can Liver-spleen scanning doses of !IYrrlTcsulfur study the rate of disappearance of colloid from colloid may be observed in static studics bc- the blood. Over 85%) of thc labeled colloid that ginning 5 to 15 minutes after the in,jection. The is presented to a set of RE cells is trapped. This biodistribution of the traccr may also be ob- results in almost all the traccr beingremoved served with serial Anger camera images. These from the bloodin its first pass through the dynamic studies are begun immediately after a liver. Thus, the rate of removal of the tracer bolus injection of the tracer. In this way one from the bloodis proportional to livcr blood canuse the inflowof B!lmTc sulfur colloid to flow. The data from such a study are normally show the vascularization of the liver and spleen obtained from a probe aimed at the head. Rapid and then the deposition of the sulfur colloid to sequential counts are recorded and plotted on show the areas of RE ccll function. Normally, semilog paper. The longer time component is the two functions ought to match; that is, the substractcd from the shorter time component, liver should be evenly vascularized and evenly and the initial disappearance constant is ob- populated with RE cells. If there is greater ra- tained (Fig. 2-8). This is the fraction extracted dioactivity in a particular location during the per minute. Patients with scvcrely diseased vascular phase of the study than during the have a slower blood clearance. To ob- static phase, a vascular lesion such as a tumor tain baseline data, patients must fast and keep is indicatcd. Areas that havedecreased activ- still before the examination. ity on both studies may becysts, abscesses, One can also mcasurethe RE system’s ca- avascular tumors, or fatty infiltrates due to cir- pacity to phagocytize particles. To do this, the rhosis, 42 Basics of radiopharmucy

while labeling them with YymTc.The most common instancesfor wanting to image the spleen without imaging the liver are(I) in cases where the left lobe of thc liver cannot be well distinguished from the spleen and (2) in cases where the spleen has been removed, but where little accessory spleens, which could be hidden by the liver, are suspected. Fig. 3-7 shows an example of a spleen imaged in a patient with a . A diseased (hyperfunctioning)spleen may remove perfectly good red cells from circula- tion, causing anemia in the patient. The usual therapy is removal of the spleen, but the at- tending physicianslike to be sure that they have identified the problem correctly. One method used in the diagnosis of this problem is a tracer study called splenic sequestrution. Red cells are labeled without damage with 5'Cr and reinjectcd into the patient. At intervals for the next three weeks the radioactivity in the patient'sspleen, liver, and precordiumis re- producibly determined with a probe-type scin- tillationdetector. Also, blood samples are taken, The radioactivity count ratios of the or- Fig. 3-7.Rectilinear scan of spleen after administra- gans to the precordium or circulating blood tion of "Cr-labeledheat-treated red blood cells. pool are calculated to see whether the spleen- Large circularregion of decreased dot density(filling to-liver ratio rises beyond 2: 1 (Fig. 3-8). The defect in nuclear medicine jargon) seenin this leftlat- radioactivity per 1 cc of red cells in the blood eral view was causcd by splenic cyst. samples is used to construct a graph of concen- tration of radioactivity in red cells versus time. Cell sequestration This slope of the curve is increased when red One of the functions of the spleen is to act as cell survival is being shortened by hypersplen- an inspection stationand filter for red cells, that ism.The disease is indicated by a shortened is, to remove (from the circulation) those cells T,, as shown in Fig. 3-9. which are no longer in primecondition. If a When a blood sample is withdrawn from a sample of the patient's red cells is labeled with patient forlabeling, the samplecontains red a radioactive tracerand damaged slightly before cells of many different ages, some young,some reinjection into the patient, a splenic image can old. Labeling of such a sample is called random be obtained without interference from radioac- labeling. If we wish to label red cells uniformly tivity in the liver. Usually a 99mTc sulfur col- with respect to age, we must label them when loid is also employed to obtain a liver-spleen they are created. To do this we give some ra- image forcomparison. The methods used for dioactive precursor, which will be incorporated damaging the red cells must be mild, otherwise into all the cellsas they are produced. One such a liver image will also be obtained. One method material is iron. Radioiron produces cohort la- is to damage 51Cr-labeled red cells with heat: beling, that is, labeling of cells all having the 50" C for an hour with gentleswirling. An- same age. Radioiron is not useful for splenic other method is to treat the red cells with Iy7Hg sequestration and red cell survival studies be- mercurihydroxypropane (MHP). Yet another cause the iron is recycled by the body and be- method is to treat the cells with excess stannous comes reincorporatedinto further generations Mechanisms of loculization 43

2.10 p Spleen: liver

1.90

1.70

1.50

1.30 A% CLI I 1.10 / 0.90

0.7C

0.5C i'

I I c I I I 2 4 6 8 10 12 14 16 18 20 22 24 Days

mC Q 0

"0 +m Standard K 0.60 - Liver

Ol 1 i a 6 8 10 12 14 16 18 20 22 24 Rays

Fig. 3-8. Plot of radioactivity to determine relative uptakeof tagged red blood cells in spleen corn- pared to liver, A, Spleen-to-liver and spleen-to-heart ratios. B, Relative radioactivity in spleen, liver, and heart. These data were used to calculate ratios reported in upper figure. 1,000

750

loo! I I , 1 , I 1 1 1 I 0 2 4 B tl IO 12 14 16 18 TO Days Fig. 3-9. Plot of radiochromiurn in RBCs measured for 2-week period. This gives T5 and is used as indicator of red hlood cell life. of red cells. 'I'he normal half-life of a newly ous steps of thyroidhormone formation, stor- created sct of red cells is 120 days, whercas the age, and use. Certain othcr negative ions can measured half-life of randomly labeled red cells be used to study the first step of this process; is 27 to 35 days, depending on labeling tcch- the initial trapping of the iodine by the thyroid niques. is mimicked by pcrtechnetate ion (Fig. 3- IO). The spleen is also active in the screening The same negative ions that concentrate in the andmetabolism of othcr bloodfractions, but thyroid are also concentrated by salivary glands less is known about the kinetics of their se- and are excreted in saliva,as well as being questration functions.White cells and plate- concentrated by the gastric mucosa and ex- lets, appropriately labeled and altered, could creted in the gastric juices. The scanning tech- probably serve as tracers for these splenic nique to locate Meckel's diverticulum is based functions. on this mechanism of tracer localization. The liver acts as a filter for removal of toxins Active transport fromthe body. If liver blood flowis unim- Active transport involves labeling by the in- paired, the rate at which such materials are re- volvement of ordinary metabolic processes moved from the blood reflects liver function, specific to individual organs. This mechanism in particular the activity of the polygonal cells can be used both to study function and to ob- of the liver. Lipophilic tracers,toxins, and tain images of specific organs. 'I'he example certain dyes are cleared from the blood by the that comes to mind immediately is the use of polygonal cells of the liver and secreted into radioactive iodine to study or treat the thyroid the bile ducts that drain intc~the gallbladdcr. gland. Iodide introduced intothe circulation, From time to time the bile is discharged into either from oral administration or by direct in- the small intestine. The can be vi- travenous injection, is laken up by the thyroid sualized whenfillcd with a radiolabeled sub- and used to make thyroid hormones. The small stance. The tracers are normally cleared from amounts of the thyroid hormones are relcased the gallbladder with a half-time of 7 to 8 min- into the circulation, where they serve as regu- utes. The tracer appears in the duodenum with- lators of metabolic rates. Thus, radioactive io- in 20 minutes (Fig. 3- 1 I). The most commonly dine can be used as a tracer to follow the vari- used materials are rose bengal and ""1

Muking rudiopharmaceuticuls safe and effective 81

103-

102-

U c " f? 101- 3 c F a

c5 100- > U m" 99-

98- v 1 " + Latent Peak Return to period response normal

97 I 0 1 2 3 4 5 6 Time in hours

Fig. 5-6. Idealized graph of body temperature of human subject given intravenous administration of drug containing pyrogen. ble, nondisturbing circumstances and accord- be used too often and must be allowed to rest ing to FDA rules for animal care, are put into after a pyrogen reaction. At thestart of its restraint in rabbit boxes, with rectal thermom- use, the rabbit must be trained to accept the eters in place.The temperatures are usually restraint, the thermometer,and the injection automatically recorded. Rabbits are used whose without becoming so cxcjted that its tempera- temperatures do not vary more than 1" C from ture goes up simply in response to fright. The each other and are less than 39.8" C. The dose animals must be challenged with known pyro- is injected into the ear vein, and the tempera- gens periodically to prove that they aresen- ture monitored. If no rabbit showsa rise of sitive. 0.6"C or more, and if the sum of the tempera- Usually the Limulus (horseshoe crab) amoe- ture rises of the three animals used does not bocyte lysate gelation test is preferred for the exceed 1.4" C, the material isacceptable. If pyrogen testing of radiopharmaceuticals and the material is borderlinc pyrogenic, it may be reagent kits because (I) it is more sensitive; tested in five more rabbits, and the results for (2) it is faster; (3) it requires smaller amounts all eight rabbits pooled. If not more than three of test material; (4) both positive and negative of the eight have temperature rises of 0.6" C controls can be performed along with each test; or more and the sum of all eight temperature (5) it does not gencrate radioactive rabbits, so rises does not exceed 3.7" C, then the material it is preferred from a radiologic safety point of is acceptable by U.S.P. criteria.Rabbits are view; and (6) it is less expensive and easier to used for the pyrogen test because they are ex- keep (Fig 5-7) tremely sensitive. They must be housed very To test kits, 0. I ml from each of the three carefully. Good records of their individual per- vials used for sterility testingis tested with formances must be maintained. They must not Limuluslysate (Table 5-2). For the negative Rabbit test

I I I I I

"" I-_I

"

Fig. 5-7. Pyrogen tcsting ctnploys cither rabbits or amebocytes obtained from blood of horseshoc crab. In tirst test, cnd point is risc in body temperature. In second tcst, cr1d point is gelation of ly- sate of arnoehocyles. control, a sample of the solution uscd to dis- curring correctly. The most common inhibitor solve the reagents is simultaneously tested. For is pH outside the range of 6 to X. If the kit the positive control, a test solution containing a reagents are acidic or basic when dissolved in known pyrogenis mixcd with thedissolved saline, an appropriate buffer is substituted for reagents or the radiopharmaceutical and tested the dissolution step. The buffcr is then used for to assure that the reagcnts or the radiopharnw thc negative control, Alternatively, a portion of ceutical does not inhibit the gelation reactions. the sample to he tested tnay he brought to the A sample of water for injection and water for proper pH range with NaOH or HCl. 'This must injection plus endotoxin may be usedas con- be done aseptically to avoid pyrogen contam- trols to ensure that the gelation reaction is oc- ination. Table 5-2. Scherrla of all ingredients necessary for pyrogen test using Limulus amocbocyte lysate and providing for thrcc typcs of controls

NegativePositive Positive controlTest control Internal control .. Lysa1e 0. I 1111 0. 1 Ill1 Test sample - - Endotox i n Double concentration - 0.05 1111 Regular conccntration - 0.I 1111 " Salinc 0. 1 It11 - " - Total volume 0.2 1111 0.2 1111 0.2 Ill1 0.2 1111 Results Should he Should be Should hc May he positive negative positivc positive or negative

Table 5-3. Comparison of standard and ncwcr methods for sterility and pyrogen testing of radiopharmaceuticals

Test Standard methods,Standard Test U.S.P. Newer methods, non-U.S.P.

Sterility Method: Fluid thioglycolate medium, M~/horl:"CO2 from 'IC glucosc in culture medium soybean-caseindigest rnediutn Atlvnrtragrs: Fast, scnsitivc Arlvuntuges: Sensitive Disarivnrrtagr.~: Automatic methodshave may back- Uisadvantagrs: Slow ground problems;bacteria ofkindssome may not give off COX

Pyrogen Method: Rabbit test Mt,tllorl: Lirrlulustestlysate Advnntnge.~:Should find all pyrogens Arhtrrnragrs: Scnsitivc to cndotoxin pyrogens, fasl, con- Uisarlvantug~,s: Not sensitive cnough venient to store and use, more anmtahlc to quantita- foritltrathccally iqjcctcd matcrials, Lion of pyrogen, good radiationsafely; controls to slow, expensive tu keeprabbit col- detect false-ncgativcs anti false-positives included as ony;rahhits may give ralse-positive part of routine tcst and falsc negative results L)iscxdvwragrs: May not cicteot all materials that cause fever; sotne radiopharmaceuticals inhibit reaction

In the standard Limulus lysate tcst, 0.1 1111 of terials.:': lt is already in usc by researchers for the lysate is addcd to 0.1 ml of properly buf- in-process tcsting of materials and by the manu- fered sample. The knownpyrogen substance, facturers of radiopharmaceuticals for cisternog- usually from Klebsiella microorganisms or E. raphy because of the cxtrcmc sensitivity of coli, is added to the selected samples. The sam- thc to pyrogens. Table ples are observed for IS minutcs to 1 hour. The 5-3 summarizes the comparison of the older and positive samples should gel, so that the liquid ncwcr ksts for sterility and pyrogens. will not run when the tubes are upended. 'I'he testmay be inhibited by incorrect pH, high Toxicity studies salt conccntrations. or enzymatic reactions, as After a formulation is fixed, that is, the man- well as by somesolvents. High lcvcls of al- ufacturing instructions are set, formal toxicity bumin may absorb the endotoxin and detoxify studies rnay be initiated. The objectives of thcsc it. The Limulus lysate test should soon be rec- , ognized by the U.S.P. for testing ccrtain ma- *Approved for biologics. 84 Basics qf rudiophurmcy studiesare (1) to approximately cstablish a out of 100 cases). One is the up-and-down sen- safety factor and (2) to determine what might sitivity test. In this test, the suspected tnxic be the expected reaction to an overdose. dose is administeredto a test animal. If this One indication of the margin of safety of a first animal lives, the next animal is given an radiopharmaceuticalis the ratio of the incrementally higherdose. If the first animal dose (the dose that produces toxicity in 50 out dies, thenthe next animalis given an incre- of 100 cases) to the usual diagnostic dose. In mentally lower dose. A small series of animals very large doscs, the toxic manifestations may is tested one aftcr the other; in each case, the be due to thechemicals, physical properties, reaction in the last animal determines whether or radiation; thus, when talking about margins the next animal receives a higher or lower dose. of safety for radoiopharmaceuticals, it is nec- This is an efficient way to measure the LDLo essary to state the type of toxicity to which one with precision,providing, of coursc, that thc is referring. The toxic effect of lung scanning toxic response is immediate.The testcan be agents is due to pulmonary hypertension in- used to demonstrate the toxic dose of lung scan- duced by injecting so many particles that a re- ning particles in mice. When overdosed, the sistance to blood flow through thecapillaries mice die within 5 minutes after the injection. of the lungs is incrcased. This is one type of Thus, to carry out this test onc mouse is in- physical cffect. In many cases, to induce toxica jected every 5 minutes; the result of the test is effect from a radiopharmaceutical, such a large thc LDsmat 5 minutes in mice. It is reported volume of the material would have to he ad- in terms of milligrams of particles per gram of ministered that the volume itself would bccome mouse. Using this method it was found that the source of toxicity. This is another type of iron hydroxide particles are more toxic to the physical effect. mouse than albumin, either as aggregates or as Two methods arc useful in the determination microspheres. The up-and-down sensitivity test of the LD,,, (the dose that causes death in SO is difficult if the onset of symptoms is dclayed.

Fig. 5-8. Idealized dose-response curve used to definc toxicity of drug. LD,, is highest dose that causes no deaths. LD50-30is dose that causes death of 50% of animals within 30 minutes. LDlw is minimum dose that kills all animals. Making radiopharmaceuticals safe and effective 85

This test also does not establish LD,, or LDlOl,, With a majority of radiopharmaceuticals it which are also important measures of toxicity. becomes impossiblc to devise meaningful tox- Fig. 5-8 shows an example of the results of tox- icity studies.To get enough of the test sub- icity study. From it you can see what is meant stance to carry out the test may be impossible. by LD,, LDs0, and LD,,,,. To get the concentration high enough to have a Oftcn it is useful to establish the whole-dose reasonable injection volume may alter the ra- response curve. A general method is the graph- diopharmaceutical so drastically that the data ic, log-probit method.A large group of animals would not be applicable. In thesecases we is subdivided, and each subgroup isgiven a par- rely on prcviously established toxicity studics ticular incrementaldose. The percent of ani- for the various ingredients. Most of the 98mT~ mals in each subgroup that manifest symptoms and ""mIn tracers are in this category. As an is determined.Thesc percentages are trans- example, "3mInC13 is soluble only in acid so- formed intoprobits* and plottedagainst the lution.Thus, it is administeredto patients in logarithm of the administereddose. Thc best 0.0SN HCI in small volumes.The injections straight-line fit of the data is determined graph- must be done with care because infiltration of ically or mathematically. From this line the the dose will cause a local burning sensation. various LD (lethaldose) or TD (toxicdose) As the acid is diluted by the blood, it is neu- values are read along with their confidence lim- tralized, and the llarnIn becomes bound to cir- its. This method requires many more animals culating transferrin. In order for the tracer to than the first method,and it also requires a work properly, it is necessary to use the acid fairly good estimate of the LD,,, (or TDSo) in vehicle. If we try to carry out a toxicity study advance ofthe test. It alsoassumes that the with this radiopharmaceutical in a small lab- dose-responsecurve will have the usual sig- oratory animal, we will merely be observing the moid shape.Its main advantagesare that the results of disturbing the animal's blood pH and wholc-dose response curve can be defined and blood volume. The data would not be informa- that endpoint measurements can be made at tive about the toxicity of InC1,. Acute toxicity times distant from the time of injection. tests that are used for regular pharmaceuticals are almost never directlyapplicable to radio- *Miller, L. C., and Tainter, M. L.: Estimation of EDso pharmaceuticals. and its error by means of logarithmic probit graph paper, The safety test is probably one of the most Proc. Soc. Exp. Biol. Med. 57:261-264, 1944. meaningful of the toxicity testsfor use with

0 1 2 3 Weeks Fig. 5-9. Example of safety test data suggesting that drug probably has some inhibitory effect on growth of mice. Data are for stannous pyrophosphate given in weekly dosesequal to 3,000 times the usual human dose. 06 Basics of radiopharmacy radiopharmaceuticals. A group of six growing Table 5-4. Practical considerations for the laboratory mice are weighed and injected intra- introduction of a new radiopharmaceutical peritoneally with a human dose of the radio- Consideration Questions to beexplored pharmaceutical, while a control group arc given the same volumc of sterile saline for injection, Will the new radiopharmaceutical U.S.P. This is repeated at weekly intervals for pay off'? up to three injections. Onc week after the last Canthe tracer be supplied who11 injection, the animals are weighed (Fig. 5-9). and where nccded'? The rncan weights of the test animals are ~0111- Quality control Are quality control tests availablc, pared to those of the control animals. If some andare thcy practical for rou- tine use if needed'? toxic ingredient is contained in the radiophar- Education Are the clinicians preparcd to ef- maceutical, its presence will be suggested by fectivcly use tcst results? difference in weights of the two groups. Even Is appropriatc detection equipment this test may not be applicable to radiopharma- availahlc'! ceuticals. In the example of 113n1TnC1:r,the test Has routine procedure been devcl- animals would be affected by the acidin the oped and evaluatcd'! vehicle; however, this test might be used if the Troubleshoot- What do you do whcn tracer does acid were first neutralized before the in.jection. ing not perform propcrly? Can mis- Even then, the results would have to be COII- performance be dcteotecl'? sidered carefully because the toxicity of insol- Follow-up Can follow-up studics be obtained uble indium is significantly greater than the studics to demonstratc cffeutivcness? toxicity of indium that becomes bound to trans- ferrin. This test is useful for checking for ex- traneous toxic ingredients that may have gotten of an existing radiopharmaceutical) is obliged into the preparation inadvertently. to file an applicalion with the fcderal govern- Chronic toxicity tests, in general,have no ment. Thesc are filcd with the Bureauof On- place in the testing of radiopharmaceuticals. cology and Radiopharmaceuticals of the Food We know of no example in which a radiophar- and Drug Administration (FDA).The initial maceutical is administered chronically to pa- filing often is the lnvestigational NewDrug tients, as are other drugs. Application (INL)), and the subsequent filing is the Ncw Drug Application (NDA). Introducing new radiopharmaceuticals In addition to legal considerations, many Nuclear medicine is still a relativcly new practical problems must be dealt with. These field of medical practice; thus, the applications are summarized in lable 5-4. Once a decision of tracer techniques to the solution of medical has been made to introduce a new tracer, many problems have just begun,Ncw traccr tests will questions are raised that need dcfinitivc answers be appcaring frequently for many years. These so that the new tracer test can be wisely used. newtests often require that :new radiopha;-- A list of several of these questions is prcscnted maceutical be provided to clinics that have not on p. 87. used the tracer previously.For limited local trials, it may be sufficient to obtain approval to THE IND start up thc newtest from a local committee Federal control of new radiopharmaceuticals who reviews the protocol,formulation, and is established with the use of a legal instrument animal studies to cvaluate the risk-to-benefit called an lnvestigational New Drug Applica- ratios associated with thc introduction of the tion. The document is a filing with the FDA of new test. When it is cxpected that the test will information showing how the tracer is prepared have wider applicability and cspecially if the and how it is to be used. All aspects of formu- radiopharrnaccutical or the reagent kits will be lation, labeling, quality control testing, animal shipped out-of-state, then the promoter of the studies,bibliography, and plans for clinical new radiopharmaceutical (or new formulation trials are detailed. Critical questions to be answered prior to widespread use of a radiopharmaceutical tracer I. What is (arc) the purposc(s) of [his radiopharmaccutical? 2. What is the cvidence that it is effectivc in fullilling its intendcd purpose'! 3. What is the normal distribution in experimcntal animals'? In normal man'? 4. What are thc indications for use of thc radiopharmaceutical'! 5. What arc the contraindications for its use'! h. How exactly is the radiopllarrnaccutical prepared? 7. What quality control tcsts are necessary and how exactly arc they performed and cvaluakd? 8. How is the radiopharmaceutical to be uscd? What is the requircd dose in ml'? pCi'! pg? 9. What is the safety factor and (he cvidence (hat this safely factor is valid and applicable'? IO. What arc the sidc effecu and untoward rcactions and their probability of occurrence'! I I. What ancillary drugs arc required, if any'? How, when, and in what dosagc levels arc they ad- ministered, and what arc the problcms associated with the use of these drugs? 12. Can (hisradiopharmaceutical bc adrninistercdrepeatedly? What are theresults of repeated animal injections, if applicable? 13. What is the radiation dose'? Wholc body'? Critical organs'! Gonads? 14. What is thcrecord of thisradiopharmaceutical'! Number of adrninistrations?Percentage of hcneficid rcsults'? Perccntage of mislcading results? Percentagc of patient reactions'! Dcscrip- tions of paticnt reactions'!

After an INL) becomes acceplcd by the FDA, justify filingan 1ND on an adrenal localizing it is the IND that controls the use of the radio- agent, even though thedetails for preparing pharmaceutical. That is, thc holder of the IND and testing the tracer arc well explaincd in the is expected to carry out the forrnulations, qual- literature. Thus, if no oneobtains an NDA ity controls,and clinical trials as outlined in on such an agent, itis nevermarketed, and the IND and report the results hack to thc FDA. somc patients will go without the advantages If changes become necessary, the holder is offered by themorc specializcd radioactive obliged to request a modification of the 1ND. tracer tests. This procedurc canwork well for ncwradio- Another problem with the IND process as it pharmaceuticals, especially if the applicant pre- applies toradiophiwmaceuticals is that it in- sents anefficient and reasonable planin the hibits the solution of minor formulation prob- application. lems. Frequently, problems are discovered with On the other hand, the IND procedure is not an existing formulation that can be simply rec- working so well for cstablished radiopharma- tified, hut these are not instituted because the ceuticals that need reformulation or those which filing of the amendment necessitates ton much are necdedin clinical settings not covcred in ofan investment of time and dollars.Often, thc original IND.The adlninistrative logistics such problcms are avoided if the initial filing often restrict the use of needed tracer tests. provides for some flcxibility in the procedures. The preparation of a new 1ND or amending, an existing INI) is often lengthy andexpensivc. CLINICAL TRIALS Frequently, thc income from the radiopharma- The first clinical trials serve several pur- ceutical does not justify the expense ofprc- poses: (1) to test the hypothesis that the tracer paring and filing the additional papers with the will perform in man as expected from the ani- FDA. Forexample, the demandfor adrenal mal studies, (2) to verify the proposed method- studies inNew Mexico is probably less than ology, (3) to establish the biodistribution of ten patients per year. This is hardly enough to the tracer innormal subjects as controls for 80 Basics of radiopharmacy futurestudies in patients and toobtain data to conductthis phase of the investigation so that that can be used in refining the radiation dose the sensitivity and specificity of the test arc calculations, and (4) to searchfor any possi- measured. bilities of adverse reactions or toxicology. This discussion of clinical trials is not neces- Since the use of radioactive tracers in normal sarily consistent with FDA policy. Rather, it is subjects is irradiating the normalpopulation, based on our experience and reflects what we these studies arc kept to an absolute minimum. believe to be current scientific wisdom. Also, Tf the first three subjects demonstrate reproduci- the suggested tests arc outlined for new radio- bility of the biodistribution, reveal no adverse pharmaceuticals rather than for ncw INDs on effects, and verify the methodology, then this existing radiopharmaceuticals or rcformulation phase of the clinical trials may be halted. How- of existing radiopharmaceuticals.In these C~SCS ever, it may be necessary to carry out the tests the minimum essential data should be obtained in more normal subjects in order to determine in the most cost-effectivemanner. The tests normal ranges of critical values. An upper limit should demonstrate that the tracer works as pre- to this initial phase is probably around forty dicted from previous experience. to a hundred subjects. A major purpose of an IND is to get data for It is customary to examine the first subjects the NDA filing. This should be done with the very carefully for any signs of toxicity. Blood minimum number of cases required to establish pressure, heart and respiration rates, and tem- safetyand effectiveness.Massive amounts of perature are monitored before and after each data become difficult to control and costly to test. Also, blood and urine samples are checked evaluate. forevidence of changes in renalor hepatic function. Replacing old radiopharmaceuticals The next phase of the clinical trials is usu- When it becomes scientifically obvious that ally directed toward patients known to have the a new isotope ora new tracer compound is disease that the test is designedto detect. These superior toa currently used tracer, then an trials are especially aimed at testing the hypoth- effort to switch should be made with dispatch. esis that this pathology can be detected by the Current FDA policy does not encourage this. proposed procedure.These patients also pro- Also, mechanisms for removing radiophanna- vide datafor further refinement of radiation ceuticals from the NDA listing are not appa- dosimetry estimates. As with the normal sub- rent. Compounds such as 2osHg chlormerodrin ject, vital signs andblood and urine analysis remain on the list in spite of considerable evi- are carefully checked for evidence of toxicity. dence that better and safertracers are avail- Again, this phase of the clinical evaluation is able. To remove this compound from the listing limited to the number of patients required to would not create any diagnostic problems. On provide statistically valid conclusions. Exccs- the other hand, YYmTclung imaging agents have sive testing only contributes to development been long established as superior to lS'I MAA. costs that drive the eventual price of the tracer The radioiodine cornpound should notyet be test upward. removed, however, because there are stilltimes The final phaseinvolvcs more patients in and places where a YYmT~product is not avail- several clinical settings. In contrast to the ini- able, whereas the longer shelf-lived I3lI MAA tial phases where thcpatients were selected can be obtained for emergency lung scans. based on whether they were normal or had the disease in question, these subjects are selected Adverse reactions because there is a possibility of the disease. to radiopharmaceuticals Each test is evaluated as to whether it was An adversereaction isthe unanticipated diagnostically useful and as to whether it pro- physiologic response of apatient to a radio- duced any suspected symptoms in the subjects. pharmaceutical.Such a response is attributed Confirmation of the diagnosis is made subse- to the vehicle rather than to the tracer because quent to the tracer test. Tt is especially desirable the chemicalamoum of the tracer is usually Making radinl,hormacruticaIs~alssafe and effective 09

inconsequential in comparison to the chemicals tient eventuallydied of radiationpoisoning. making up the vehicle. Adverse reactions may, In the past, when l3IT MAA and 113mTnor at times, be psychosomatic in origin. Exam- 99mTc-Fe(OH),flocs were in more widespread ples of adverse reactions arc anaphylaxis, use as lung scanning agents, overdoses or toxic hives, bronchospasm, and othcr allergic mani- doses were occasionally reported. These cases festations:fever, headache, infection, - usually were seen when several milligrams of like states, flushing of theskin, and metallic the tracer were administered to young or very tastes in the mouth. In the case of intrathecal sick patients already suffering from pulmonary injections, the symptoms can include stiffness hypertension.Apparently, the additionalob- of the neck, headache, confusion, and aseptic struction to pulmonary blood flow in these pa- meningitis. Thcse symptoms have been traced tients was not tolerated. The patients who died in the past to contamination of the radiophar- exhibited the samesymptoms observed when maceuticals with pyrogens. mice were overdosed with these particles: faint- Adverse reactions are often associated with ness,cyanosis, tachypnca, agitation, and dia- ancillary drugs used with the radiopharmaceu- phoresis progressing to sinustachycardia and tical.Lugol’s solution, given to prevent ra- death. With current agents, ggmT~microspheres dioiodine accumulation in the thyroid and ad- and ogmT~MAA, which havehigher specific ministered in conjunction with compounds con- activities and thus fewer particles per dose, no taining canbe responsiblefor adverse re- new cases of overdose of lung scanning par- actions in iodine-sensitive patients. Perchlorate ticles have been reported. and atropine, given to block 99mTcO; uptake Underdosing can result in insufficientdata in the choroid plexes and salivary glands and for a successful study and thus the patient is administered in conjunction with brain scan- irradiated without benefit. Underdosing usually ning procedures, may also contribute to adverse results from calibration error, infiltration of the reactions. dose, or adherence of the tracer to the syringe Adversereactions should be promptly and or needle. The counting of spent syringes prior carefully investigated to prevent further inci- to their disposal is a way of checking for hang- dence.The reports should be filedwith The up of the tracer in thc syringe. As was pointed United States Pharmacopeia, who in turn report out in Chapter 3, underdosing with lung scan- to the manufacturer, theFDA, and the Registry ning particles leads to patchy pictures because of Adverse Reactions maintained by the Society individual particles can be imaged. of Nuclear Medicine, Jnc. The Registry is of great importance because it allows forthe docu- Injection problems mentation and analysis of reactions that occur Faulty injectiontechniqucs can adversely with very low frequency. affect the results of tracerstudies. Dynamic studies,for instance, often require precisely Overdosing and underdosing controlled injectionprocedures. Usually, this To assure that patientsget the appropriate requires that the dose being injected be con- dose of a radiopharmaceutical requires careful tained in a volume of no more than 1 ml and checking of the radioactivity prior to each ad- that standardizeda procedure, such asthe ministration. If the dose is injected prior to its Oldendorf procedure, be used.* When particu- calibration time, or if an adult dose is given to late radiopharmaceuticalsare injected, special achild, overdosing occurs. In such cases, no precautions are required. Blood withdrawn into effect of the excess radiation is expected; how- the syringe tends to clot more rapidly because ever, the images may be inferior if the count of the catalytic action of the particles. Some- rates areoutside the optimumrange for the * Various injection techniques are described by Robinson, procedure that is used. Excessive overdosing is R. G.: Standardization of theinput function. In Rhodes, rare but has been documented.For example, B. A,, editor: Quality control in nuclear medicine: radio- a 200 mCi dose of lsHAu was administered in- pharmaceuticals, instrumentation, and in vitro assays, St. stead of the indicated 200 pCi dose. The pa- Louis, 1977, The C. V. Mosby Co. 90 Basics of radiopharmacy times radioactivc cmboli are produced and in- Litchfield, J. T., Jr., and Wilcoxon, F.: Simplified methcd jected into the patient. These show up as ob- of cvaluatingdose-effect cxpcriments, J. Pharmacol. Exp. Thcr. 96:99-113, 1949. vious “hot spots” on thc lung scan. To avoid Lootnis, ‘1. A,: Essendals of toxicity, Philadelphia, 1968, this, syringes in which blood is allowed to stand Lea & Fehiger. for more than a minute are discarded, and a new Miller, L. C., and ‘l‘aintcr, M. L.: Estimation of ED,, and dose is obtained for the study. Lung scanning itserror by tncans of logarithmicprobit graph paper, agents should be administered slowly over scv- Proc. Soc. Exp. Riol. Md.57:261-264, 1944. Ovary, Z.:Immediate reactions in the skin of experimental era1 breath cycles whilethe patient is supine. animals provoked by antibody-antigen interaction, hog. This gives a distribution of the tracer more Allergy5:459-508, 19%. representative of the average perfusion to the PublicHealth Service, Foodand Drug Administration: lungs. The dependent portion of thc lungs re- Guidelines for theclinical evaluation of radiuphma- ceives more blood flow, so consistent position- ceutical drugs, Publication No. HEW(FDA) 77-3044, ing during injection of a lung scanning agent Washington, D.C., 1977, U.S. GovernmentPrinting Office. is important. Rhodes,B. A,, editor:Quality control in nuclear medi- cine: radiophartnaccuticals, instrumentation, and in vitro Suggested readings assays, St. Louis, 1977, The C. V. Moshy Co. Banzigcr, R., and Pool, W.: In Cooper, M., editor: Safety Rhodes, R. A,, Zolle, I., Buchanan, J. W., anti Wagner, testing of pharmaceuticals. In Qualitycontrol pharma- H. N., Jr.: Radioactive albumin microspheres for studies ceuticalindustry, New York, 1972, AcademicPress, of the pulmonary circulation, Radiology 92: 1453-140, Tnc. 1969. Brisman, R., Parks, I.. C., and Haller, J. A,, Jr.: Ana- Smith, A. E., and Benford, R. J.: Birth of a drug, Wash- phylactoid reactions associated with the clinicaluse of ington, D.C., 1963, PhartnaceuticalManufacturers As- dextran 70, J.A.M.A. 204:824-825, 1968. sociation. Brownlee, K. A. Hndges, J. C., and Roscnblatt, M.: The TheUnitcd States Pharmacopeia, seventeenth revision, up-and-downmethod with small samples, J. Am. Stat. New York, 1965. The IJnited States Phartnacopcial Con- Assoc. 48:262, 1953. vention, Inc. (See p. 810 for methods of sterilizing Campbell, D. H., et al.: Methodsin : a lab- drugs, p. 813 for aseptic filing, p. 829 for sterility test- oratorytext for instructionand research, New York, ing, and p. 863 for pyrogen testing.) 1963, The Benjamin Co., Inc. Weil, C. S.: Table lor convenient calculation of median- DeLand,F. H., andWagner, H. N., Jr.: Earlydetection effectivedose (LD,, or ED,,,) andinstructions in their ofbacterial growth, with carbon- 14-labeledglucose, use, Biomctrics 8:249-263, 1952. Radiology Y2: 1.54- ISS, 1969. Zaimia, E., and Elis, J.: Evaluation of new drugs in man, Dixon, W. J., and Mood, A. M.: A method for obtaining Procccdings of the Second Intcrwational Pharmaceutical and analyzingsensitivity data, J. Am. Stat. Assoc. Meeting, Prague, 1963, New York, 1965, The Mac- 43: 109-126, 1948. Millan Co. I CHAPTER 6 t with radiopharmaceuticals

Design carefully to avoid the possibilities of can- This is a discussion of radiation therapy us- cer induction and genetic damage. Under no ing radiopharmr~~euticals,not of thc use of vari- circumstances should a prcgnant woman be ous nuclides as sealed sources orpieces of wire. treated because indinc crosses the placental The behavior of radiopharmaceuticals used for barrier andcan accidentally treat the thyroid radiation therapy must be very wcll understood of the fetus, leaving it athyroid. Iodine therapy toavoid radiation close to othcr than the in- is also used to treatthyroid , usually tended areas. after surgery. It is uscful for ablating remain- Whenradiation therapy is the intended use ing thyroid tissue and for treating metastatic of a radiopharmaccutical, the design criteria thyroid tissue. The iodine is used in the iodide change slightly. We arc still intending to use ion form, with noadded carrier. The thyroid easily produced,available, inexpensive radio- may be stimulatcd before the dose is admin- nuclides of high specific activity. Most impor- istered to thyroid cancerpatients. The iodine tant is that the target-t<)-nontarget ratio be cx- is a normal constituent of the thyroid and its tremelyhigh in order tominimize the danger hormones, so the mechanism for uptake for to other organs. Most rddiopharlnaceuticals in thcrapy is the same as that of other iodine in- usenow do not have the high ratio needed to corporation into thyroid hormone.The many satisfy this criterion. Since we do not intend to gamma rays of r:nI create a radiation hazard to minimizethe radiation dose to the targetbut the people surrounding thc patient. li51 has also rather to maximize it, different radiation char- been usrd in thyroid therapy. acteristics must be sought. The dose should be delivered fairly quickly, so the effective half- 32P sodium phosphate lifc should be short, primarily because of the Phosphorus 32 is a pure beta emitter with physical half-life. The material should be a beta a 14.3-day half-life. It hasbeen used in the emitter with no external radiation, so that the soluble sodium phosphate formfor the treat- dose can be localizcd in the patient and so that ment of scveral hematologic conditions such as his attendants and visitors do not get anun- and polycythemia vera. It is admin- wanted dose. If the material cannot be made to istered either orally or intravenously and con- remain at the site of localization, it wust be re- centrates in the blood cell precursors of the moved from tbc body quickly, as by hydrating marrowwhere there is rapid proliferation of the patient or by using cleansing enemas. cells. There is some evidence that thc treatment can cause leukemia in people who do not have 131 I itand that chemotherapeutic and othcr treat- By far the most radiation therapy in nuclear ments may be prcfcrred (Table 6- 1). medicine is performed with 19'I. Iodine therapy is practiced on patients suffering from hyper- Colloids thyroidism, who are not terminal patients being Phosphorus 32 in the insolublc colloidal form treated palliatively but are people who have of chromic phosphate and gold 198 as the col- long lives ahead of them. They must be treated loid have been used to treat effusions, both of 91 92 Basics of rudiopharmucy

Table 6-1. Therapeutic uses of radionuclides

Nuclide ChemicalNuclide form Target organ Indications

1311 I- Thyroidcancer, thyroidThyrotoxicosis, 32 p Sodiumphosphatc Bone marrow Leukemia, polycythemia vera 32 p Chromicphosphate Body cavitics Malignant effusion I "Au Colloidalgold Body cavities Malignant effusion

the synovial membrane in rheumatoid arthritis Once the radiation exposure dose is set and and of the peritoneal cavity often after incom- the mCi dose required to produce this exposure plete surgery. The colloid, diluted in saline to dose is estimated, the dose must be measurcd fill the space, is instilled into the cavity in ques- out and dispensed to the patient. Some clinics tion. The dose is deliveredon the surface of the have policies that require two individualsto cavity to which the colloid adheres. In perito- check each other to assure that both the calcu- neal instillation itmay be that lSHAuconfers lations and the radioisotope measurements are lessharmful doses to otherstructures in the correct. Great care is always taken to assure patient; becauseof its shorter half-life,it spends (1) that the correct mCi amount is measured more of its lifetime in the correct cavity and out and administered, (2) that the dose is given less as acolloid that has passed through the to the correct patient, and (3) that appropriate diaphragmaticsurface and made its way into radiation safety considerations are met. Radia- the liver. 32P,on the other hand, is a pure beta tion therapy, though usually less traumatic to a emitter, whereas the gold emits a patient than surgery, is a procedure with con- at 410 kev, which presents a hazard to the sur- sequences similar to surgery. To make a rnis- rounding tissues. All the colloids behave simi- take with a therapy dose is a very serious rnat- larly, though not identically because of particle ter similar in magnitude to operating on the sizedifferences. Itis possible to image the wrong patient. Thus, it is often wise to request cavity into which the 32Pcolloid is to be in- verification of calculations and measurements stilled by giving a tracer dose of YsmTc sulfur from a radiation physicist or nuclear medical colloid prior to the :izP procedure. scientist.

Handling therapy patients RADIATION SAFETY CONSIDERATIONS ASSURANCE OF RADIOISOTOPE DOSAGE The possibility of personnel radiation expo- Some physicianswill prescribe the exact mCi sure during the drawing,handling, and mea- dose and chemical form of the radionuclide to surement of therapy dose should be carefully be used for therapy. At other times, it may be considered. The same precautions required for necessary for the technologist or radiopharma- handling diagnosticdosages are used. How- cist to assist withthe calculation required for ever, often asecond trained person is avail- arriving at the required mCi dose. For example, able to survey the operation and monitor the in treating the thyroid with radioiodine,data radiation exposure levels with a hand-held sur- from a previous radioiodine uptake study and vey meter. estimation of gland size either from a radioiso- With doses of l3'I larger than 30 mCi, hos- tope scan or palpation can be used to estimate pitalization of the patient is required. The pa- the required number of mCi of l3II to be ad- tient is placed in isolation until the body burden ministered to provide a given radiation expo- is less than 30 mCi. During this period, special suredose. A previous study of YemTcsulfur procedures are followed to minimize radiation colloid can sometimes be used to help estimate exposure to nurses and other per- the required number ofmCi of colloidal 32P sonnel. Also, special procedures for disposalof or lDflAu. radioactive body wastes and clothingare fol- Radiution therapy with radiopharmaceuticals 93

Fig. 6-1. Radioiodinesolutions are being given to patient in lead-shieldedcup and disposdblc straw (or pipette if straw is not available). Radiopharmacist discusses procedure with patient so that patient coopcration is assured.

lowed so that radiation contamination of the hospital environment is avoided.

TALKING WITH THE PATIENT Each person who deals with a patient under- going radiation therapy with a radionuclide has the responsibility to help make the procedure safe and effective by relating kindly and care- fully to the patient. Patient cooperation is often best achieved by clear and precise cornmuniea- tion with the patient. We have found that if we explain exactly what we are doing and why, the patients usually feel more at ease withthe process, When administering oral radioiodinesolu- tions, often the solution is dispensed in a cup within a lead shield (Fig. 6-1). Absorbent pa- pers are used to guard against spillage. Tf the reasons for use of this are explained, the patient usually will not be upset by what appears to be a strange procedure.

Fig. 6-2. Radioiodine container is rinsed with water two to three times. Patient is asked to drink washing to assure that total dose is taken. After explaining the procedure to the patient, counting instrumentation by increasing and question him as to whether he has a settled causing unpredictahle fluctuations in back- stomach. If a paticnt is nauseated, it iswise ground radiation levels. to postpone oral doses of radionuclides. Also, instructions are given to assure that the patient Suggested readings takes all of the dose. The cupmay he rinsed two Brucer, M.: From surgerywithout a knife to the awmic cocktail.Vignettes in Nuclear medicine, No. 2, St. to thrce timcs withwater to assure that the Louis, 1966, Mallinckrodt Chemical Works. whole dose isswallowcd (Fig. 6-2). Avoid Larose, J. H.: Radionuclidc therapy. In Early, P. J., Raz- rinsing the cup with saline solution or warm xak, M. A., and Scdee, D. B., editors:Textbook of watcr because this can induce nausea. Once the nuclear medicine technology, St. Louis, 1975, The C. V. dose is administered, it is expedient to release Mosby Co. , S.: Radioactivenuclide in medicineand biology, the paticnt so that exposurc toself and other Philadclphia, 1968, Lea & Febigcr. individuals in the nuclear medicine clinic is Werner, S. C.: Radioiodinc. In Werner, S. C.,and Ingbar, minimized. Radioactive patients interfere with S. H., editors: The thyroid,New York, 1971, Harper & Row, Publishers. CHAPTER 7 Radiation dosimetry

EARLY OBSERVATIONS OF RADIATION define such a curve for long-term radiation ef- EFFECTS fects, no threshold could be dctermined. Thus, The discovery of was soon it is generally assumed that the probability of followed by the discovery of its acutc harmful radiation and radiation-induced effects. The story is told that Marie ’spro- geneticabnormalities is never zero,regard- fessor proudly displayed the first sample of the less of how low the exposure dose. We know new element, , in a small vial attached to that the rates become too low to measure by his lapel. A short time later, the first radiation most feasibletechniques. We know that the was observed. To verify the association time between exposure and manifestation of between radioactive elementsand localized ery- symptoms incrcases as the dose dccreases. We thema, experimenters taped pieces of the new know that at low exposure rates biologic repair metal to their skin to observe the result. Their mechanismsoperate to correctsome ofthe experiments proved that exposure to . Thus, we proceed knowing that there can indeed cause to the skin. Canyou is some risk associated with all radiation ex- imagine the response of a current radiation posure. This is accepted just as we accept the Safety committee to such an experiment? risks of riding in a car or walking across thc The association between radiation exposurc street. and canccr took longer to discover. A major Because we realize that the usc of radiation epidemiologic study of radium-watch dial paint- always involves some risk, one of our guiding crs revealed that the dial painters whotipped principles behind the compounding and admin- their brushesto a fine point in their mouths istration of radiopharmaceuticals is that every nlust have swallowed large amounts of radium. attempt must be made to keep the radiation ex- Some of the ingested radiumwas sequestered posure to workers and patients at a level as low in bone, where it remained for years. The in- as possible, consistent with the production of a cidence of bone cancer in this group was sig- satisfactory examination. The maximum cumu- nificantly greater than expected for the general lated whole-body dose for radiation workers as population, An increased incidence of thyroid a function of age, N, is 5(N - 18) rem, or cancer has likewise been observed in adults 5 rem per year. The general public should not who underwent neck during child- be exposedto more than 0.1 of this amount hood. except for medical purposes. To assure that we are careful, exposure doses arc monitored, and REVIEW OF RADIATION BIOLOGY lifetime records of accumulated exposures are The toxic effects of most drugs arc demon- maintained. Almost no other industry has thc strated only when a threshold level of the drug safety records of the nuclear industry because is exceeded. An examination of a typical sig- of the strict adhercnce to this policy for safe- moid dose-response curve such as the one stud- guarding both the public and radiation work- ied in Chapter S reveals this threshold amount ers. as the LDo or TI),. When investigators tried to Ionizing radiation is defined as radiation that 95 96 Basics of radiaphurmcy

can cause in the absorbing medium. painters and,medically, to patients inwhom Charged particles, , and other products dioxide (Thorotrast) wasused as a liver of natural and induced nuclearreactions are . ionizing radiation. In the course of their slow- Beta particles are emitted from the ing and stopping in any medium, they leave a nucleus either as or negatrons. They track of ionizedatoms behind. Thc electrons have a range of a few millimeters of tissue in are removed from atomic shells in the path of which they deposittheir energy, so they are theparticle. This ionization may lead todis- not useful radiationsfor nuclear medicine; ruption of the containing that atom or however, they are often present as part of the to the molecule transferring its charged status radiation coming from the nuclides in use. The to anothermolecule, damaging it. Most bio- isnot ordinarily absorbed but instead logic systems contain high percentages of wa- meets an at the end of its path; the two ter, so the water is what is most likely to be annihilate, causing two51 1 kev photons, which ionized by the impinging radiation. The water are absorbed according to the rules for photons. then transfers its excited ionization to another An energetic electron leaves a trail of ioniza- molecule that it is surrounding, leading to the tion in its wake as it slows down.All electronic radiation damage ofthe secondmolecule. At or beta radiation from a decaying atom behaves low radiationdose rates, molecules can pos- the same way and can be treated as depositing sibly repair themselves;at high dose rates, they its energy within a few millimeters of its cre- areirreparably damaged (at these dose rates ation. complicatedbiologic molecules will bedam- Gamma radiation consists of photons. These aged beyond any functional capability). At in- particles are pure energy with no mass and have termediatedose rates the molecules maybe appreciable ranges in tissue so that they can be damaged and unable to be repaired, so that they detectednoninvasively. All photons of these malfunction and causeproblems, sometimes , whether gamma rays from nuclear de- immediately or sometimes much later. cay or x rays created from the de-excitation of The effects that have been accorded to ioniz- atomic electrons, behave similarly. In the en- ing radiation are acuteburns, dermatitis and ergy ranges that are generally used in nuclear through chronic effects such as pre- medicine, photoelectric absorption and Comp- mature aging, and carcinogenesis. Genetic ef- ton scatteringare the mechanisms for trans- fectsare also possible, inwhich succeeding ferring energy from the to the surround- generationsare affected, while the actual ab- ings. Both of these cause ionization of the sur- sorber of the radiation is apparently unaffected. roundings,over a distance as appreciable as many centimeters in tissue.At the lower energy REVIEW OF THE PROPERTIES OF RADIOACTIVE ranges, below 10 kev, the rangc is short, so the ” . MATERIALS AND ABSORPTION OF RADIATION dosefrom low-energy photonsis mathemati- In preparation for learning about how radia- cally treated like the dose from beta particles. tion doses can be calculated, it is necessary to When a nucleus decays, it is adjusting itself review the properties of the particles emitted from a higher energy state to a lower and more during radioactive decay and how they are ab- stablestate. Its decay usually affects the nu- sorbed (Table 7-1). The first of these is the cleus, often changing its chemical identity and , which is a nucleus, 4He. the electronic shells surrounding it. It is massive, has a range of a few layers of In order to discuss radiation dose it is neces- skin, and is not usedin nuclearmedicine. sary to take into accountall the emanations Alpha-particleemitters are dangerous when from the nucleus and its electronic shellsand to they are incorporated in tissue or bone because knowwhat the proportion of eachis. These then the energy isabsorbed in thattissue or factshave beenwell documented,since they bone.Alpha emitters have been indictedfor are partof the “signature” of a particular radio- radiationdamage to the radium-watch dial active state, and they areprinted in tabular Radiation dosimetry 97

Table 7-1. Dosimetry calculations for technetium 99m sulfur colloid*

Energy *nph Radiation (mev) (grarn.rad/pCi.hr) AP dw-u A+L+L) ~(L-s) A(L+s)

Internal convcrsion electrons M. Y1 0.0017 0.0036 K, Y2 0.1195 0.0225 L, Y2 0.1377 0.0032 M, Yz 0.1401 0.001 1 K, Y3 0.1217 0.0025 L7 Ya 0. I399 0.OooY M. Ya 0.1423 0.0003 L x rays 0.008 I 0.0000 Auger electrons KLL 0.0 I55 0.0005 KLX 0.0178 0.0002 KXY 0.0202 0.0000 LMM 0.0019 0.0004 MXY 0.0004 0.0010 X rays (>0.01 mev) Ka I 0.0184 0.0017 0.82 0.0014 0.0000 0.0000 Ka 2 0.0183 0.0008 0.82 0.0007 0,0000 0,0000 KP 1 0.0206 0.0005 0.78 0.0004 0,0000 0.0000 KP2 0.0210 0.0001 0.77 0.0001 0,0000 0.0000 Gammas Y1 0.0021 0 .oooo 1.00 0.0000 0.0000 0.0000 Y2 0.1405 0.2643 0.16 0.0423 0.0071 0.0019 Y3 0. I427 0.0001 0.16 0.0000 0.0071 0.0000 zA,&,,, = 0.0362 TP&,,, = 0.0449 ZAh,,, s) = 0.0019

*Calculations are based on output data, biodisrrihution data, and phantom geometry; courtesy Roger J. Cloutier.

form in several sources, the most accessible of from the whole atom. This list is longer than whichis the MIRD tables.For each nuclide the list in the first table because it contains, in listed,thcre are two tables and a schematic addition to the previously listed nuclear radia- drawing. An example is shown in Fig. 7- 1. The tions, all the conversion electrons, x rays, and drawing shows the parent nucleus, the various Auger electrons. Again, there is a column for energy levels, and the radiationsconnecting the mean number perdisintegration, N,, ex- them,as well as the identity of thedaughter pressed as afraction, themean energy (Ei), or product nucleus. The first of the tables, la- which is the same as the energy for the gamma beled “Input Data,” describes the kinds of ra- rays but which differs from the maximum en- diation (beta and gamma) that are emitted by ergy for the beta particles (there is no interest thenucleus, their relative frequency per dis- in neutrinos forradiation dosimetry), and a integration as apercentage, their energy in quantity called AI = 2.133 n& where the con- mev, and some comments, such as the percent- stant 2.133 incorporates the conversion factor age of and which electrons of 1 pCi * hr = 1.332 X loRdisintegrations and are involved. The second table, labeled “Out- the conversion factor of 100 ergs = 6.25 X IO7 put Data,” is a list of all the radiation emitted mev to give units for AI of gram * radslpci. hr, 90 Basics oj radiopharmacy

Chromium 51 decay

MFB" number/ Msm dlalnie- energy 1, gralion (my) (n,) (El) .. - ." 0 OR99 0 3190 110612 11 uuu I n :1i49 u 000l 0.129 OOObO 00014 0 0669 0 0049 0 0007 0 0226 0 0064 0 0003 0 0003 0.0065 0 woo 0661 00044 0 0053 0 124 00043 00013 1.63 0 0005 00016 322 , 00001 0.0000

"

Fig. 7-1. Decay scheme for "Cr with MIRD data tables. (From Dillman, L. T.: J. Nucl. Med. lO[suppl. 21: 1-32, 1969.)

where the rad equals 100 ergsdeposited in 1 to be the quantity of x or gamma radiation such gram of tissue. that 1 esu of ions is created in 1 ml of air at standard temperature and pressure (00 C and Dosimetry calculations 760 mm pressure), which is 0.001293 gram of PHYSICAL AND BIOLOGIC CONTRIBUTIONS air.The rad expressesabsorbed dose of any The aim of this section is not to make dosim- kind of radiation and is equal to the absorption etry thcorists or even experts of the readers, but of 100 ergs of radiation energy per gram of to make it possible for them to consider the matter.The rem givcs the equivalent of any various important parts of adose calculation type of radiation to that which would deliver 1 and to perform such a calculation. Because the rad from x or gamma radiation. For tissue, all MIRD schemc proposed by The Medical In- three units are essentiallyequal. One should, ternal Radiation Dose Committee of the Society however, be careful to use rads in discussion of of NuclearMedicine, Inc., is now so nicely . documcnted, withnew simplifications coming To calculate the dose to an organ, it is neces- out periodically and with calculations on new sary to considcr the sources of radiation to that radiopharmaceuticalsbeing performed, re- organ. Beta radiation and low-energy gamma viewed, and published, this chapter will exam- radiation areessentially nonpenetrating radia- inedose calculations from the MIRD view- tions with a short range, so any dose conferred point. The notation and vocabulary used in the on an organ from these radiations must come MIRD publications will be used here.The from sources within the organ. If the concentra- methods and discussion can be generalized to tion of the radioactive material in the organ is radiopharmaceuticals as yet unheard of. essentiallyzero, then thereis no dose to the Thedose equation willbe stated, its parts organ fromnonpenetrating radiation. Gamma examined carefully and separately, and then the radiation, on the other hand, acts at a distance, parts returncd to the whole in a sample calcu- so the distances from the target organ to the lation. source organ must be considered, as well as the Theterms you have heard associated with geometry of each. In the MIRD scheme, a hy- radiation dosimetry are the roentgen, the rad, pothetical construct known asreference man and the rem (roentgenequivalent man). The (Fig. 7-2), who is actually bisexual, has been roentgen (r) is a unit of emitted dose, defined used to make the geometric factors required to Radiution dosimetry 99

from source. The target’s own radioactivity must he considered in this sum, so there will be a

term A(#,(.l.+ T) it’ thc target itself is radioactive h intensity of transition (t, = absorbed fraction

The physical datafor the particularnuclide gives all the information For the A’s. These are tabulated in the output data table. For nonpene- traling radiation, Onll = 1. The MIRD tables in Pamphlet No. 5 contain the data calculated from reference man’s geometry and the ener- gies of thc gamma rays involved that are put

together to give (t(T + s), where S is the source and T is the target. Thc pages of the pamphlet give the sourcc organs. The target organs are listed down the side, energies vary across the page. Some laboratorieshave adaptcd all of this for the computer, but if you do not have access to such a system, you must interpolate linearly in order to get 9’s for energiesnot listed. MIRD Pamphlet No. 11 has gone further to combine all the k!!(T +- S) terms for a particular nu- Fig. 7-2. MIRD reference man (see tcxt). 111 T clide for all the source and target organs into a term called S, thc absorbed dose per unit cum- consider the effects of a sourcc, for example, ulatcd activity. S incorporates,then, all the in the liver and its cffcct on organs such as the data from the nuclide as to its radiations and spleen, thyroid, and brain. Thus, it is seen that from the reference man data for the organs in every dosccalculation will contain contribu- question. In terms of S: tions from nonpenetrating and penetrating radi- I h = 2 ASS,,, + s) (2) ation, and contained in the latter is a geometric factor. In the following exarnplc, the S factor will be The general equation can be given by calculated and also drawn from thetable in Pamphlet No. I 1. Notice that so far nothing has been said about the distribution of the radiopharmaceutical in where ‘I’ stands for target the patient or about the half-time of residence

- S stands for source in the patient.These are the factors that are DT = total radiation dose to target combined in the term labeled A, the cumulated (rads) activity. These arethe factors to which much of A,,. = cumulated activity in target the ongoingdosimetry research hasbeen di- (pCi * hr) rected. m.,. = mass of targct in grams The cumulated activity in pCi*hours is a A, = cumulated activity in sourcc number representingjust that: the number of ( pCi hr) An,,&,, = absorbed fraction for nonpene- pCi in residence for how many hours. One can, trating radiation for example, plot acurve of activity versus A+(T s) = absorbedfraction in target as a time for an organ as shown in Fig. 7-3. The result of radiation emanating cumulated activity would be the area under the 100 Basics oj radiopharrnucy

IO0

10

1 1 I I I 2 4 6 8 10 12 Time in hours Fig. 7-3.Idealizcd activity-time curvc for radioactive tracer in given organ of body.

~

curve. Very oftenthe material is takenup tofind outthe percentages of thedose con- quickly, as after a bolus injection, and then is tained in the variousorgans. Therefore, ex- removed slowly,following one or more ex- ternal counting, using standards for cornpari- ponential decay curves, as in the example pic- son, is often used. The standards usually cannot tured in Fig. 7-4. The contribution of each of be simplebecause the organs themselves are the exponential segments can be determined as not, so elaborate phantoms may be constructed to its half-time and percentage of the total at for comparison (Fig. 7-5). Blood,urine, and t = 0. In this case as well, the cumulated ac- fecal samples may also be obtained to help tivity is the area under an activity-versus-time quantitate the amount remaining in the body at curve. a particular time. It is usually helpful as well If one is dealing with human data, it is usu- to have in mind a mathematical model of the ally not possible to get samples of the patient kinetics of the radiopharmaceutical in the Radiation dosimetry 101

5

10 '

'"" _"_ """""""""~"""~ T<,? 2 11.8

10 ' I- .- -r I -, 2 4 6 -; 10 12 14 Time in hours

Fig. 7-4. Biexponential decay or clearance curve for radioactivity in organ. organ. Animal studiescan be very helpful in sary to start all over again to determine cumu- the formulation of such models. It must be lated activity for lZsI once the data for I3ll are remembered that although the datafrom the known. It is sufficient to account for the dif- system seem to fit atheoretical model, this ferent physicalhalf-lives. Of course,scrupu- model is not necessarily a true model for the lous care must be taken to be sure the chemical organ. forms are identical. Thecumulated activity has a contribution All elements of a dose calculation can now from the behavior of that element in that chemi- be assembled. The physical datafor the nuclide cal form in the bodyand a contribution from involved are incorporated in the A term, along he physical half-life of the particular isotope with data from reference man in the 4 term, of the element that has been chosen. This can particularly, and in themT term. Data about be usedin many ways to work fromthe be- the behavior of this chemical form is used in A, havior of onc isotopeto another. It is not neces- in A, for the target for nonpenetrating radia- tion, and in A, for the sources for penetrating radiation, along with physical half-life data.

SAMPLE CALCULATION For the sample calculation, !'9mTc sulfur col- loid as a liver scanning agent has bcen chosen. A ccrtain simplicity occurs bccausc the agent can be presumed to go to the liver, spleen, and bone marrow and to remain there for as long as predicted from physical decay calculations. The input data, output data, and decay scheme are given in Fig. 7-6. Our problem is to calculate the dose to the liver from the intravenous in- jection of 3 mCi of IIYtnTcsulfw colloid. The important terms in the equationare those ac- counting for nonpenetrating dose to the liver from theliver, penetrating dose to the liver from the liver, and penetrating dose tothe liver from the splecn. The bone marrow contributes an insignificant amount.

Fig. 7-5. Thyroid phantom, available from Picker COT. Let us consider A, and A, first. The question

INPUT DATA

Technetium 99m Isomeric level OUTPUT DATA decay Me*" ""rnDC"/ Mea" dilinle- anergy \, grallon 1mev1 0.1427 In,) IL) "- n on 0 0021 0 ooou 0 086 0.0017 0 (1036 0 803 0 1405 U.2643 n 0883 11 I196 0 0215 11oioo 0 1377 0,0032 0 0035 0 1401 0.0Oll 0 0003 0 1477 0 11001 0.009Fi 0 1717 11 0025 o no:^ 0 1:wY 0 0000 000111 0 1423 0 0003 n.w1 no184 00017 li11216 I10103 0 0000 llOiO3 0 0206 0 000s n oole 00210 o owI 0 0081 0 0074 o nu00 0 0149 0 0155 o nnoci n 005s 00178 0 0002 n uno7 u 0202 o ooon o 1nc 00019 0 oouo 1 13 o onu4 UOOlO

Fig. 7-6. Decay scheme for DYmTcwith MIRD tables. (FromDillman, L. T.: J. Nucl. Mcd. IO[suppl. 2]:1-32, 1969.)

104 Basics of radiopharmacy on the A term, or the variations from reference ful information per rad of exposure dose. One man. If a dose calculation on a particular pa- index of the ratio is the number of detectable tient is required, some attempt must be made to photons per rad. If two alternative proccdures gather the requisite datain order to approximate are equal in other respects, the one giving the the calculations. The calculations arc made not highest ratio is chosen. as calculations on individual patients, but as a guide in the use of radiopharmaceuticals so that Suggested redngs the risks associated with a given injection for a Kcreiakes, J. G., and Corcy, K. R., editors: Biophysical particular examination can be estimated. With aspects of the medical use of technetiutn-99m, AAPM these dose estimates, one isotope can be com- Monograph No. 1, Cincinnati, Ohio, 1976, American Association of Physicists in Medicine, Committee on pared to another and one tracer to another on Nuclear Medicine. the basis of their radiation dose characteristics. MlRD reports, New York, Society of Nuclear Mdicine, The overall aim is to maximize the ratio of use- Inc. CHAPTER 8 Production of radionuclides

The radioactive materials in use in nuclear irradiatedmaterial. The medicine are almost all man-made.*They must may also be used as a signature of the material be produced from materials wc have at hand or irradiated and hence identify or even quantify can create. It wasnot possible to haveother the material present in the irradiatedsample. than naturally occurring radionuclides until the This is called activation analysis. In discovery of nuclear reactions and the clarifica- the case we areinterested in, the neutron ir- tion of the structure of the atom and the consti- radiation is usedto createradionuclides for tuent parts of the nucleus. Some research had radiopharmaceutical production.The parame- been begun in the 1930s, but the real spurt in ters that control the amount of radioactivity growth came after World War 11, when the data produced are shown in equation 1. collected by the ManhattanProject were re- A()) = cr4,N( I - e -0.CWti'rl ) leased, and the reactor began to be used for (1 1 isotopeproduction. Currently many radionu- t = time of clides are also produced in and linear A = activity produced in disintegrations/second accelerators. u = activation cross section N = number of nuclei of a certain type presented Activation of stable elements to neutron beam CALCULATION OF PRODUCTION RATES 4 = flux of in neutrons/cm'"sec AND REACTOR PRODUCTION T, = half-life of material produced Many of the nuclides in use today are re- N will be affected by the amount of enrich- actor produced (Fig. 8-1). The nuclear reactor ment that has been performed on the target can be viewed as a source of thermal or low- material. energy neutrons. Neutrons are neutral particles N = 6.023 X IOt3 X weight (gram) (2) with a mass of 1 amu. Because they are with- abundance of isotope in question out charge, they cannot be aimed into beams X atomic weight like charged particles. Instead,they are allowed to escape from the reactor elements and irradi- A neutron is added to a stable nucleus in ate materials presented to them through ports reactor production. Hence, the that run down into the reactor core alongside does not change, and the atomic massis in- the moderator tubes. The flux (amount of neu- creased by 1 in the general case. This produces trons available for reactions) is highest at the neutron-richnuclides that usually decay by core of the reactor. emitting a beta or alpha particle. We are in- When thermal neutrons impinge onmany terested only in the beta emitters, whichmay materials, they areabsorbed into the nuclei, also have some gamma rays. Ideally, we use very often creating an unstableradioactive the activated material as a precursor to some nucleus of thesame chemical identity asthe gamma emitting material so that we do not have to inject the beta emitter into the patient;9YmTc *An exception is 40K. is a nuclide produced in such a fashion. "Mo 105 106 Basics of rudiopharmacy

Water in pool

Fig. 8-1. Swimmingpool type of nuclear reactor. Solid rods are uscd to control rate of neutron multiplication. Hollow rod is for inscrtion of samplc into core for neutron irradiation.

forms 23.78% of natural molybdenum. Molyb- have high cross sections should be eliminated denum irradiated for 1 week at a flux of 2 X if possible. For example,there are traces of IOl4 n/cm2-sec yields 1 Ci of 99M0. in natural molybdenumtargets that lead to radioactive tungsten in the product. It SEPARATION TECHNIQUES is also possible to allow undesirable short-lived A,(t) = rri4,NI(1 - e-"-'io3t'Ttl) (3) products to decay away before using the prod- uct. This is another way to improve radionu- This equation (which is very similar to the clidic purity. preceding one, except it has lots of i's init) Oncethe target has been irradiated andis means that the same equation holds for every ready forprocessing, it is, of course, very species in the sample that has been irradiated. radioactive even afterthe ultrashort-lived nu- Therefore, if you wish to have a pure product,it clides have decayed away. The targetis usually helps to enrich the target in the material of processed remotely by robot hands either be- primary interest. Onecan obtain up to a 99% en- hind leadglass or under TV control, so thc richment of 98Mo.High enrichment is betterfor operator is not irradiated. The target holder is irradiation. Most important, the impurities that removed and the chemicalseparation of the Production of rudionuclides 107 target from its impurities performed so that the isotopes. When NaIis used as target material radionuclide isprepared in the desired chemical forthe irradiation, both isotopes cxist as the fornl. Precipitations are often uscd to separate same chemical speciesand are inseparable. the dcsiredradionuclide from the impurities. Thus, the irradiation of ethyliodide canbe Conversionto the gaseous state may beem- used to producea higher specificactivity of ployed to effect a separation. Extraction of the the product radioiodine. product may involve chromatographyor extrac- tion in a liquid-liquid system. Sometimes, dis- EXAMPLE: 18F FROM LiCO, tillation can bc used to separate the product We have previously referred to rnolybdcnum from the impurities. Molybdenum targets are 99 production as an example of radioisotope dissolved in ammonium hydroxide to form the production. It is typical of productions where ion that is adsorbed on the column the product is identical chemically to the target. from which we subsequently elute ""mTc. Fluorine 18 is produced by a more complex set of reactions in the reactor that illustratethe SPECIFIC ACTIVITY possibilities for such processes. One starts with We have not suggested that the neutron ac- a target of lithium7 carbonate, and the reac- tivation process is ablc to turn all the atoms of tions are: target material intoproducts. The flux ofthe 'Li (n, a) "H nr 'Li + n 3 "H + 4He reactor and the will de- and termine that.Therefore, when the product is "0 (t, n) or I6O + IsF i-n obtained, and when thcre has been no change "F + 3H in chemical identity, it will not be possible to When '*F is produced by this method, the scparate the unreacted target nuclei from the tritium (3H) also produced must be rigorously radioactive product nuclei by chemical means. removed, since it has a long half-life and there- The unchanged target material is called currier fore can be responsible for significant patient because it carries the trace quantities of radio- radiation exposure. The material does not have active nuclei through the chemical separation to meet rigorous specifications otherwise, since steps. Specific activity is the term describing it can be administered by mouth for bone scan- the number of millicuries produced compared ning. to thc number of milligrams of the element present. A higher neutron flux for the irradia- Linear accelerator and cyclotron tionwill produce a higher specific activity in production the product. Another way to make radioactive nuclei is to TheSzilard-Chalmers reaction can somc- bombard stable nuclei with chargedparticles, timesbe used to increasespecific activity. such as electrons, protrons, and dcuterons.This When a nucleusaccepts a neutron,a prompt may be done by accelerating ions along a linear gamma ray isemitted, releasing the excess path using an electric current for acceleration nuclear energy. Thc atom's nucleus recoilswith and voltage for control. The machine for doing the release of this gamma ray. The recoil en- this is a linear accelerator (Fig. 8-2). Alternate- ergy can effect chemical changes such that the ly, a beam of chargedparticles may be pro- radioactivated nuclei are converted into a dif- duced by accelerating ions around in a widen- ferent chemicalspecies. This alteration of ing circle using a magnetic field for control and chemical state allows us to separate the radio- electric current for acceleration. The machine active isotope from the nonradioactive isotope. for doing this is a cyclotron (Fig. 8-3). At the An example of this is the production of IZsT- outside of the circle the particlesare sent by the thermal neutron irradiation of ethyl io- against a target, The current and the magnetic dide. The prompt gamma recoil that occurs as fields determinethe focus and the energy to the lZ7I is converted to lzeI ruptures the carbon- which the particles will be accelerated. It is iodine bond and permits the subsequent use of necessary to accelerate charged particles topro- simple chemical techniques to separate the two vide them with sufficient energy to overcome 108 Basics of radiopharmacy

Fig. 8-2. Aerial view of LAMPF, accelerator at Los Alamos, New Mexico.

the barrier surrounding the nucleus. This barrier When the velocity approaches that of , repels the particles that do not have the energy the mass rises. This can be compensated by required forpenetration, The cyclotronequa- field changes or by the shaping of the magnets. tion is: Usually, it is the positively charged particles r2H"C2 E=- that are accelerated. 2M (4) greaterAgain, product specificity can be achieved by purifying the target materials be- where E = energy produced fore irradiation and by using the same types of r = circle radius H = magnetic field strength product preparations asin reactor production. e = electronic charge Thereare many morealternative routes for M = rest mass of particle achieving the same product.For instance, when Production of radionuclides 109

Cloud Accelerating Magnet Target station Target rnotor-generator location I n

Magnet rectifiers Cockcroft Walton desk I 1- 11 \ 'Outline of Shielding Magnet Linear building wall accelerator floor area

Fig. 8-3. Schematic of cyclotron.

Table 8-1. Positron-emitting tracers of C, N, and 0

Isotope Tva Radiation Productlon Compounds

I IC 20.4 rnin P+ log (d, n) llC "CO, I1CO2,fatty acids, glucose, "CN- 13N 9.96 min P' 12C (d, n) 13N 13NNH3, CI3N-, glutamic acid 1 so 2.05 min P' 14N (d, n) lSO OW, C'50, HZi5O IRO(p, pn) lSO IT(a, n) "0

a enters the nucleus at one energy, one startingmaterial. This means the product is set of products emerges. When another energy carrier free, which may have advantages when is used, another set of products emerges. In all itsuse is considered.Competing reactions, cases the chemical identity of the target and however, may produce a whole battery of ra- product will not be the same, so the product dioactive products, so energy and target selec- element will be a differentelement than the tion are important. The products will in general 1 IO Basics of radiopharmacy

WOcarboxyhemoglobin

Fig. 8-4. Positron tomograms of head with "CO as radiopharmaceutical. (Courtesy Washington University School of Medicine, St. Louis, Mo.)

20.1 h

23 rnev

(We.3n) 42 mev

Fig. 8-5. lnnI can be produced from many different combinations of nuclear reactions and radio- active dccay schemes. Production of rurlionuclidps 11 1

~

Cyclotron-produced nuclides

is ptoduccd from 'ioNi(p,a)"Co Cor long-lived sources of energy close to 99m'rcand for thc Schilling tcst. %a is produced by one of several reactions starting with ""Zn, "7211, '%n, or 65Uu and is used for tumor and abscess localization and appears to hc carried nn iron-binding sites. 'l'ln is produccd from '09A~(cu,2n)"'In,which is used as "'In chloride and in bone marrow imag- ingand DTPA thathas hcen used for CSF studics. LO'Tl is producedfrom 20"Tl(p,3n)2"1Pha '"'TI for an analog traccr of potassium,used pri- marily for ilnaging thc normal myocardium.

have an excess of over neutrons in their Table 8-2. Comparison of reactor and nuclei and will tend to decay by electron cap- accelerator production of' isotopes ture and/or positron decay. Production method "C, 13N, Reactor Accelerator Table 8-1 shows the most widely applicable positron emitters. Thcir half-livcs are short,and Bombarding product Thermal n p, d, t, cy Ncutron rich Proton rich the positron radiation is not easy to collimate. Kind of product Kind of decay path If one has a positron camera near a cyclotron, p- p', EC Comment Carrier pres- Other carricr these are exciting nuclides to work with. The ent free short half-lives allow repeatcd or complemen- tary studies,such as imagingthe blood flow with 'TO and theheart muscle with '"NHa. energy emissions (27 kev, 35 kev); these emis- Thcreare several positron-computed axial to- sions do not degrade the image, but the long mography instruments in use that can visualize half-life means a highcr radiation dose when thcse nuclidcs in threc dimensions(Fig. 8-4). it is administered as a contaminant of lz3I.

HALOGENS (1231 AS AN EXAMPLE) OTHER CYCLOTRON-PRODUCED NUCLIDES Iodine 123, with a half-life of 13.3 hours The most widely used of the cyclotron-pro- and a principal gamma-ray energy of 159 kev, duced nuclides are 57Co,"Ga, "'In, and surTI. is a very promisingnuclide. There are many Production and use of these as diagnostic trac- pathways to it, depending on the starting ma- ers are summarized above. terials and thc accelerator beam. Fig, 8-5 shows Table 8-2 compares the two major methods the possibilities. for preparing radionuclides. The two general methods are (1) direct re- action or (2)preparing r23Xe,then allowing the Fission production lz3Xe to decay into lz"I. This second method Thehigh-atomic-weight nuclei of atomic avoids the lZ4I impurity, butnot the lZG1im- number 92 and above arc capable of fission or purity. Thc directmethods usually yield a prod- breaking apart,giving off neutrons and two uctwith lp4I contamination. lZ4I is a problem lower-atomic-numberproducts. 23sU is the because it increases in relativeconcentration most common of these fissioning nuclei. The and limits the shelf-life to 4 days. Another products can be collected and separated by problem with la41 contamination is its positron chemical means. "Mo, for example, can be ex- annihilation radiation and its other high-energy tracted from fission products in curie quantities gammas that cannot be collimated out very with high specificactivity and used to make well. These radiations contribute to image fuzz- 99mTcgenerators with high specificactivity. iness. 1251is long lived (60 days) with low- 13'1 is also a fission product, as are lasXe and 112 Basics uf radiophurmacy

"H. These last three are unavoidable fission by- International Atomic Energy Agency: Radioisotope produc- productsand, because they are volatile, can tion and quality control, IAEA Technical Report Series present reactor radiation safety problems. No. 128, Vienna, 1971. Koch, R. C.: Activation analysis handbook, New York, 1960, Academic Press, Inc. Suggested readings National Bureau of Standards: A manual of radioactivity Friedlander, G., and Kennedy, J. W.: Nuclearand radio- procedures, Handbook 80, U.S. Department of Com- chemistry, ed. 2, New York, 1964, John Wiley & Sons, merce, Washington, D.C., 1961, U.S. Government Inc. Printing Office. CHAPTER 9 Generator systems

General characteristics the parent; usually, this occursbecause the The study of parent radionuclides and their daughterdiffers by I in atomicnumber from relationships to their daughters is as old as the the parent and is therefore a different element. knowledge of radioactivity. 222 gas The differences in chemical properties are used separatcs from its parent, radium 226, becausc to effecta chcmical separation between the it is a gas (Fig. 9- I). The 22sRaprovides a sim- two. Usually, the separation occurs chromato- plc source of 222Rn;this system is still in use graphically. Thc parcnt is absorbed on a chro- today. The National Bureau of Standards sells matograph column and remains there while the calibrated quantities of 222BRaC12,which can be daughter is eluted with a suitable eluant. The made up in an airtight system to generatezzzRn vocabulary used is that of chromatography, in as a standard foralpha counting. This illus- which thc original separations and observations trates the use of a generator, which is a parent- were made on moving color bands. (For a prac- daughtercombination designed to yieldthe tical example of chromatography, put spots of daughter for some purposethat is usually sepa- pen ink on a napkin or tissue. Dip a corner of rate from the parent. The reason for our em- the paper into water and allow the water to be ploying such a system, that is, for having the picked up and flow past the ink spots. Observe parcnt nuclide in our laboratories, is that thc the scparation of the colors. This is chromatog- important daughternuclides have short half- raphy. ) lives compared to the travel time from the man- In addition to chemical properties that permit ufacturer to us. To be useful, the parent’s half- easy separation of the parent and daughter ra- life must be long, compared to the travel time. dionuclides, the chemistry of the daughter nu- In the modern world there are many differences clide should also permit its rapid formulation in transportation and in the timeit takes to travel into radiopharmaceuticals that can beused in a few thousand miles. Thus, it is necessary to clinical nuclear medicine. Usually, this means use parent nuclides with half-lives of several that reagent kits in aclosed preparation pro- months in some parts of theworld, whereas cedure can be developed to compound the parent nuclides with half-lives of less than 3 radiopharmaceutical on shortorder. The re- days are satisfactory for other regions. In some search that goesinto creating these kits may regions it is possible to ship daughter nuclides take severalyears. The pharmaceuticals often directly, even whenthe daughter’s half-life is go through many phases of development, be- only 6 hours.Thus, there are many areas of coming simpler to use at each reformulation. the United States wherc 99mTccan be separated Thegenerator system permitsa constant by a radiopharmacy and shipped directly to the supply of the daughter nuclide. Propertiesof an user. ideal generator are listed on p. 114. The use of Daughter nuclides from generators must ful- kits with generator eluants permits the formula- fill essential characteristics to make them suit- tion of several compounds, allowing us to ad- able for biomedical applications. The daughter just to meet day-by-day variations in demand. must have differentchemical properties from The demand dependson the patient examination 113 114 Basics of radiophurmucy

Ideal generator system I. Sterile and pyrogen-free eluate 2. Saline eluants 3. No violent chemical conditions 4. Room tcmpcraturc storage in air 5. Idcal gamma-emitting nuclide daughter, usu- ally for cxaminationstaking a day or less 6. No parentpresent in eluate (no break- through); thus, good separation chemistry 7. Parent of half-life short enough so daughter rcgrowth is rapid but long enough for practi- cality 8. Daughter chemistry permitting kits Cor prep- aration of a number of radiophanrlaceuticals 9. Long-livcd or stable“granddaughter” nu- clidc so that no radiation dose is conferredby b+-N, subsequent generations of nuclides Fig. 9-1. Radon 222 generator. 10. Shiclding of parent-daughtercombination not too difficult to effect I It Separation not rcquiring a great deal of hu- manintervention, keeping radiopharmacist radiation dose to a minimum 12. Gcncrators easily recharged Glass beads

Glass wool filter load. Thus, it is more economical to use gcn- erators and kits than it is to stock a sufficient Parent on supply to meethigh demand periods. In this porous latter situation, the quantity ofeach material absorbent that radioactively decays away to nothing with- material out ever having been used is excessivc. Frit Construction Generators have been made in several ways, depending on important chemical differences between the parent and daughter nuclides. The Radioactive chromatograph column has come to be the most II element widely used system because of its ease of op- Fig. 9-2. Chromatograph-column type of generator, cration. It can be remotelycontrolled with such as is used for separation of 99mrk from S9M~). excellent reproducibility. Systems for shielding, packaging, and transport of column generators are currently well worked out. kccp the column material in place during ship- Fig. 9-2 shows a diagram of a typical column ping; the column material itself, with the parent generator. Thc model column is a glass tube, nuclide adsorbed on it in the propcr chemical closed at either end with stoppers. The glass form; a piece of fritted glass for the liquid to tube contains, inthe order the liquid flows exit through but which retains the column ma- through, a disk with holes init or a piece of terial; and very often, a filter to remove bacteria fritted glass, often backed up by glass wool to and any other debris before the outflow. Elution spread out the entering liquid evenly and to is accomplished by the cluant flowing through Generator systems 1 15

Radioactive

of solvent

I

I

Fig. 9-3.Liquid-liquid extractor type of generator. This typc of generator can be adaptcd for separa- tion of 99ml'~ from HHMowith rriethylcthyl ketone as cxtracring liquor.

the column. The source of eluant may be in- in minute volumes of saline. Other systems are dividual unit-elution bottles external to the gen- based on distillation, sublimation, or gaseous erator or a bottle of eluant used for multiple diffusion to separatethe daughter from the clutions over a period of timc, or it may be in- parent nuclide. ternally packed within the generator shielding. The generators are constructed in general to A vial is often evacuated to pull a given volume be stcrile and pyrogen free. Because they are of cluant through the column. The whole elu- eluted many times throughoutthcir life, thcy tion process is usually enclosed with a system must be treated carefully to maintain this initial of tubing and needles to prevent contamination state. The elution vials and eluant solution are by microorganisms. Packing materials and lead usually supplied by thc manufacturer, but if shielding around the generator column keep it thcy are not, care should be taken in their use. from being damaged during shipping and prc- The YlrmT~generator is usually eluted with bac- vent radiation to the surroundings. teriostat-free saline because the oxidant quali- Othersystems have been employed that ties of the bacteriostat intcrfere with radio- do not use chromatograph columns. Liquid-liq- chemical reactions. Sterile, disposable supplies uid extraction can be used to effect the parent- are used with generators. Sterilization can often daughter separation (Fig. 9-3). In general, this be used in cases of suspected septic technique; requires more manipulation than the solid gen- however, this will not affect pyrogen contami- erator,although itcan be automated.Liquid- nation. Thus, extreme care must be exercised liquid extraction may pcrmit very high concen- whenever the generator is in use. tration of the daughter when the solvent contain- Somegenerators can be reloaded.For ex- ing the extracted daughter nuclide is evaporatcd ample, rechargeableggMo/lromTc generator sys- to drynessand then the radioactivity isdissolved tems are usually usedwhen the demand for 116 Basics of radiopharmacy

Column description

Glass column

Tomkins septul nJ- uPump 1" Fig. 9-4. Rechargeable generator suitable for repeated loading with "Mo.

33mT~begins to exceed a curie per day. Fig. 9-4 shows one such generator system.

Operation A,O = activity of daughter left in generator after last elution The relationship of parent-daughter radioac- A, = decay constant of parent tivity in a generator is calculated with the decay Ad = decay constant of daughter constants for the two species, as shown here in A,O = activity of parent after last elution equation I: t = time of last elution

Nd = N;(e-bl - e-Adt) + N$~-M (1) In addition, if the daughter nuclide is only N,O and N{ denotethe number of parent (p) one of several products of the parent nuclide, atoms and number of daughter (d) atoms at the the fraction of parent decayingthrough daughter time of the last elution; t is the elapsed time of interest must be taken into account. Equation since the last elution. 4 is used for this situation: If we wish to express the results as radioac- tivity, equation 3 is used; it follows from equa- tion 2, the definition of radioactivity. A0 A, = XdNUand A, = A,N, or N: = -x (2) where fpd = fraction of parent that dccays to daugh- A, ter in question Generator systems 1 17

Often it is more uscful to exprcss these equa- Ad(t) = 67 x 0.92 x A; (e-lLl;t13t/67 - (9) tions in terms of half-livesrather than decay 67 - 5 e-~~.~;~~3t16) + AU~-O.IMt/a constants.The two constantsare related as (1 Shown in equation 5. Equation 6 is identical to where t is expressed in hours equation 4 except for the substitution of con- stants. Equation 9 allows the calculation of the amount of ggm Tc radioactivity at any time after 0.693 A=- (5) elution. T; Ai(j) = Ai! 0.695 titi7 (1Q) A, = & f All(C-ll.H!j3 t/Ty - ad I' (6) T" - T, Equation 10 allows the calculation of the e-lJ.f+!J31/Tq + A$e-lLl<$j3!lTd amount of YYMoremaining since the time of the lust elution. As the time since the last elution where T, = half-life of parent grows long, the daughter's half-time becomes Td = half-life of daughtcr insignificant to thc calculation. Thus, equation Several general casesdescribe the various 9 simplifies to equation 11 or 12. relationshipspossible between parent and TP f,,, A: e-O.tiWi t/Tp daughter radioactivities based on their relative Adf) = (11) half-lives. Secular equilibrium is the case where the parent half-life is many times greater than where A,, = AO, e--11.1s!J3liTy describes parent dccay , the daughter: TUBT,. Hence, after an elution so that the amount of parent radioactivity shows little T change while the daughter radioactivity grows AJt) = A fp, A, (12) TI, - T, in. Radium 226 (T = 1,620 years) and radon 222 (Td = 3.8 days) are typical of such a sys- There isno equilibrium if the daughter's half- tem. If the system is allowed to rest for many life is longer than that of the parent's. days (more thanten times the daughter half- If the "granddaughter," or the product of life), the decay terms for the daughter radioac- daughter decay, is not stable, this set of equa- tivity of the equation become negligible, and tions governs that, too. the equation simplifies to equation 7 or 8: WMo/WrnTcgenerator A, = f,,dAje-0.G%3tiTp (7) DESCRIPTION or if f,,d = 1 (and e-".Swd TI> r= 1) The arithmetic of the operation of a "Mo/ ggmTc generatorhas been described in equation A, = AP, (8) 9. This generator system is one of the oldest The radioactivity of radon 222 eluted from a in use in nuclear medicine and is still the best fully rested (regenerated) generator is equal to because of the nearly ideal properties of ggmTc. the radioactivity of radium 226 in the genera- It does have a radioactive third-generation de- tor. cay product, II9Tc, but this has a long half-life Trunsient equilibrium is the casc wherethe (Ta = 2 X lo5 ycars).This means millicurie half-life of the parent nuclide is greaterthan the quantities of ggmT~create micromicrocurie daughter, but not bymany times. The daugh- amounts of the radioactivegranddaughter of ter's decay termsbecome small compared to "Mu, that is, "Tc. that of the parent but enter into the calculation The most widely used s"mTc generator con- at less than fouror five daughterhalf-lives. tains at its heart a glass or plastic cylinderfilled Y9m Tc from the 90M~/YYmT~generator is an ex- with alumina (A1203),which is acommon chro- ample of such a system. "Mo has a half-time matograph column-packing material.The of 67 hours, the fraction decaying to ggmTcis ggMo molybdate produced from the neutron- 0.92, and 99mTchas a half-life of 6 hours. irradiated MooJ target is solubilized and then Elution number

\ ,dConcentration

Elution number Fig. 9-5. A, Fractionalelution histogram for 600 mCi NewEngland Nuclear 99mTc generator (fission ““Mo). Gcnerator was eluted repeatcdly with 1 rnl aliquots of saline; radioactivity of each millilitcr was measurcd. Data werc normalized using total activity in 20 ml as 100%. B, Cumulative totalradioactivity: running sums for elutions reported in histogramare plotted. Concentration: values for running cumulative total radioactivity are divided by cumulative volume. Generator systems 119 put onto the column atpH 3. The column is Methylethyl ketone (MEK) is added; MEK is thoroughly washed (with 0.9% saline) to re- not miscible with water. It forms a layer over move unbound radioactivity and then packaged the water. Asthc two liquidsare shaken to- insidethe generator. Aseptic techniquesare gether, the !'lrmTc0; dissolves in the MEK, re- used. 'To assure stcrility, the generator is steril- nloving it from the aqueous solution of "Mo. ized after preparation, Thc two liquids are allowed to clear and sepa- Elution is carried out by attaching a sourceof rate.The MEK is cvaporated. The residual 0.9% saline(without bacteriostat) solution, Ysn'Tcis reconstituted with 0.9% saline to any which may be, as just explained, in individual desired concentration. This system, which can vials, in an external bottle, or packed inside the be used to make lrBnlTcwith aconstant con- shielding and permanently connected by tubing centration every day, can be shielded,auto- to the column. An evacuated vial of 5 to 30 ml mated, and rnadc to perform in a very repro- volume is attached to the exit side. The saline ducible fashion. flows from the saline sourcethrough the column Another method of separation involves sub- and then into the evacuated vial.The volume of liming Tc,O, away from molybdenum that has eluant is such that it exceeds the void volume been deposited on fritted glass. The system can ofthe column by several times. Fission "Mo he scaled up to multicurie sizes but has the dis- has a vcry high specific activity and can be put advantages of high temperatures and high initial onto small columns. The void volume is small; costs.The impurities are in extremely low the elution volume is therefore small so that the quantity when this mcthod is used. product has a high concentration of lronlTc. Re- actor "Mo contains carrier Y8Moand therefore EVALUATION OF ELUATE takes a larger volume column to absorb all the The technetium 991n comesfrom the gen- molybdate. This limits the concentration of the eratoras lrlrmTc0;, a highly solubleproduct. 99mTceluate. The graph in Fig. 9-5 of radioac- There is, of course, some carrier "TcO; pres- tivity-eluted-versus-elution volume for a typical ent as well because all !'lrmTc decay leads to column shows that a large part of the activity 9ST~,as docs the other 8% of "Mo that does comes through in the first fewmilliliters of not decay through !)BmTcmetastable state. Thus, eluant. Thus, in order to achieve higher concen- every molybdenum atom that has decayed since tration in the product, one may fractionally the last elution of the generatoris converted into elute the column by stepwise flushing itwith either 99mTcor "Tc. small elution volumes. For a generator whose The 0.9% saline solution used to elute the normal elution volume is 20 to 30 ml, fractiona- generator should be essentiallyunchangcd from tion into 5 ml aliquots is satisfactory and is when it went into the generator.The added especially helpful when a part of the eluate is OgrnTcamounts to all of about 2 X lop8 grams needed for tests requiring high concentrations of YSmTcOpand perhaps 5 X IOp8 grams of of radioactivity. Y9Tc0; for every 100 mCi of Y9Mothat was An examination of the arithmetic of the 09Mo/ present 24 hours previously. The saline may be 99mTc parent-daughter rclationship shows that chemically and radionuclidically contaminated the daughtcrhas grown in significantly afterone in several ways. Itis possible for some "HMO daughter half-life. Thus, 6 hours after a previ- (from reactor 09Mo preparation) and alumina to ouselution, 50% of the maximum amount appear in the eluate. It is also possible forO9Mo of 99mTccan be obtained by another elution. to appear, along with products of irradiation of Thiseffect, combined with fractional elution, molybdenum contaminants, such as lo3Ru, makes it possible to achieve an almostcon- I3'Te, 13'1, and 13yI (a132Te decay product). stant supply of 99mT~of the required conccn- Under usual circumstances only the BgMocon- tration. taminant is large enough to be detected by the Other methods forseparating 991nT~from tests performed routinely on generator eluate. A "Mo have been devised. The SlrMo as molyb- solid-state, gamma-ray detector such as Ge(Li) date is kept in a stock solution of 5N NaOH. can detect these and other gamma radioactive 120 Basics of rudioppharmur.y impurities in small amounts. If the elution prod- species of technetium that cannot beeluted. uctsare saved and the 991nTcallowed to de- Keeping the generator dryafter each elution cay, a studymay bemade of theimpurities helps minimize this effect. by a Ge(Li) detector with multichannel spec- Thcrc are several causes for decreased yield tral analysis (Fig. 9-6). la4Cs, I3'I, 239Np, in generators: ln3Ru,BGRb, GnCo, and Iz4Sb are themajor im- 1. Self-radiolysis leading to reduced 98mT~ purities. If generatorcolumns are saved for species many months and the 09Mo allowed to decay 2. 99n1TcO; cannot get to the surface to be away, the impurities in the molybdenum can be eluted studied; 134Cs,124Sb, 95Zr, and daughters 05Zn 3. Channeling of eluant in the column so and "Co have been found. The MEK cxtrac- thatnot all the columnis exposed to tion method produces a cleaner eluate, as does eluant the sublimation mcthod. 4. Other column factors The generator may be subject to self-radioly- Since generators differ slightly in the details sis by its contents. This problem is particularly of construction and maintenance, we recom- acute in fission SSMogenerators. The result is mend that you read the package insert of your that all contents are subject to attack by free generator and use it according to the manufac- radicals, especially if there is liquid water turer's instructions. Generators are not particu- present in the system.The free radicals may larly delicate, but they can be ruined by im- cause alumina breakdown or produce reduced proper use.

> Y lD m t. t.

105 i > Y I

- 104 ar C c m r u L 103 w c c z 0 0 102

10'

100 E( kev)

Fig. 9-6. Gamma-ray spectra of !'"mTc eluate made aftcr tmmTcradioactivity has decayed so that long-lived trace-radioactivc impurities can be deterrnincd. (From Colombetti, L. G.: Performance of YtlmTcgenerating systcms, In Rhodes, B. A,, editor: Quality control in nuclear medicine: radio- pharmaceutical~, instrumentation, and in vitroassays, St. Louis, 1977, The C. V. Mosby Co.) Generutor systems 121

I~3Sn/~r3mlngenerator tectcd in the presence of the 113mIneluate. To DESCRIPTION test for '13Sn breakthrough, the leftover eluate lr:lmIn(Ti = 1.6 hours,gamma-ray energy is saved for 24 hours. The next day, any llamIn = 393 kev) can be made from a tin 113hdi- present in the 24-hour-old eluate must have urn 113m gencrator system.The l13Sn has a come from breakthrough l13Sn in the vial, since half-life of I IS days, which means it nced only all the original '*31nshould have decayed away be replaced every 6 months, Kit recipes are by then. Chemical impurities can include zir- available for the preparation of various radio- conium oxide and stable tin, which can be pharmaceuticals, so that 113mTn can be almost tested for. Radionuclidic impurities may in- as versatile as L)9mTc.Kits for the preparation clude tin and antimony nuclides that have long of UBrr'Tcradiopharmaceuticals may be adapted half-lives. for usewith indium. The energy is perhaps a bit high for the Anger camera, but it is very sat- Generators for ultrashort-lived nuclides isfactory for the rectilinear scanner. USES Generators whose products have half-lives EVALUATION OF ELUATE in theseconds and minutes rangehave been The column material is zirconium oxide. used for examinations taking place rapidly or Reactor-produced r'sSn is applied to the col- as constant infusions. One canimagine the gen- umn in HCI solution in its most highly oxidized erator connected between an IV bottle and the (stannic, +4) state. The column is eluted with patient's arm for a constant infusion (Fig. 9-7). 0.05 N HCI. In 24 hours this column can be At least one system has a gaseous product that eluted for up to 100 nlCi of '131n1nfor each 100 can be usedin rebreathing fashion.The ad- mCi of I':jSn. The cannot be easily de- vantage of the ultrashort half-life is the large

Fig. 9-7. 82 gencrator that dclivers radioactive tracerdirectly into an IV catheter. (From Budinger. T. F., Yano, Y., and Hoop, B.: J. Nucl. Med. 16:429-431, 1975; courtesyDonncr Laboratory, Berkeley, Calif.) 122 Basics qf radiopharmac*y

The 81Rb/HI't1Kr generator has a short-lived (4.7 hours) parent and a very short-lived daugh- ter, Kr (Ti = 13 seconds with a I90 kev gamma ray). The short physical half-life means that thc radiation dose is low, so large quanti- ties can be used for ventilation studies in place of 133Xe.This material is currently in use in several institutions. s'Rb is cyclotron produccd from sodiumbromide that is dissolved in a water solution.Air is bubbled through to re- move the 81rrlKr. The H2Sr/R2RRhgenerator is currently being tested inseveral institutions. The parent "'Sr has a half-life of 25 days, and the daughter H2Rbhas a half-life of 75 seconds. The MSRb is R positron cnittcr being tested as a myocardial imaging agent . The accelerator-produced #'Sr is adsorbed on an ion-exchange column and eluted with con- centrated sodium chloride solution. The quality control procedures are conducted after the8'Rb has decayed away, so high standards must be adhcred to in storing and in eluting the columns. Several decay schcmcs that are the basis of generators of importance in radiophannacy are listed on the left.

Suggested readlngs Bruccr, M.: A herd of radioactive cows: there are I18 po- tentially useful low systems. Vignettes in Nuclear mcdi- amount of radioactivity that can be used. This cine, No. 3, St. Louis, 1966, MallinckrodtChernical leads to very satisfactory count rates and per- Works. mits rapid sequential studies. Colombetti, L. G.: Perfimnance of RRrr'Tcgenerating sys- tems. In Rhodes, B. A,,editor: Quality control in nuclear EXAMPLES: 137Cs/137mBa,81Rb/81mKr, and medicine:radiopharmaceuticals, instrurncntation, and a2Sr/82Rb in vitro assays, St. Louis, 1977, The C. V. Mosby Co. Evans, R. D.: The atomicnucleus, New York, 1955, Thc 30 ~ear-l~~W2.6 rnin~te-~~'~Basys- McGraw-Hill Book Co. tem is interesting. For most purposes in nuclear Radiopharmaceuticalsfrom generator-produced radionu- medicine this combination is kcpt togcther and clides, proceedings of a panel, Vienna, May 11-15, used as a standard source of 662 kevgarnma 1970, International Atomic Energy Ggency. Radiopharmaceuticals and labeled compounds, proceedings rays for instrument calibration.The 662 kcv of a syrnposium, Copenhagen, March 26-30, 1973, gamma ray actually belongs to the I:j7"'Ba. The Vienna, 1973, International Atomic Energy Agency. scparation can be accomplished byflowing Lamson, M., 111, Hotte, C. E., and Ice, R. D.: Practical 0.IN HCl through a column of resin-asbestos, generatorkinetics, Nucl. Med. Tech. 4:21-27, 1976. followed by an ar~ti-'~~Cscartridge of ammoni- Richards, P.: Thc tcchnetiurn-99m generator. In Andrews, G. A., Knisely, R. M., and Wagner, H. N., Jr., editors: um phosphomolybdatc. A commercial genera- Radioactive pharmaceuticals, CONF-65 I I I 1 National tor of this type is availablc, but not for human TechnicalInformation Service, Springfield, Va., 1966, use. U.S. Departmen[ of Commerce. CHAPTER 10 Production of radiochemicals

Basic concepts Radioiodination The subject of production of radiochemicals There arc 24 radioactive ; is much larger than nuclear medicine because this is close to the largest number for any ele- the labeled compounds arc widely created and mcnt. They are evenly spread on either side of used in chemical,biologic, biomedical, and the one stable isotope of iodine, lz7I. Of these, biochemical research as well as inthe clinical r2aI(13.3 hours, 159 kev), la5T (60 days, 28, pathology laboratory. Thus, research radiophar- 35 kev), and I3'I (8 days, 364 kev) are in com- nlacists keep an eye on developments in many mon use, while lr21 (2.3 hours, 760 kev) was fields in order to take advantage of the findings used more in the past; 1241(4.2 days, p+) has in these fields to improve nuclcar medicine. possible uses. Most labeled compounds arc organic (there lodine is a halogen. It exists in the elemental are more organic compounds to start with),and form as a -purple, shiny, nonmetallic solid most of the currently available radiolabels are that sublimes easily and is not very soluble in 14C and "H,with a peppering of 32P- and 35S- water. All nonelemental forms of iodine can be labeled cotnpounds.These are all beta emit- returned to I? by heat and light. Since elemental ters. These tracers are used primarily in tracer radioiodine will evaporatefrom the liquid studies that do not involve human subjects. The phase, iodinations can create a radiation safety analysisfor the radioactivity is accomplished problem becausc of airbornecontamination. with liquidscintillation counting techniques. The thyroid's great affinity for iodine will lead Liquid scintillation counting has evolved to the to a concentration of the radioiodine contami- point that it is handy for almost any application. nants. Thus, iodine should be handled in radio- Thepractice of nuclear medicine primarily isotope hoods to prevent personnelexposure requires gamma-emitting nuclidcs, and, as we during radioiodination reactions. have seen in Chapter 4, we are therefore some- Several methods are in use for the iodination what limited to elements 20 through 83. Many of largeorganic materials. A common thread of thesc elements are metals, so the labeling running through the discussion of allthese techniques in use in nuclcar medicine are often methods is the balanceof the seventy of the re- somewhat different from those used for other action conditions against the required specific applications. We shall concentrate here on the activity of the radioiodinated product. To get methods and elements that are most useful for the highest radiochemical yields, largeamounts nuclear medicine studics. These will be tagging of the reactants can be used together with a re- with iodine, technetium and other metals, and ductant that will completely reduce all the io- syntheses for thc incorporation of the positron dide to iodine. However, severe reaction con- emitters: "C, 13N, and I5O. We shall make ditions can damage the molecule that is to be la- little mention of nuclides used in their simple beled or can lead to side reactions producing ionic forms, such as 22Nai-,.IzKf, and j'Cr0' 4, unwanted radiochemical impurities such as because these forms are stable and do not re- dimerized proteins. Severe conditions can also quire synthetic methods. lead to uncertainty as to the position and num- 123 ber of iodinesper labeled molecule. On the product may be damagcd, even if chloramine other hand, low specific activity often follows T concentrations are limited carefully and es- the use of mild conditions unless special tcch- pecially whcn the reaction time is prolonged. niques arc employed and very high-spccific ac- Several methods require reaction times of less tivity iodineis used. For most applicationsa than a minute (Fig. 10-2). There is little con- high specific activity is a requirement that must trol over thelevel of substitution per labeled be met for the material to be useful. species. One of the most useful methods for labeling Excitation, or recoil,labeling can be per- proteins is an enzymatic method using lacto- formed under certain circumstances. When thc peroxidase to catalyze the oxidation of iodine parent of one of the isotopes of iodine decaysto by H,Oz. The materials are mixed and flowed iodine, thc newly created nuclide, because of through a chromatography column (Fig. 10-1). the recoil energy, is aspecies that is quite The resulting iodinated product has the radio- chemically reactive. As such, it will form stable iodine attached to the tyrosinc of the protein. chemical bonds with many types of molecules. Radiolabeled proteins of high specific activity Forexample, Iz3I produced by the decay of are created for radioimmunoassay; lZ5Iis usu- lZaXecan he usedto label proteins and other ally the isotope of choicefor these radio- molecules directly. When Iz3Xe decays to 12:11 iodinations. in thepresence of Clz, IC1 isproduced. The The chlorarninc T (N-chloro-p-toluene sul- IC1 has high specific activity and is an excellcnt fonamide) method oxidizesiodide into reac- reagent for radioiodinations (Fig. 10-3). If re- tive species under somewhat severe conditions. coil labeling is used with larger species, there All of thc radioactiveiodine is incorporated, may be problems of damage and low spccific producing a high-specific activity product; the activity of the product.

Hz02 -, Protein

Solid-phase lactoperoxidase

b

\L 3. I protein

Flg. 10-1. Schematic procedure for radioiodination crnploying solid-phase lactoperoxidase. Production qf mdiochemit'als 125

thiosulfate

Product (radioiodinatdd protein)

Fig. 10-2. Radioiodination of proteinwith microliter quantities of reagentsand chloramine T. MicropipetteA contains 20 pl of 0. I rn barbital buffer, pH 8.4, 5 p1 (5 pg) of hhman growth har- mone, 5 pl of carrier-free 13T, and IO pl (100 pg) of chloramine T. Micropipette is emptied into small tube; 35 seconds later, contcnts of micropipctte B are addcd to neutralizc chloraminc 7'. B contains 10 p1 (-1.50 pg) of sodium thiosulfate.

I I I I I I I I I I I I I

Direct recoil I Indirect recoil labeling I labeling I I I I

Fig. 10-3. Rccoil labeling of protcins in 12aXe/'a:rlgenerator. 126 Busics of radiophurrnucy

The iodinc monochloride (IC1 = carrier, cicswill participate in the chemical reactions *IC1 = radioactive form of the molecule) has required for effective radioimmunoassay pro- beenused for many years buthas now been cedures. Reagents of high specific activity mostly replaced by newer methods, except make possible the great sensitivity of this when the *IC1 is produced by excitation label- method. ing, asjust described.This method involves the reaction of *IC1 under mild conditions. Presum- Technetium chemistry ably, *IC1 disassociates into *I' and CI-. The Ofall radiopharmaceuticals administered in positive iodine atom undergoes repl.dLLmcnt re- the United States, 82% to 86% are made with actions. The IC1 itself may add across a carbon ggmT~.More than two thirds of these adminis- double bond, followed by the replacement of trations require chemical modification of the the chlorine with an iodine from a second mole- technetium as a major step in their formula- cule of IC1. tion. Therefore, this section will explore some Othcr methods involve the use of electrolysis of the reactions of technetium in dilutc aqueous to make a high-specific activity product under solution as they are currently understood. mild conditions and the use of chlorine gas or Technetium is element number 43; it is a hypochlorite insolution to oxidize the iodidc metal in the second of three rows of the transi- ion to make it reactive (Fig. 10-4). Both of tion elements, which are also called heavy these approaches have been used to produce ex- metals. It falls between and cellent products. When direct iodination is im- and shares many propcrties with these ele- possible, it is sometimes feasible tosynthesize a ments, especially rhenium. Unfortunately, little derivative of the parent compound that can be is known about rhenium chemistry. Although iodinated. all are radioactive, small Much of the iodination occurring todayis metallic chunks have been made, and some of used to label antigens for radioimmunoassay. its colligative chemical properties havebeen To be useful, the labeled antigens must rctain ascertained. their antigenic function so that the labelcd spe- Our technetium is obtaincd in solution from the 99M~~/ggmTcgenerator described in the pre- vious chapter. As such, it is in amounts on the order of IOp7 grams in 5 to 30 mlmolar) and is in the chemical form TcO;, which is the oxidation state +7. It is called pertechnetate, analogous to pink Permanganate, MnO;, and is the most stable form of I'c in water and air. Pertechnetate is a weaker oxidizing agent than permanganate and a stronger one than perrhen- ate. The size and charge of pertechnetate are similar to perchlorate, CIO;, and iodide, I-, so its hiodistribution is similar to thcse ions in that they are alltrapped by the thyroid and have similar behavior in the GI and renal systems.

REDUCTION The radiopharmaceutical chemistry of tech-

I netium involves the reduction of the pertechne- Pate ion to one or more of the possible lower Magnet oxidation states, between $6 and +3. The stirrer charge on the TcO; spccics is negative, but the Fig. 10-4. Elcotrolytic radioiodinalion. (Modificd charge on some of the ions of these lower states from Rosa, U.: Atornpraxis 6,1966.) may be positive, permitting positive ion rcac- Production oj radiochemicals 127

tions. After reduction of the pertechnetate, thc been prepared. The tin should have no pharma- radionuclide can be complexed to a wide vari- cologic cffcct when injected; the amounts are ety of cornpounds chosen to control its biologic fir below the levels at which any toxic effects behavior. Reduction and complex formation dc- are seen. However, the tin chemically alters red pend on at least the following parameters: blood cells for several days to make possible I. Redox potentials of Tcstate produced the technetium labeling of rcdblood cells in and of the reducing agent vivo as well as in vitro. A dose of OO1nTcO;, if it 2, Concentration of reducing agcnt, corn- has been injected after a dose of some tin con- plcxing agent, and Tc taining a radiopharmaceutical such as a bone 3. Complex stability-ability to hold onto scanning agent, will be incorporated into red the Tc blood cells. It may be that smaller quantities of 4. Timeafter production and temperature tin can be used in the future to minimize this 5. Order of adding reagents effect . The reducing agents employed are, in de- scending order of utility, Sn+2, Fef2 with as- LIGAND EXCHANGE corbate, SzO; in acid solution, concentrated Like othcr hcavy metal species, the various HCI, HCl/HI, organic thiols (-SH), NaBH,, Tc ions have unfilled electronic orbitals that can and clcctrolysis. Nonmetallic agents do not be filledwith electrons supplied on othcr at- keep well; the reduction by thiols is compli- tached chemical groups called ligands. Some of cated by sulfur colloid forrnation. Electrolysis, the more common ligands arc listed here: with zirconium electrodes,has proved quite Anions: CI-, F-, OH- successful when it has been used. Stannous ion Molecules: HzO, ROH (alcohols), UO 'Sn+2)is the most popular reducing agent, fol- Groups: Amines, sulfhydryl, phosphatcs lowed by ferrous ion (FC+~)with ascorbate and thiosulfate (&On) in acid solution, whichis During the reduction process,some or all used for making sulfur colloid. of thc surrounding the Tc can be re- Let us usc thc reduction of TcO; by Snt2 as placed by one of thc aboveligands, depend- an example of the reduction. Tc(1V) is assumed ing on its concentration and that of competing to be the product. The separate pairs of the re- ligands inthe solution. Ligands can exchangc dox reaction arc: with other ligands (Fig. 10-5); the process de- pends on the bond strengths and conccntra- sn+2- Snf4 -t- 2c- - tion of the competing groups. The kinetics of TuO; + 8 H' + 3e e Tc(IV)+" + 4 H,O Balancing the numbers of electrons and adding the two reactions together gives 2 TcO; + 16 H' + 3 Sn+?-'- 2 Tc(IV)+~+ I 3 Sn+' + 8 H20 as a balanced redox reaction. Just because this reactioncan be written does not prove that it happens. There may be a mixture of Tc(III), Tc(lV), and Tc(V) after reduction, withthe proportion of each dcpcnding on the conditions. This reaction is reversible and will not keep the Tc reduced to the (TV) state unless it is sta- bilized by the addition of a complexing agent. Stoichiometrically, it takes only a trace of Sn+2 &- to reduce all the Tc present, but in practicc 100 Fig. 10-5. Ligandexchangc inwhich chloride to 400 mg of Sn+2 arcrequired to assure an ade- groups surrounding Tc(IV) aredisplaced by water quate shelf-life for the radiochemical after it has molecules. 128 Basics of radiopharmacy exchangeare variable: some exchanges occur CHELATION instantly;others take several hours. Tc(1V) Thechelating agents are anothcr class of complexes in which theligands are OH- or complexing agents used with reduced techneti- H,O can lose water to becomethe insoluble um. Chelates are complexing agents with more oxide, TcO, (like Mn02). In neutral or basic than one ligand or cornplexing site. They arc solution the reaction is: rather like an octopus enfolding the metal ion. The chelates have thcir own biologic behavior, which the central metal ion does not greatly Reduced hydrolyzed Tc(1V) (H20)z4 is affect. Two very common chelating agents arc capable of oxalation or loss of water between EDTA (ethylenediaminetetraacetic acid) and two such complexes in neutral or basic solution. DTPA (diethylenetriaminepentaacetic acid). EDTA is in such common use that its salt 2 Tc(H20)i4+ hasbeen nicknamed “edetate.” Fig. 10-6 showsthe chemical structures of EDTA and TczOz ’ HZO,,,, - 4)+4 f 2 H,O+Ht DTPA . Wc can speculate that technetium can par- DTPA has eight possible complexing sites: ticipate in hybrid olation and oxalation with the three and the five carboxylic acids metals such as tin,aluminum, or iron inthe (-COOH). It is unlikely that it can get all its solution. These reactions could account for the “hooks” onto a Tc(TV) at once. DTPA holds persistence of the reduced hydrolyzed ions in Tc(1V)very tightly, as it does the Pb’4 ions; the presence of concentrations of ligands that DTPA is used for lead detoxification. It chelates otherwise wouldbe expectedto complex the the metal and promotes its excretion by the kid- technetium, neys. Chelates like DTPA are very efficiently

0 0 \\ // C-CH, CH,”-C C-CH, \ HO’\ / OH A - N-CH,-CH,-N ‘ HO \ / \/OH CHZ-C //C-CH2 \ 0 0

0 0 \ // C-CH,

HO’\ lH2-, \ OH -CH, -N OH \/ CH2-C B 0 0

0 OH Fig. 10-6. A, Chemical structure of EDTA, ethylenediamine tetraacetic acid. B, Chemical struc- ture of DTPA, diethylenetriamine pentaacetic acid.

130 Basics of radiopharmucy phytate. The molecular structure isgiven in forms, the avoidance of reaction conditions Fig. 10-8. The Tc phytate complex isformed that might denature the protein becomes un- using the stannous reduction mcthod. The corn- necessary, since the proteins are, for the most plex is soluble in aqueous solution, but it is im- part, denatured already. mediatelyprecipitated when injected into thc In addition to serum albumin and its deriva- bloodstream. Serum precipitates thc tives, several other proteins have been labeled radiolabeled complex. It is then cleared from with reduced technetium, Included in this group the blood by the RE system. are the proteins involved in thrombogenesis and thrombolysis. In these reactions great careto PROTEIN LABELING control the reaction conditions is required bc- Proteins are so designed thatthey arc very cause the biologic activities of themolecules effective in complexing or chelating metal ions. must be preserved for the product to be useful A protein molecule hasmany ligands, so the as a tracer. possibilities for binding technetium arc great. It has also been demonstrated that chelating Some of the bonds arc likely to be less stable functional groups can becoupled to proteins than others; thus a fraction of Tc-labeled pro- and other moleculcs to provide a means for the tein is almost always less stable than the anal- stable incorporation of tracer technetium. ogous radioiodinated species. Serum albumin is the most readily available human protein. It SULFUR-BASED REDUCTION PRODUCTS can be labeled with rcduced technetium under a Sulfur-containing compounds, thiols in par- variety of conditions. Initially, theiron- ticular, are often able to both reduce and com- ascorbic acid method was most widely used, plex technetium. Fig. 10-9 gives the structure but this method always required a separation of of several molecules that are used for this pur- thc labeled product from residual pertcchnetate. pose. When an acid solution of thiosulfateis The electrolytic method was introduced. It gave heated in the presence of pertechnetate, several higher yields, and thus the final separation reactions occur, including the formation of col- could be avoided; however, the reaction condi- loidal sulfur. The technetium is converted from tions were somewhat difficult to control, mak- a soluble pertechnetate into an insoluble SUI- ing product reproducibility a problem. Cur- fide. Whether or not the technetium is rcduced rently, the stannous rcduction method has been during the reaction is not established. perfected so that it works fairly well for pro- When the thioamino acid, penicillamine tein labeling, The insoluble forms of albumin, (Fig. 10-9), is reacted with pcrtechnetate under macroaggregates, microaggregates, and micro- basic conditions, a technetium complex is spheres are more readily labeled using the tin formed that isprinlarily excreted throughthe methodthan is the native protein. Withthese kidneys. Up to 30% of theinjected dose ac-

HOOC -CH - CH, - COOH HOOC -- CH -CH -COOH I 11 SH SHSH TMA DMSA

CH, I CH~-CH~-CH-~CH~I~-COOH CH,-C-CH,-COOH I I I SH SH SH DHTA Pen

Fig. 10-9. Chemical structure of thiocompounds that both reduce and complex teohnctium. TMA, thiomalic acid: DMSA, dimercaptosuccilli~ acid;DHTA, dihydrothioctic acid; Pen, penicillamine. Production oj radiochemicals 131

tually becomes fixed in the renal tissues, which tween molecules isdocumented for Cr(TI1) makes this complex a good radiopharmaccuti- where oxygen bridges form square structures of cal for renal imaging. Whenthis samecom- very high stability,as shown in Fig. IO- IO. pound is reacted with pertechnetate in acidic This process can progress to form Cr(OH)S, reaction conditions, a different technetium com- which is really Cr(OH):, . 3 HzO. In time the plex is formed that is rcmovcd from thc blood chromium precipitates out or forms a colloid. by the liver rather than the kidneys. Anions present during thc process may be cap- tured. The very strong oxygen bonding may be Chelation and complexation of prevented or even reversed when other compct- other metals ing complcxingagents are available. The re- The discussion of other elements in use in verse reaction may be kinetically slow and, nuclear medicine is by no meansexclusive. therefore, hard to effect. Cr(II1) is a label for New compounds and new ways to make anduse proteins, apparently as an olated complex. thc old onesare invented everyday. The From the chemistry of tanning, the pragmatic principles will be similar to thosc alrcady dis- useof Cr(TT1) for protein labeling wasde- cussed and thus arc aimed at drawing together veloped. the common threads. We shall beginwith the \?'Cr (323 kev, T; = 27.8 days) decays by transition metals and treat the nonmetals after- electron capture. It has been used as a label for ward. Thecompounds made in biologic sys- blood clemcnts. Thc most common of these is tems and those relegated to the discipline of the red cell label. To label rcd cells, Nag'Cr04 will be discussed in other is mixed with whole blood in a special ACD* sections. solution in vitro. lhe reaction of the Cr(V1) It can be said about all transition metals that with the red cells appears to involve reduction they have multiple oxidation states, one or more and tagging of the "Cr to the red cells. The re- of which are stable under air and in water. Be- action is stopped by adding ascorbic acid to re- cause the transition metals have unfillcd clcc- duce and complex unreacted Cr(V1) before the tronic shells, they can formcomplexes and cells are reinjected. Cr(lI1) is a label for plasma, chelates of various kinds andstrengths. The bothin vivo and in vitro. If other blood cle- manipulations of the transition metals for radio- nlents are separated, they can be labeled by re- pharmaceutical purposes often involve chang- duction of "CrO;. The binding is more or less ing the oxidation state. For some of the metals, stable, depending on the compound, 51Cris also like technetium,chromium, indium, , a label foralbumin, to be used in such GI and iron, these possibilitics have bcgun to be studies as protein-losing enteropathy diagno- exploited. For others, such as , , sis.Because chromium is not an important , lead, and , the chemicalmanipu- body metal, it is not reused by the body for any lations to date have only been of the simplest proccss. Once the chromium is released in the kind. body from its parent substance, it is excreted Chromium is a transition nletalin the first from the circulation into the urine and from the row of thc pcriodic chart. Chromium is an es- GI tract into the feces. sential trace element. The common oxidation lndium is a metallic element of Group 3. The states areCr(VI), represented byCrOT and most stable oxidation statc is 1-3. The ions arc Cr,0;,and Cr(ll1) as Cr+:'.Cr(II1) is coordi- complexed to other species inwater solution nated in water and other solutions, with coordi- and can form numerous stable chelates. It may nation number of six in an octahedral arrangc- be worth noting that gallium and indium have ment. Chelates form even morestable com- plexes with Cr(TT1) than do the simple complex- *ACD is acidcitrate dextrose, 8 mg citric acid, U.S.P. ing agents. Cr(HZO)G+D,Cr(H20)5Cl+2, and (anhydrous base), 25 rng sodium citratc U.S.P. (dihy- drates), and 12 mg dcxtrose U.S.P. (anhydrous) qs to 10 1111 Cr(H,O).,CI+, are all known and interchange withwater fur injection U.S.P. Available from Mallin- watersand chlorides in chloride solution. ckrodt, Tnc., St. Louis, Mo. 63134, as A-C-D Solution The olation process of splitting out bc- (Modified). Fig. 10-10. Olation reaction of chromium complex.

many similar chemical properties. The two iso- !. topes of indium are indium 1 13m (390 kev, :o: H:C :C::O: 1.7 hours) and indium 1 I I (173, 247 kev, 67 H:N : hours). In DTPA chelates of both isotopes have H been used. "'In DTPA is currently the agent of choice for cisternography . The blood clearance Fig. 10-1 1. Electronic structure of , half-time of In DTPA is about 70 minutes. It glycinc. can be usedas a brain scanning agent, espe- cially in places where l'gmIn is more readily available than wrnTc. The carbon-carbon bond is a covalent bond Indium can be labeled to iron hydroxide par- in which the electrons are shared between the ticles for lung scanning; kits are available out- atoms.Carbon-carbon bonds can involve 2 side the United States for such labeling. Liver, electrons shared between 2, 4, or occasionally 6 spleen, and bone marrow scanning may be per- carbon atoms,forming single, doublc, and formed withan indium colloid made by pre- triple bonds. There are 4 single bonds possible cipitation of indium at pH 7 to 8 in the pres- from each carbon atom, I single bond from ence of a gelatin stabilizer.With indium tracers each hydrogen, 2 from each oxygen, and 3 from no radioactivity appears in the gastrointestinal each .The structure of glycine (Fig. tract or bladder as often happens with techne- 10-1 I), the simplest aminoacid, illustrates tiurn-labeled tracers. Indium canbe used for these bonding ideas. blrwd-pool scanning by injecting gelatin-stabi- Organicsynthetic methods are necessary lized InCI, at pH 3.5 to 4. The indium is bound when we wish to incorporate "C, I3N, or 150 by transferrin when it is injected into the blood- into organic compounds. These must be very stream. rapid because the half-lives of these nuclides are so short.Thus, a subbranch of organic Organic and biochemical synthesis chemistry dealing with fast synthesis has been Organic chemistry broadly covers all reac- developed. Very often a metallic surface is used tions of carbon. From this chemistry we can as a catalyst to promote a reaction. Thecatalyst find many ways to incorporate radioactive spe- itselfis not changed in the reaction. Altcma- ciesinto carbon-containing compounds, Car- tively, enzymes may be employed as the cata- bon has the almost unique ability to bond tetra- lyst;solid-state enzymes are being developed hedrally to itself to form longchains, rings, especially for this purpose. Solid-state enzymes and complex structures, thus enabling the com- are produced by covalently bonding the cnzy- plex mechanisms that we associate with living matically active proteins to beads or surfaces. systems. Biochemistry or the biologic part of The synthesis of I'C chlorpromazine can be organic chemistry also provides us with many used as an example of . The mechanisms for the synthesis of radiolabeled "C from thc cyclotron production is made into molecules. 'TO, by flowing the cyclotron products across Production of radiochemicals 133

HCOOH >

I CI I/H ICH* 13 - N \

labelcd chlomromarine.

hot copper with an excess of oxygen. Thc C02 the reaction and causes it to be very specific. is made into methyl alcohol by reaction of thc Theenzymes havc very complex chemical CO, with aluminumhydride and di- structures: even if we could writc them down, ethyl and dibutyl carbinols. The products of the we would not want to do it very often because first reaction arc carried by flowing nitrogen they would be so large and their spatial char- through silver wool in a furnace, which re- acteristics wouldnot be obvious from a two- duces thc alcohol to formaldehyde. The formal- dimensional picture. Thus,the enzymes arc dehyde then flows to a flask containing nor- named for whatthey do, not for their struc- chlorpromazine in dimethylformamide and for- ture. A dehydrogenase, for instance, catalyzes mic acid, which functions as a cold trap for the the removal of -H from a particular site in a formaldehyde "C. Once it is trapped, the mix- particular compound. The -aw ending indicates ture is sealedand heated. Under these condi- that the substance is an enzyme. tions, a hydrogen atom is replaced by the The synthesis of 13N-l- can be used to -WH3 of the formaldehyde "C. The product illustrate the enzymatic methods. I3NH3 is ob- can be extracted from the reaction mixture with tained from the cyclotron and is trapped in acid. ether or separated by . It is It is separated from the acid by ion-exchange made up in saline and purified through a Milli- chromatography under pressure. At this point, pore filter. Fromthe time the l'C0, is made, 80% to 90% of the initial radioactivity is pres- the synthesis takes 25 minutes if the ether ex- ent in an NaOH solution of pH 8.2. The ammo- traction method is used. About 7% of the radio- nia solution is incubated with an enzymc, glu- activity is in the product. Thus, the amount of tamic acid dehydrogenase,and a salt of glu- activity to start with must be about a hundrcd tamic acid while pyruvic acid is incubated with times that needed at the end. The reaction sc- glutarnic-pyruvic transaminase. The two solu- quence is outlined in Fig. 10-12. tionsare mixcd, and both '"N-l-alanine and Biochemical synthesis involves theuse of en- ':'N-l-glutamic acid result. The sequence of re- zymes as catalysts to promote the reaction. The actions is shown in Fig. 10- 13. enzymes arclarge organic molecules synthe- sized by living systems that have certain active Biologic synthesis shapes to their electron shells. Apparently, the When the synthetic systems of chemistry and enzymesact as templates. The reactants sit biochemistry do not produce a product with the down on the template andare thus arranged requisite ease, speed, or specificity, a biologic into an electronic configuration that facilitates system may be called into service. Vitamin BIZ, 134 Basics of radiopharmacy

Glutamic CH, - CH ---COOH acid I '~CH,-[d,n]--':NH, 13NH, + +

HOOC-CH2--CHz- C---COOH HOOC - CH, -CH, -CH - COOH /I I 0 '3NHz

Fig. 10-13. Outline of synthesis of "N-lahclcd I-alanine and I-glutamic acid.

Table 10-1. Properties of radioactive tine and . The most common radio- cobalt isotopes pharmaceutical use of seleniumis as 75Sc in '"e selenomethioninc. It participates in pro- Principal tein synthesis where methionine does and can Isotope Half-life raysgamma thus be used toimage the pancreas andthe 57 co 270 days I20 kcv parathyroid glands and for many metabolic 58 co 72 days 35 kcv studies. It can beprepared by chemical syn- co 5.2 years I. 17, I .33 nlcv thesis or bygrowing yeast in a low-sulfur, medium. It is possible to make which contains cobalt at the heart of the mole- selenium-labeled antibodies in vivo in animals. cule,is made commercially by bacterial syn- 75SeO;- can be metabolized to 75Se(CH,), in the thesis. A bacterium,such as Strcptomyces liver; thc 75Sc(CH:1)2measured in the breath is griseus, is harvested after it has multiplied an indicator of liver transmethylation function. through many generations. If radioactive cobalt llC glucose is made photosynthetically by isadded to thegrowth medium, radioactive Swiss chard. The Swisschard is grown and then vitamin B,2 will result. "70, "Bo, and put in the dark. After the"C02 is prepared, it is have been used as labels. Table 10-1 compares put into the atmospherearound the Swiss chard, the radioactive properties of these isotopes. The and the are turned on. The Swiss chard labeled vitamin B,,, in submicrocurie amounts, usesthe "COz to makeglucose. After a few is used to study metabolismand minutes of exposure, the Swiss chard is ground kinetics. The long biologic half-life of vitamin up and the glucose extracted. B,, requires a tracer with a long physical half- White blood cells can be labeled in vitro us- life in order to trace the substance completely. ing a biologic method. The cells are separated Oneelement mayprofitably be substituted by centrifugation from the other blood compo- foranother under certain circumstances. We nents. They are then mixed with 991nTc-labeled see this occurring inthe chemistry of certain albumin minimicrospheres less than 3 p in di- species, such as SO,' and S,O;, where a sul- ameter. The cells ingest the microspheres and fur substitutes foran oxygen. The human are then reinjcctcd. Labeled white cells can be bodyis satisfied under some but notall cir- used to image absccsscs. cumstances when a substitution ismade that The humanbody is also used at times as a involveselements with similar electronic and biosynthetic system. Inorganic iron, ':'Fc, is in- chemical properties.One of these substitu- corporatcd into rcd blood cells; 1'3'1" is incorpo- tions, which has notbeen used nearly so rated into thyroid hormonc. 7sSe can be used in much as itcould be, is the substitution of Se vivo as a label in many systems in place of sul- for S. Selenium falls under oxygcn and sulfur fur. The analogy between Se and S can be es- in the periodic chart. It can be substituted for tablished by thc comparative testing of 75Se sulfur in the sulfur-bearing aminoacids, cys- compounds against their 35S analogs in animals.

CHAPTER 11 Daily preparations and their quality control

At the present time almost all radiopharrna- ing 40 mCi, then the person who modified the ceuticalscompounded in radiopharmaciesare manufacturer's instructions is obliged to estab- OYrnTc compounds.These compounds have lish the quality of thc product and to demon- half-lives of 6 hours and shelf-lives of from YZ stratc that the modification did not cause sub- to 24 hours, which means that the preparations standard performancc. must be made daily. THIN-LAYER CHROMATOGRAPHY Routine quality control Thin-layerchromatography (TLC) isthe GENERAL REQUIREMENTS most widely used method for rapid determina- Whenan NDA*-approved kitand an NDA tion of radiochemical impurities in radiophar- w1n T~ generator are used and the person prepar- rnaceuticals. Many commercially available sys- ing the radiopharmaceutical followsthe instruc- tems are satisfactory for theperformance of tions exactly for both the generator and for the these tests (Fig. 11-11; however, an easy-to-use kit, there is no legal demand that quality con- system may be designed in-house that is much trol tests be perfornmed. The generator has been less expensive than thecommercial products. designed, as have the kits, to ensure a very high Levit,Adams, and Rhodes*explain the con- probability of success in the preparation of the struction and use of one such system. radiopharmaceuticals when the instructions are In general,a microdrop of the radiophar- followed. Quality control tests serve as an in- maceutical is spottcd on a dry-gelthat is fixed to ternal check to assure that the person preparing a support matrix such as fiberglass. This TLC the radiopharmaceuticalhas not made some gel is often a small strip that can be placed in a blunder in carrying out the instructions. In a small jar containing less than a milliliter of the few cases, the kits themselveshave notbeen solvent. Thesolvent migrates up thc geland 100% reliable, so quality control also permits moves away from the origin any materials that the preparer to assure that the kitused gives aresolubilized. The insoluble forms of the satisfactorytagging. Quality control tests can tracer remain where they were spotted. Devcl- alsoprovide information about whether the opment usually requires 3 to 5 minutes. When preparation was successful in situations in the solvent has reached the top of the strip, it is which following the exact instructions was not removed and allowed to dry. Usually, it is suf- feasible or was not what the preparer deemed ficient to merely cut the strip into two parts, the best for the current situation. For instance, if origin (or bottom one third to one half of the the kit instructionsstate that the maximum strip) and the solvent front (or upper one half to number of millicuries to be added in the prepa- two thirds of the strip). After counting both ration is 30 mCi and if the kit was prepared us- pieces and subtracting background, the percent

'New Drug Application approved by the Food and Drug *Levit, N., Adams, R., and Rhodes, B. A.: Manual of ra- Administration. diopharmacy procedures, Cleveland, CRC Press, Inc. (in prcss). 136 Daily preparations and their quality control 137

Fig. 11-1. Commercially available kit and rcagcnts for doing thin-laycr chromatography

soluble or insoluble radioactivity is calculated. YgmTc-labeled proteins,or SSmTc-labeledbone When acetoneis used as the developing sol- agents. vent, technetium complexes, particles, and ox- ides are insoluble; onlyfree pertechnetate is GEL-COLUMN SCANNING soluble. Acetone is used when we assay for free The radiochemical purityof routinely pre- pertechnetate. When saline is used as the sol- pared YymTcproducts can also be determined by vent, technetium complexes and free pertech- gel-column chromatography(Fig. 11-2). A netate are soluble; hydrolyzed technetium and drop of the radiopharmaceutical is placed on the technetium particles remain at the origin. Saline column; after thc drop enters thegel bed, a vol- is used when wc assay for hydrolyzed techne- ume of solvent equal to the void volume of the tium in complexes such as Y9mTcDTPA, column is added. Once thc solvent has passed 138 Basics of rodiopharmacy

s9mTc -albumin -streptokinasei colloid 20 k"""" Sephadex G-25 kolurnn length Cm

4

Fig. 11-2. Gel-column chromatography.A, Distribution of different 99rnTccompounds on columns. B and C, Gamma-cameraimages of columns. (From Persson, B. R. R.: Gelchromatography column scanning. In Rhodes, B. A,: Quality control in nuclear medicine: rddiopharmaoeutioals, instrumcntation, and in vitro assays, St. Louis, 1977, Thc C. V. Moshy Co.) through the column, the different 8ymTcspecies molybdenumitself is not. Thus, as the saline will have moved various distances down the passes through the column, 75% to 85%)of the column. The columns are scanned or imaged to t)nmTccontents of the column is washed out with detcrminc the relative amounts of the different the saline. The saline with the YymTcis usually 99mTcchemical species. collected in an evacuated, sterile, pyrogen-free vial. Aseptic techniques are used in the elution Sodium pertechnetate solution of thc generator to prevent contamination of the The two primary sources of sodium pertcch- generator and of the eluate with microorgan- netate solution are (I) instant 99mTcsolution, isms, pyrogens, or foreign particles. which is purchased on a daily basis and is ready The generator column is housed in a lead to use asis, and (2) 99Mo/S9Tcgenerators, shield to protect the operator from radiation. whichthe user elutes with sterile saline as Theoperator should alwaysplace the elution ""n1TcO-. isneeded. Generators are eluted by vial in a lead container to minimize the radia- following the instructions supplied by the man- tion exposure during the elution process. Elu- ufacturer, In principle this involvcs passing a tion of generators usually takes 3 to IO min- sterile solution of 0.9% sodiumchloride utes. During the waiting time,the operator through the alumina column that contains the should step away from the generator to avoid "Mo; the ggmTcformed by the molybdenum unnecessary radiation cxposure. When the elu- decay is soluble inthe saline, whereas the tion is completed, the vial in the lead container Daily preparations und their yuulity contrvl 139

Fig. 11-3. Radiation dose calibrator. (Courtesy Capintcc, Inu.) is removed, and the sslllTccontent is assaycd. cise, and it exposes the operator to some radia- The operator next faces the problem of deter- tion. Usually, however, operators become very mining the concentration of the radioactivity in fast and can carry out the procedure with mini- the eluate and its radionuclidic purity. In some mal radiation exposure. An alternate way is to laboratories, the radioche~nical purity of the use a scale. The empty vial in its lead shield is pertechnetate is alsodetermined, using thin- weighted and recorded as the tare weight. After layer chromatography. the elution, the vial is reweighed in the same shield. The differencc is the volume of the sv- ELUTION VOLUME lution eluated from the generator. This method The methodthat has been used most frc- takcs a little longer but has the advantages of qucntly for the determination of the volume of being precise and eliminating radiation expo- thc eluate is visual inspection after removing sure. the vial from the shield with tongs. Working be- hind a leaded glass shield, the radiopharmacist ASSAY OF TOTAL RADIOACTIVITY visually examines thc vial, which has calibra- One way to mcasure the total activity in the tion markings in milliliters. Visually deterrnin- vial is to transfer the vial with tongs from its ing thc volume is easy, but it is not very pre- shield into a dose calibrator (Fig.11-3). The 140 Basics of radiopharmacq, radiation levelis directly read from the dose elution vials that effectively shield out thr: calibrator. In order to get precise measurement SYmT~gamma rays (140 kev) but permit thc by this method, the dose calibrator must have passage of the more energetic !'>Mo gamma been calibrated with standarda calibration rays (740, 780 kev) (Fig. 11-4). The "OM0 in a check sourcetraceable to an NBS standard. vial and housed in one of these shiclds can be Also, the dose calibrator must have a linear re- counted using gamrna-ray spectrometry.The sponse. By this, wemean that the readout is spectrometer is setto accept pulses between 6oc) proportional to theradioactivity being mea- and 900 kev. The shielded solution is countcd, sured in the range from a few microcuriesup to and the gamma-ray emission in the 600 to r)OU the total activity of theeluate (usually I to 2 range determined. Subsequent to this,the OBmTc curies). Also, for precision the operator needs solution is replaced with a 137Cssource, This is to know the correction factors for the elution counted under identical conditions. The ""Cs vial and for the volume of eluate contained in sources available for thispurpose are calibrated the vial. For many of the modern dose calibra- in terms of equivalent microcuriesof 09Mo. The tors this correction factor is very close to 1. amount of "Yo in the solution is calculated us- Another method for determining the radio- ing ratios of cpm/mCi.Alternatively, some activity of the eluate is to remove, using aseptic dose calibrators are equipped for the measure- techniques and working behind a leaded glass ment of the OgMo contentdirectly. Again, a shield, exactly I ml of the eluate. This 1 ml is special shield must be used; this is supplied by assayed in thcdose calibrator, whichhas the the manufacturer of the calibrator. The QsmTc advantage that the operatordoes not havc to solution in the special shield is inserted into the transfer and expose himself to the entire source calibrator and the instrument set for "Mo. The of ODn'Tcirradiation. The value directly mea- microcuries of OQMoin the osmTcsolution are sured isconcentration. This method isespc- read directly. cially useful when the total amount of OQrnTcis outside the linear range of the dose calibrator. The disadvantage of the method is that manual manipulations of the radioactivity are required, and thedetermination of theconcentration is subject to several errors. One error is the dead space in the syringe; that is, the measurement of an exact I ml volume with a syringe is usu- ally not precisc because some volume of solu- tion is contained in the needle and in the hub of the syringe onto which the needle is fastened. This dead space varies with different syringes. Thiserror can be overcome by weighing the syringe to determine its exact volume. A sec- ond loss of precision is that the measurement of theradioactivity in syringes may not neces- sarily be precisebecause the position of the syringe in the calibrator is difficult to reproduce exactly.Again, acorrection factor maybe used. Usually the errors of measurement are in- significant in the handling of technetium 99m solution.

ASSAY OF RADIONUCLIDIC PURITY Specially designed vial containers are avail- Fig. 11-4. Shield for assay of 99Moin t'nmTcsolu- able for holding the technetium solutionsin the tion. (Courtesy Capintec, Inc.) Doily prrpurutions and their quality control 141

There have been times when UDmTcsolutions activity on the strip. 7'1:is gives the pcrcent of have been contaminated with iodinc 132 (TI = UBmT~pertechnetatc in the 9!'1nT~solution. 2.3 hours; 670, 770 kev). This is revealed by gamrna-rdy spectromctry of the shielded eluate SPECIFIC ACTIVITY or by the fact that the determinationof the "Mo t19mTc decays to thc long-livedisotope "Tc. breakthrough is high, but when it is reassayed The concentration of technetium in solution an hour or so later, the OOMobreakthrough has (i.e., ""Tc + 99mTc) remains constant. During apparently significantly decrcascd. This means chemical manipulations, the "Tc competes that the gamma rays from the lazl were being stoichiometrically with the Y9mT~in oxidation- assayed as ""Mo radioactivity. Because of the reduction reactions andin tagging reactions. short half-life of the '?!X, the repeat assay gives The amount of DOTcdepends on the previous a different and lower value. history of the solution. Total technetium accu- Multichannel gamma-ray spectrometry is mulation depends on the millicuries of molyb- also used todetermine radionuclidic purity denum in thegenerator and the timc elapsed (Fig. 1 1-5). sincc the last elution. If a generator has been sitting for several days without elution, it will ASSAY OF RADIOCHEMICAL PURITY contain more total technetium atoms than a gen- Using a syringe with a very tine needle, a erator that has been elutedthe previous day. small amount of the solution is removed from The reader is referred to Larnson, Hotte, and the vial into the needle. Then, this drop of a few Ice* for the radiation-decay equations that al- lambda in volume is transferred to a small strip low for the calculation of the technetium con- of TLC medium, which is developed with 85% tent in pertechnetate solutions. methanol. The percentage of the radioactivity with an R, = 0.68 (TcO;) is determined. Usu- ally, it is casicst to determine the percentage of *Lmson, M., 111, Hotte, C. E., and Ice, R. TI.: Practical the radioactivity remaining at the origin and generator kinetics, Nucl. Med. Tech. 421-27, 1976. (See subtract this from thc remainder of the radio- Appendix B for a revised version of the original article.)

Fig. 11-5. Multichannel analyzer attached to NaI(T1) crystal dctcctor, used for determination of radionuclidic purity. (Courtesy Canberra Industries, Meriden, Conn.)

Fig. A-5. Special isolated arca in radiopharmacy is used for quality control testing of freshly prc- parcd radiophannaceuticals. 160 AppendixA

Fig. A-7. Special arca used for packaging radiophamlaceuticals for shipmcnt to distant nuclear medicine clinics.

Fig. A-8. Spccialty equipment used for prcparing and testing radiopharmaccuticals. In background a freeze drier is shown that is used for manufacturing radiophamlaccutical kits. On bench behind radiation monitor is watel- hath used for incubating samples during Limulus testing for pyrogens. Layout of a mdiupharmncy 161

Fig. A-9. Lead-shielded areas cncloscd in a fume hood uscd for dispensing of volatileradio- pharmaceuticalssuch as iodide 131 solutionand 133 gas. In forcground is raditionsafcty officcr monitoring background levcls in radioisotope hood. 162 Appendix A

Fig. A-10. Computcr equipment used for accounting, quality control record kceping, radioisotope inventory,and dccay calculations. A currenttrend in radiopharmacy is tocornputerize cntire rccord keeping system,

Fig. A-11. Isolated from rcst of activities of radiopharmacy is separate area for storing radioactivc wastes until they have decaycd or can be transfcrrcd into permancnt storage. Note in background lcad bin for storing such isotopes as gallium 67, iodine 13 I, and 169. APPENDIX 6 Practical generator kinetics *

Myles Lamson 111, M.S., Cllfford E. Hotte, Ph.D., and Rodney D. Ice, Ph.D.

Abstract able photon fluxin imaging studies, and pro- Equations describing the decay and buildup duced a dramatic reduction in cost per study of nuclides in the !'9Mo/99111Tcgenerator are relativc to the radionuclides used previously. presentcd and discussed. The three basic time The technetium gcnerator has allowcd even the functions which describe the quantities of "Mo, smallest of institutions to maintain a continual r)!llIITc, and 99Tc are then manipulated to yield supply of this short-lived radiopharmaceutical. time-dependent factors that simplify the calcu- The decay kinetics of parent-daughter sys- lations of generatordecay. These factors are tems arc well known, with one of the earliest (1) the fraction of rnaxirnurn OIJmTc radioac- descriptions by Ruthcrford and Soddy in 1902'! tivity at t hours after prior elution, (2) 9Yn1Tc Evcn so, the complex exponential relationships radioactivity as a fraction of 4!'M~radioactivity needed todescribe the decay and buildup of at time t following priorelution, and (3) the nuclides in the Yeln'l'cgcnerator are too cumber- mole fraction of total technetium present in the some for routine clinical use without the aid of generator as the nletastablc isomer at time t. a computer or programmable calculator(see These factors allow simplc and accurate calcu- Appendix 2 for HP-67 program). Transicnt lations of relativc yields of OgrnTcat different equilibrium is not attained for 2 to 3 days; there- times after prior elution, expectedyicld in milli- fore, an cstimate of OOrnTc activity that assumes curies and generator elution efficiency, and total an equilibrium condition priorto this time is molar quantity of technetium eluted. Examples invalid. However, a close examination of the arc presented. Solutions of the basic differential classical decay kinetics indicates certain simple equations are described in detail in Appcndix 1. and accurate rnethods for predicting such pa- ramcters as the activity of""'Tc to be eluted Introduction from the generator, the generator elution ef- The 9gmTcion-exchange generator is one of ficiency, and the total mass of technetium pres- the primary reasons for the remarkable growth ent in an eluate. of nuclear medicine during the past decade. In addition to the steadily increasing capabilities Theory of nuclear medical instrumentation, the rcady 'The following differential equations (I to 3) clinical availability of 99n1Tchas reduced patient describe the decay and buildup of nuclides in radiation exposures per microcurie by two to the technetium generator,where subscripts I, three orders of magnitude, increased the avail- 2, and refcr to "Mo, oonlTc,and 99T~,rc- spectively: "Portions of this scction were previouslypublished in J. Nud Med. Tech. 4:21-27, 1976. For reprints of the origi- nal article contact Myles Lamson, Collegc of Pharmacy, "dNf - -h,N, N,(O) N? (1) The University of Michigan, Ann Arbor, Mich. 48109. dl 163 164 Appendix R

99~0 "dN2 - 0.86A,Nl - hzNZ N,(O) = N! (2) dt

"dN'' - 0.14A,Nl + h2N2 N3(0) = N!j (3) 13.95% 86.05% dt

The superscript O in the initial conditions refers to the number of atoms present at time t = 0; the quantitics N,, N2, and N, then refer to the numbers of atoms of each respective nu- clide at time t. The equations indicate that the dN . time rate of change, -, proportional to the dt 1s number of atoms, N. Thus thc rate of change equals N times a proportionality constant,or Fig. B-1. Branching decay of ""Mo decay constant, X. Thc minus sign in equation 1 indicates a decrease in thc number of atoms of "Mo initially present, while the positivc term in equation 3 indicates a buildup of "Tc. (Al- though YYTcis radioactive, its Ti is so long rela- tive to "Mo and ""'Tc that it is considered stable.) Equation 2 dcmonstrates a buildup of !'omTcequal to a fraction of the decay of !ISMo, in addition to its own dccay, -h2N2. The co- cfficients of 0.86 and 0.14 are introduced as a result of the branching decay of "Mo: 86% decays to BgmTc,while 14% goes directly to "Tc (see decay schcme in Fig. B-l and refer- ence 2). The methods for solving thcse equa- tions, that is, removing the differential terms by integration, are presented in Appendix 1. The solutions of cquations I to 3 are indicated by equations 4 to 6, respectively:

Time since previous elution (hours)

Fig. 8-2. Buildup and dccay of 99mT0from 99Mo. Maximum technetium radioactivity is 67.7% of ac- tivity of ""Mo at t = 0 (time of previous elution).

If only OBMo is prescnt initially, then Ng = = In 2 Ng 0 and equations 5 and 6 simplify to where3 = -= 0.01043 hr" A, 66.48 hr

h2 = ~ In = 0. I IS1 hr" 6.02 hr Practical generator kinetics 165

Table 1. Radioactivity of 99n1Tcin generator as fraction of maximum OgrnTc radioactivity

where Arilx = 0.677 A:

Time Time Time (hr) f(t) (hr) f(t) (hr) f(t)

0.5 0.071 10.0 0.817 27 0.992 1.0 0.137 10.5 0,836 28 0.987 1.S 0.200 11.0 0.852 29 0.983 2.0 0.258 11.5 0.86X 30 0.977 2.5 0.314 12.13 0.882 32 0.965 0.3h5 13.0 3.00.907 34 O.Y.52 3,s 0.414 14.0 0.928 36 0.937 4.0 0.458 15.0 0.946 38 0.922 4.5 0,501 16.0 0.961 40 0.906 5.0 0.540 5.0 17.0 0.Y73 0.X74 44 Time since previous elution (hours) 5.5 0.578 18.0 0.982 4X 0.841 6.0 0.612 19.0 0.98Y 54 0.793 Fig. 8-3. Fraction of maximum "!'Tc radioactivity. 6.5 0.645 20.0 0.994 60 0.746 Technetium activity is SO% of maximum at 4.5 hours 7.0 0.675 21.0 0.9% 66 0.701 after prior elution; APxoccurs at 22.9 hours, 7.5 0.703 22.0 0.999 72 0.659 8.0 0.729 23.0 1.000 78 0.619 8.5 0.754 24.0 0.999 84 0.582 25.00.776 9.00.998 90 0.546 In the following sectionrelationships are 0.798 26.0 9.50.995 96 0.513 derived that allow tabulation of several time- dependent kinetic factors. These factors in turn permit simplecalculation of basic stoichio- Since A = metric data regarding the technetium generator. AN, The only information needed for these calcula- (9) tions is the calibration activity of 9YMoand thc time elapsed between generator elutions. Applications Threeimportant questions about available technetium can be answered by manipulating these basic decay equations to yield time-de- pendent kineticfactors. The first question is "How long after a prior elution is the radioac- tivity of es"lTc in the generator maximized'?" A related yuestion is "What is the 9!'mTcactivi- ty at various times as a fraction of this maxi- mum activity'?''The first step necessary to answer thesc questions is to multiply both sides of equation 7 by A, to give units of disintegra- tions per second (A) rather than atoms (N):

The maximum activity of YsmTc ispresent in I 166 Appendix B the generator at 22.9 hours following prior elu- a fraction of """o radioactivity after any time tion. Using equation 9, if t = t,,, = 22.9 t?" This information allows the calculation of hours, then solving for A, yields the tnaximurn el~tionefficicncy as well as the cxpccted yield activity of g9mTcas a fraction of the initial ac- of 991nT~,based on the calibration activity of tivity of SgMo.ApZix is thus equal to 0.677 A?. SgM~.The function g(t) is equal to A2 (equation By substituting various time intervals intoeyua- 7 multiplied by X,) divided by A, (equation 4 tion 9 and dividing by A:';'", the fraction of the multiplied by A,) and reduces to: maximum activity of "'"'Tc present at any time following prior elution is determined.This function is: 'The limit of this function as t becomes very large is:

The equation was evaluated at several values oft and the resultant data are presented in Table 1 and Fig. E-3. The f(t) factor allows oneto de- termine relative activities of !IDrnTc on the col- umn at various times (example I, p. 168). Note that within 2 hours after prior elution, 25% of the maximum BglrLT~radioactivity is rcgen- When t is large, for example, greater than ap- erated. proximately 2 to 3 days, the radioactivity of A second question regarding the gsMo/!'9mT~ lrBnLTc becomesa constant fraction of the !49Mo system is "What is theradioactivity of YgmT~as radioactivity (0.946) and dccreases withthe half-life of "Mo; this isknown as transient Table 2. Radioactivity of 9YmTcin generator as fraction of present 99M~radioactivity

g(t) ~ AL = 0.8605 A,(c-'J - e A, (A, - h,)(e-Al')

Time (hr) a(t) 0.5 o.04~ 10.0 0.614 27 0.890 I .o 0.094 10.5 0.631 28 0.896 1 .s 0.138 11.0 0.647 29 0.Wl 2.0 0.17Y 11.5 0.662 30 0.90s 2.5 0.21x 12.0 0.677 32 0.913 3 .0 0.255 13.0 1.704 34 0.919 3.5 0.290 14.0 0.728 36 0.924 4.0 0.324 15.0 0.750 38 0.929 4.5 0.35h 16.0 0.769 40 0.932 5.0 0.386 17.0 0.787 44 o ,937 5.5 0.414 18.0 0.803 48 0,940 6 .O 0.441 19.0 0.8 17 54 0.943 6.5 0.461 20.0 0.830 60 0.944

7.0 0.492 21.0 0.841 66 0 I 94s Time since previous elution (hours) 7.5 0.515 22.0 0.852 72 0.946 Fig. 9-4. Radioactivity of OgrnTcas fraction of !'!"o 8.0 0.s37 23.0 0.861 78 0.946 radioactivity. Transient equilibrium is demonstrated 8.5 0,558 24.0 0.870 84 0.946 as tcchnetium activity approachcs constant fraction 9.0 0.578 25.0 0.877 00 0.946 of rnolybdcnumactivity (0.946), 2 to 3 days after 9*5 0,596 26.0 0.884 96 0.946 previous elution. Practical gmcmtor kinetics 167

quilibrium. Function g(t) was evaluated versus atoms of technetiun~(both the metastable and ime,The data are presented in Table 2 and ground-state isomers), and reduces to: lisplayed graphically in Fig. B-4. Withthe radioactivity of "DMo from the stated calibra- tion activity, this factor allows onc to calculate X,(e-"t I- e-%') the present radioactivity of OYnlTcin the gcn- 1. 162(A2 - A,) (1 - erator.Comparing this with the eluted radio- activity yields the elution efficiency (examples This function was also evaluated versus timc; 2 and 3, p. 168). results are shown in Table 3 and Fig. B-5. The A third question answered by the basic kinet- mole fraction is undefined at t = 0 (the denomi- ic equations (4, 7, and 8) is "How much of the nator is zero when t = 0).but by using l'H6pi- technetiu~min a generator is present as themcta- tal's rule it can be shown that the limit of h(t) stable jsomer?" Another tnanipulation of thc as t approaches zero is 0.8605. This is another equations allows one to prepare a table of 99m way of arriving at the branching ratio and re- mole fractions at various times following prior states the facl that the first "Mo nucleus to elution, that is, the fraction of the total molar decay after t = 0 has an 86% probability of quantity of technetium which is present as 99111. going to the metastable isorncr. Since Ntclttrl= Thus the total quantity of technetium canbe Ng9,,,/h(t)and A,,, = X9~nlN~!~m,then calculated from a knowledge of 99m radioac- tivity in theeluate and the time elapscd be- tween elutions.qThc function describing the mole fraction,h(t), is simply the nutnber of The total number of atoms of technetium in atoms of ovnlTcdivided by the total number of an eluate can be calculated from the activity of

Table 3. Mole fraction of technetium in generator as rnctastablc isomer t "_""""""" t

Time Time (hr) h(t) (hr) h(t)

0.5 0.X36 10.0 0.506 27 0.248 1.0 0.X13 10.5 0.494 28 0.239 1.5 0.790 11.0 0.482 29 0.231 2.0 0.768 11.5 0.471 30 0.223 2.5 0.147 12.0 0.4(10 32 0.209 3.0 0.727 13.0 0.439 34 0.196 3.5 0.707 14.0 0.419 35 0.I X4 4.0 0.68X 15.0 0.401 38 0. 173 4.5 0.670 16.0 0.384 40 0. I63 5.0 0.653 17.0 0.367 44 0. 146 5.5 0.636 18.0 0.352 48 0.131 6.0 0.619 19.0 0.338 54 0.1 I3 Time since previous elution (days) 6.5 0.603 20.0 0.324 60 0.098 Fig. 8-5. 99111 mole fractionas function of time. 7.0 0.588 21.0 0.311 hb 0.086 This allows calculation of totalmolar yuantity of 7.5 0.573 22.0 0.299 72 0.077 technetiutn in eluatebased on A, and time since 8.0 0.559 23.0 0.288 78 0.068 previous elution. Since first 99M~)nucleus to decay 8.5 0.545 24.0 0.277 84 0.061 after t = 0 has 86%probability of decaying to Y9mTc, 9.0 0.532 25 .0 0.2ci7 90 0,055 mole fractionapproaches 0.8605 astapproaches 9.5 0.519 26.0 0.257 96 0.050 - zero. 168 Appertdix B

Table 4. Molybdenum-99 decay factors iseluted at 7 A.M., the Y"mT~in thegenerator will be back to 36% of maximum activity at 10 Factor = c-hr A.M., if more activity is needed. Time Time Time 2. How many millicuries of' 881nTcwill youexpect (hr) Factor (hr) Factor (hr) Factor to elute from the generator at8 A.M. Friday mom- ing, assuming 95% elution efficiency, if the prior -168 5.76 -48 1.65 36 0.6X7 chtion was at8 A.M. Thursday'! The molybdenum -144 4.49 -44 1.58 40 0.6.59 is calibrated For 200 mCi at noon Friday, Friday 3.64 - 114 -40 1.52 44 0.632 at 8 A,M. is 4 hours prior to calibraticln tirne, so -120 3.49 -36 1.46 48 0.606 from Table 4 ("Mo decay factors): -116 3.35 -32 1.40 52 0.S8I -112 3.22 -28 1.34 56 0.558 -]OX 3.08 -24 1,28 60 0.535 From Table 2, after 24 hours the Bc'lnT~radioac- -104 2.96 -20 1.23 64 0.513 tivity is 0.870 of !IBMoradioactivity: -100 ?.X4 -16 1.1X 68 0.492 -94 2,72 - 12 1.13 72 0.472 -92 2.61 -8 t.09 96 0.368 With 95%) elution cfficicncy, the yield would be -88 2.50 -4 1.04 I20 0.286 approximatcly 172 mCi eluted from the column. -84 2.40 0 1.00 144 0.223 3. A generator is eluted daily at 8 A.M. On Thursday -80 2,30 4 0.9S9 168 0.174 morning 442 mCi are washed from the column. -76 2.21 8 0,920 192 0.135 Themolybdenum is calibrated for 40(> mCi at -72 2.12 12 0.882 216 0.105 noonFriday. What is theelution ef'iiciency? -6X 2.03 16 0.846 240 0.082 Thursday at X A.M. is 28 hours prior to calibm- -64 1,95 20 0.812 264 0.064 tion time of the molybdenum; therefore there are -60 1.87 24 0.779 288 0.050 536 n1Ci of molybdenum on the column: -56 1.79 28 0.747 312 0.039 -32 I .72 32 0.716 336 0.030

(536 mCi? (0.870) = 466 mCiHYmTcon the colutnn 9Ym and from the 99m mole fraction, which is based on time elapsed since prior elution. (Ex- 'Therefore,elution efficiency = 442/466 x ample 4 below illustrates this calculation.) The 100 = 9S%. One should be aware,however, thatthere may be son~einaccuracy in generator number of moles (NtOt,,divided by Avogadro's calibrations and dose calibrator readings.5 number) multiplied by the atomic weight gives 4. Similarly, what is the total mass (grams) of tech- the mass of technetium in solution. netiumpresent in theeluate that contained 442 mCi of ""'Tc at the time of elution'? Examples h(t) at 24 hr = 0.277 1. On Friday night a technologist is called to do a lung Scan and elutes thc generator at 9 P.M. S~V- era] patients are scheduled for studies 011 Satur- day,and as much radioactivity as possible is (442 mCi) (3.7 X 10' dps/mCi) (3,600 seclhr) - needed. the technologist waited until A.M. If I(? to (0.277) (0.1151 hr-l) elute the generator rather than eluting at 7 A.M., by what percentage would the yield be increased'?

f(t) ffom Table I 9 I'.M.-7 A.M. = 10 hr 0.817 9 P.M.-10 A.M. = 13 hr 0 907 Conclusion As illustrated in the previous examples, the factors presented in Tables 1 through 4 allow The yield of a 10 A.M. elution will be I I8greater simple and accurate calculation of various pa- than at 7 A.M. However, note in Table 1 that if it rameters in regard to the 9t"~/S9mTcgenerator. Practical generator kinetics 169

EQUATION 2

By rearranging:

Multiplying by theintegrating factor gives

By substituting the value of C back into equa- tion 2a and rearranging: 170 Appendix B

Substituting the value for C back into equation 3s and rearranging yields:

Sincc N! = 0.14Ny + 0.86Ny,

Appendix 2: HP-67 program for By the initial conditions, when t = 0, N3 = technetium generator kinetics N?. Solving for C: ABSTRACT Calculates nine generator elution parameters NP = -0.14N:' - NB t based on one to four input variables. Deter- mines total concentration of Tc in eluate in atorns/milliliter, gramsimilliliter, and molarity; !IYmTcactivity as a fraction of maximum osmTc activity and as a fraction of 99Moactivity; mole fraction of Tc as metastableisomer; elution efficiency and expectedyield in millicurics. Required input may be any or all of (1) rremTc activity at time of elution, (2) time between elutions, (3) time since "Mo calibration, or (4) calibrated activity of 99M~. Pructical generator kinetics 171

USER INSTRUCTIONS

Input Step Instructions (datalunits) Keys 1 Load side I and side 2 2 Initialize (store constants in R,-R,,) A 3 Enter time since previous elution, t H .“SS B or 3 Enter time since previous clution, 1 1i.MMSS c or 3 Enter time since previous elution, t tI . MMSS n or 3 Enter time since previous elution, t H.MMSS ENl‘ER Enter previous elution efficiency “UE’* ENTER Enter calibrated activity of “!’Mo mCi ENTER Enter time since !’,Mo calibration, t“ n .MMSS E or 3 Enter time since previous elution, t H.MMSS ENTER Enter gsmTc activity (6ij elution), A mCi/ml I’, a or 3 Enter tjn~csince previous elution, t H.MMSS ENTER Enter Y!””Tc activity ((in elution), A mWml f, b or 3 Enter time since previous elution, t H.MMSS ENTER Enter !jgrnTcactivity (61. elution), A rnCi/ml f, c or 3 Enter decay time, t 13. MMSS ENTER Enter initial activity of 9NnT~,A ntCi or Iml f, d or 3 Enter time since previous elution, t H.MMSS ENTER Enter total mCi of SYmT~eluted, A mCi ENTER Enter calibrated activity of 9L’Mo mCi ENTER Enter time since 9!’Mo Calihi”dtiOn, t“ H MMSS f, e

Problems

1. We are required to keep a "Mo/S"T~U~ patient is delayed and does not present generator in decay for ten half-lives before himself for the study until 1215. The phy- turning it over to the radiation safety de- sician asks you if there is enough activity partment for disposal. remaining to dothe study. You tell him a. How many days must the generator be that the dose is now worth kept after the date c~fcalibration? mCi . b. What isthe activity d thc "Mo left 8. What activity is represented by 0.6 ml of on the column if thc initial activity was 75Se selenomethionine on July 31 if the 600 mCi? concentration of radioactivity on June 30 2. a. How much activity of 5"TcO- 4 re- was IO0 pCi/ml? mains after ten half-lives if the initial 9. A nuclear medicine physician desires to in- activity was 100 mCi? ject his patient with 20 mCiof 99mTc b. What percent of theoriginal activity DTPA at 1300 for a dynamic flow study does this represent? and brain scan. He requests an injection 3. If you desire to reconstitute a cold MAA volume of 1 ml or less to assure a good kit with 75 mCi of R9mTc0i,and you milk bolus. Your OgrnTc-DTPAkit was pre- a generatorthat yields 823 mCi of "mTcO-4 pared at 1000 with 75 mCi YRmTcO;in a in 1 I .4 ml of saline, how many milliliters volume of 3 ml. of the generator eluate do you need to in- a. What volume must you draw? ject into the shielded MAA vial? b. Do you need to prepare a new kit? 4. If you had q.s.ed. the "mTc-MAA kit IO. You read a vial containing rslI solutiw for (problem 3) to 4 ml with normal saline, therapy and find that you have 75 mCi on howmuch volume must you draw into a hand.The solution was received 4 days syringe in order to obtain a patient dose of earlier. How much radioactivity was in- 4 rnCi 9Qn1TcMAA'? (Assume no radioac- itially received? (Tt = 8 days.) tive decay.) 11. TheT, of indium 113m is 100 minutes. -3 -I 5. If the reconstituted YDmTc-MAAkit (prob- Calculate the decay constant. 2= 4,y3 lems 3 and 4) contains S million MAA 12. What isthe number of atoms needed to particles, how many particles would be in- produce 1 pCi of activity of IlxmIn? 3.2P''- jccted into the patient for the 4 mCi YgmT~- 13. What is the weight of I mCi of 113mln?.L ~/a'"'F' MAA dose? 14. 5 ml 99Mo/99mTc-generatoreluate con- 6. A 9gmTc-sulfur colloid kit is prepared at tains 75 mCiof S"TcO; and 52 pCi of 0900 with 60 mCi of 9QmTcO; in a totdl ggMo breakthrough. If the maximum al- volume of 7 ml. How many milliliters must lowable human doseis 5 pCi of "Mo, be injected into a patient's vein at 1330 to what is the maximum activityof pertechne- provide a dose of 3 mCi? tate that can be injected based on this cri- 7. A nuclear medicinedepartment sets its terion alone? dosage requirements for a thyroid trapping 15. In problem 14, what is the maximurn vol- study at 3 to S mCi 5ymTcO;. A dose of 5 ume of 99mTc0; solution that can be in- mCi is ordered calibratedfor 0800. The jected? 173 174 Problems

16. Stillconsidering problems 14 and 15, if 28. If the physical half-lifc of tritium oxide is you wait 2 hours, what isthe maximum 12.3 years andthe bialogichalf-lifc of activity of "mTcO;- that can be injected? tritium oxide is 10 days, whatis the ef- (Assume negligible "'Mo decay.) fective half-life of the isotopc? 17. Considering problems 14 to 16, what is the 29. If a radionuclide has a physical half-lifc of maximum volume of "'lllTcO; that can be 12 days and a biologic half-life of 14 days. injected? what is its effective half-life? 18. If the intensity(exposure rate) at 2.S cm 30. If the number of photons emitted from a from a point sourcc is 256 mr/hr, what is point source is 10,000 per second, what is the intensity (exposure rate) at 5 cm from thc flux at a distance of 5 cm fromthe the point source? point source? 19. What is the exposure rateat 20 an in prob- 31. What is the flux at 10 cmfrom the point lem IS? source (problem 30)') 20. If the exposure rate at 50 cm from a point 32. The conclusion that canbe drawn from source is I mr/hr, what is the exposure rate the evaluation of calculations in prob- at 25 cm? lems 30 and 31 is that doubling the dis- 21. If one doubles the distance from a point tance from a point suurce decreases flux source, the exposure drops to t 0 its originalvalue. (Express as the initial value.(Exprcss as a fraction.) a fraction.) 22. If one triples the distance from a point, the 33. What is the radioactivity of a point source exposuretodrops the initial for g9mTc04if the flux is 32 photons/cm2/ value. (Exprcss as a fraction.) sec at S cm? 23. Radiopharmacist A transfers a reaction vial 34. What is the radioactivity of a point source from alead container to a calibrator by of '311 if theflux of primary rays is 32 holding the top of the vial with his hand; photonslcnP1sec at 5 cm'? the transfer takes 10 seconds. By doing so, 35. AssumingPoissona distribution, how his hand is about I cm from the point- many counts represent 1 standard deviation source activity. Let us assume his hand is of 10,000, 1,000, and 100 counts'? exposed to 500 mrlhr. Radiopharmacist B 36. What percent of thc total count rate is rep- uses a 16 cm pair of tongs to transfer the resented by 1 standard deviation when the same vial; the transfertakes 20 scconds. mean count of a sample is 10,000? 1,000'! What dose does radiopharrnacist B receive I OO? to his hand? 37. As the count increases, does the percent of 24. A radium source of 40 mCi may be used the total counts represented by I standard to calibrate survey meters. How far do we deviation increase or decrease? have to be away from the source to cali- 38. Within how many standard dcviations of a brate the survey meter at I00 mr/hr? mean count of 73,441 is 479? 39, What is the 3 standard deviation interval of r = 8.3 r/mCi. hr at 1 ctn a count with a mean of 395,64 1 '? 25. If thehalf-value layer of g°Co is 1.2 cm 40. If one nanogram of element A decays at a of lead, how much lead is required to re- rate of 3.7 X IO7 dps, what is the specific duce the exposure rate frorn 2,048 mnrlhr activity of I microgram? to 2 mrlhr? 41. A physician wants all his samples rcportcd 26. Threehalf-value layers will reducc cx- to him ata 2-sPandard deviation confi- posure from a source to its dence level and at no no re than a 3% error. original value. (Express as a fraction.) What is the minimum number of counts 27. How many radioactive atoms remain if 3.7 that his technologist must collect? X 10" atoms of ''jll have decayeddur- 42. If a physician is willing to acccpt results ing the last X days? For g9mTcO; after 6 with a 2-standard deviationcontidencc hours'? level and a 10% error, what isthe mini- mum number of counts that must be col- kit and wish to run a yuality control check Iccted? on our product with TLC procedure. We 43. A technologist has 8 hoursto count 100 spot one strip each for solvents of saline samples for Dr. Hurry. He is a demanding and acetonc, separate, and count. Our re- person and requires that his lab results bc sults are as follows: statistically signilicant and on time. It takes Saline Acetone 30 minutes to gathcr the samples.The technologist finds that the samples read ap- 725 cpm proximately 5,000 cpm, and the sample control blank is 50 cpm. The most efficient use of thc remaining time wouldbe to What is the percent hydrolyzed, oxidized, count each samplefor I min- and tag in our product'? utes andutes each blank for min- 49. Given the following data, what is the per- utes. 44, Assume we have 100 reactive Ab (anti- cent hydrolyzed and pcrcenl free Y9mT~O; body) sites and 1,200 cold Ag (antigens), in our generator eluate? along with X00 Ag* (radioactive antigcns). Aftcrequilibrium, whatis thc bound-to- frce ratio? 45. Refer to problem 44. What is the ratio of the bound Ag and hound Ag*? 46. You arc asker1 to run an in vitro T4 test on 50. A sulfur colloid quality control test gives a patient sample and choose a cornpe,titive us the following data. What is the pcrcent protein binding assay. To generate your oxidized and the pcrcent tag? standard curve, you chooseto runtubes containing 0, 5, 10, 15, and20 pg%~of sodium levothyrnxinc (Synthroid) (T,) and add *T4-TBG in cach tube that gives 10,000 counts/min. You allow each tubc to come to equilibrium, separate the bound T,* from the frce T4*, and gct the follow- 5 I. A sample of oomTcpyrophosphate is in- ing results. jected into the tailvein of a mouse. The injection syringe reads 20 pCi at 1000. At 1200 the injection syringe residual is read at 6.4 pCi. A standard of 9on'Tc pyrophos- phate is also prepared and reads 18.9 pCi at 1000. This standard is diluted to 2 ml; 0.1 ml of this will bc uscd for cornparison a. Plot the standard curve. with the organ counts. The mouse is sacri- b. A normal value in your area is 5 to 14 ficed 4 hours after injection, and thc fol- pg% T4. Your patient counts4,000 lowing organs are dissected and counted: cpm. What is his pg% of T4'?Is he in heart, stomach,liver, skeleton, muscle, nonnal range'? blood, and urine. 47. Assume we have a sample with 3.5 X IO4 a. Howmuch activity was injected into counts/ml. If we add I ml of this to a sam- the mouse? 'The organ system counts ple of unknown volume and lind that 1 ml obtained are: of this after mixing gives us a count ratc of 625 cpm, what is the volume of the unknown solution'? 48. We prepare a technetium-pyrophosphate 176 Problems

Skelcton 1,010,792 cpm volume and inject 10 pCi of '"RISA in 1 Muscle 60,647 cpm ml volume. You take 1 nil patient plasma Blood 40,431 cpm samples at 10 minutcs and 20 minutcs after Urine 808,636 cpm injection and obtain count rates of 2,450 b. Howmany countsrepresent 1 pCi of cpm and 2,385cpm, respectively. Your the standard at sample counting time? standard, eluted to 1.000 ml, gives a count c. How many counts represent I pCi of rate of 4,872 cpm/ml, the sample? a. Plot the data to find T,,. d. How many cpm represent 1 pCi initial b. Calculate the patient's plasma volume. activity after 5 hours for the standard 55. You desire to determine the clearancc of' and sample'? 100 pCi of '@Yb DTPA in a rabbit. The e. Calculate the organbiodistribution for dose is injected intravenously, and a probe each of the organs listed below. Ex- is placed over the animal's head. Counts press answers as (1) total pCi in each obtained over the head are: organ and (2) percent injected dose per 3,000 cpnl at time of injcction each organ. Note: Your organ distribu- 1.800 opm at IS minutes tions should add up to 100%of the I, 100 cpm at 30 minutes injected activity in this hypothetical 620 cprn at 45 min1~te.s problem. 370 cpnl at 60 minutes a. Plot the data on linear and semilog Heart "" -" Stomach __-_ ____ graph paper. b. Assuming thedrug is cleared only by Liver -___ the kidneys, plot the theoretical radio- Skeleton "- activity that would be in the bladder at Muscle times 0, 15. 30, 45, and 60 minutes on Blood -___ the graph paper usedin part a. (As- sume that urine passed from the Urine " no is bladder during the course of the study 52. If you have 100 ml of a radioactive sub- and that once the drug is clearcd by the stance and the concentration is 420 pCil kidneys, it isimmediately transferred ml: to the bladder.) a. What would the concentration be if you c. What is theapproximate time during were to dilute the sampleto 140 mi with the study that the amount of isotope is normal saline? thesame in the bloodpool and the b. What is the amount of total radioac- urine? tivity contained in each of the organs d. Calculate K. mentioned above'? e. Using the formula At = Aoe-kl, calcu- 53. Given the following data, calculate the red late the activity remaining in the blood cell mass. pool at the times I5 and 45 minutes. 56. The content of one 1311 NaI uptake capsule AWB,= 460cpm/ml - dilution Go ) reads 75 FCi and weights 870 mg.This AwH2= 340 cpndml (no dilution) is mixed thoroughly with an unknown amount of powder; a 1-gram aliquot of the A,, = 49 cpm/ml -dilution combination reads 3.54 $3. What is the (la ) total weight ofthe powder after mixing'! A,, = 30 cpm/ml (no dilution) 57. A patient is given a ''illNal uptake capsule Hct, = 0.60 measuring 15 pCi. The patient's thyroid is HCt2 = 0.67 counted at intervals of 2, 6, and 24 hours. VI = 9ml An identical capsule is counted as a con- 54. You desire to calculate to patient's plasma trol. The net counts obtained are: Problems 177

Tirw Patimt Strrndurrl shell) fills a K shellvacancy, what is 2 hours 3 3 I2 cpm 54,296 cpm the energy of the resultant x ray? 6 hours I 1,3 14 cptn S2,87 I cptn 61. Complete the followingreactions and list 24 hours 27.913 cpm 49,592 cpm intermediate reaction products. a. Calculate the percent uptake of the thy- Inter- roid gland at each time intcrval. lf the upper range of normalthyroid radioiodine uptake in your geographic area b. :iZn (p, 2d-I is 20% at 24 hours, if it is decided that this c, elcctruo capturc patient is hyperthyroid, and if the patient's 1 physician decidcs to use 13'1 solution to ablate the thyroid in order to return thc pa- ticnt to a euthyroid state: b. Calculatc the volume of the gland if the following. measurements aremade:

Left lobe: r = 1.2 cm, h = 8 cm 62. Arsenic injection in man will cause acute Right lohe: r = 1.6 cm, h = 7 ctn toxicity symptoms in a dose of 100 mg. If c. If the physician decides to give 100 2 mCi of 72As is used as a brain-scanning pCi of I3'I NaT solution per gram of agent (Tt = 26 hours): thyroid, what activity should he ad- a. How many milligrams of arscnic would minister to the patient? Hint: Consider be injected into a patient'? uptake! b. How much activity of 72A~represents 58. 1 mCi of rsllMAA delivers a dose of ap- 100 mg of arsenic? proximately 6.6 rads to the lungs, and I 63. A normal dose of e!'mTc pyrophosphate in a mCi of 99mT~MAA delivers approximately 70 kg man is 20 mCi, which contains 4 mg 0.4 rad to the lungs. If the usual dose of of pyrophosphate. Calculate on a weight: 1311 MAA is 300 pCi and the usual dose weight basis the dose for a 20-gram mouse of o!)mTcMAA is 3 mCi, how much of an (injected activity and milligram amount of increase dose is delivered to the lungs if pyrophosphate). ':'I1 MAA is used instcad of ""'Tc MAA? 64. A patient is given 150 mCi of I3lI solution 59. If bone scans with 99mTccompounds are to treat a thyroid cancer. The urine is col- often perfr,rmed 3 hoursafter injection, lected for 24 hours, and its radioactivity is what is the optimum effective half-life for assayed at 63 mCi. Hospital policy allows such a tracer? the release of a patient when total remain- 60.Consider this hypothetical atom that will ing body activity is 30 mCi or less. If the decay by electron capturc: urine is collccted for another 24 hours and measures 41 mCi, how much activity re- BindingShell energy mains in the patient? Can the patient be rc- 0 leased from the hospital? 0.4 kev shcll N 65. Thewhole-body maximum permissible 1.Y kev M shell 12.8 kcv 12.8 L shell dose to an adult is 5 rem/yr. Howmuch 15.0 kcv K shell cumulatedexposure is allowed for a 21- i year-old radiation worker? a. If an e- from the L shell fills the hole 66. Howmuch OgmTc is present in a ""Mol in thc K shell andan e- from the M 99TcO- generator 4 hours after a milking shcll fills the vacancy created by the L if the initial activity of 9gM0 was 400 mCi, shell, what are the two resultant x-ray and 32 mCi of 9s"'Tc remained on the col- energies'? umn after the milking? b. If an ambient electron (not in an orbital 67. How many mCi of YYmTcare on the column 178 Problems

of a 99Mo/99mTcgenerator 4 hours after a. How much IZM1is formed in 1 hour'? loading by the manufacturer if the amount b. How much lZMlisformed in 3 hours? of "Mo loaded was 400 mCi? (Assume no c. How rrluch lZR1would bc formed in I !'9mTc0: is loaded onto the column.) hour if the ncutron flux wcre reduced to 68. How long after an elution does it take for one half its initial valuc'? the!'i'm'rc buildup from a "Mo generator d. How many half-livzs are requircd to to reach rnaximum activity? produce SO% of the maximum radio- 69. How many rnCi of "Mo remain in a gen- activity at the initial neutron flux'? erator 48 hours after calibration if the cali- e. How many half-lives are required to bration activity was 550 mCi? produce 80% of the maximum radio- 70. 10 mg of lZ712 is subjected to neutronir- activity at the initial neutron flux'? radiation at a flux of 1 X IO9 neutrons/ f. If a 3-hour irradiation is used and the cm2-sec for a periodof 1 hour, thereby radioactivity is assayed 3 hours after the forming 9,which has a T+ of 25 min- end of the irradiation, how much radio- utcs.The activation cross section is 7 activity is expected'? barns. * -. ._ * IO-"/cm'/atorn. Glossary

accelerator Commonlyreferred tcr asan “atom smash- carrier Stable at~n~sthat are mixed with radiodctive atoms cr.” A device uscd to impart a highkinetic energy to of the same clement (i.e., same atomic number) in the a chargcd particle to cause it to undergo nuclear or par- same chemical firm for the purpose of carrying out a ticlereactions. From the standpoint of theassociated chemical process. “temperature” in the light of the kinetic theory, the ac- carrier free The adjective applied to a nuclide that is essen- celeratoroccupies the same position with respect to tially free of its stablc isotopes. nuclear reactions that the Bunsen burner occupies in the catalyst A substance that hy its presence alters the rate of a field of chemical rcactions. Common accelerators are the reaction and itself remains unchangcd at the end of the cyclotron,synchrotron, Van de Graffaccelerator, and reaction. . cation A positivcly chargcd ion. acidic Having the characteristics of an acid, that is, a sub- channeling (for chromatography columns) Duringcolumn stancewhich gives hydrogen ion in solution or which chromatography, channeling is a process in which liquid neutralizcs bases, yielding water. In general, an acid is flows through a fewpathways instead of washingthe a nlolecule with a positivc field that is capable of neu- whole column. tralizing a basic mvleculc having a “free” electron pair. chelate A metal iron attachedto a complexing agent at more aerobic Growing only in the prcsence of molecular oxygen. than one point (i.e., by more than one ligand). allquot A small but representative and reproducible part of colligative (properties) A property of matter numcrically something, such as part of a solution, a sample. the same for a group of substances, independent of their anaphylaxis An unusual or exaggeratedreaction of the chenlical nature. organism to foreign protein or other substances. An apparatus used to confine radiation to a nar- anion A negatively charged ion. row beam for the purpose of directing that beam or lor aquatlon The replacement of coordination groups by water measuring radiation from an extended source. molecules. collold A phase dispersed to such a degree that the surface aseptic Notseptic (alive); free fromseptic (living) ma- forceshecome an important factor in determining its terials. properties; the particle size is usually 50 to 500 ,u. Avogadro’s number The number of molecules in a mole, complex A compound 01- two or more parts, in which the 6.0228 X loz3,or the number of atoms in a gram atomic constituents arc more intimatelyassociated than in a weight. simple mixture. baderla (PI.), bacterium (s.) In general, any microorganism compoundlng To form by combining parts, to form a of thc order Eubacteriales; a nonsporc-forming, rod- whole, to put together. A pharmacy term describing the shapedor nonmotile, rod-shaped microorganism. A making crf a drug or radiopharmaceutical. looselyused generic name for any rod-shapedmicro- DX Medical shorthand for cliapmslsis; the determination 01 organism, especially enteric bacilli and morphologically the nature or cause of a disease; also used to indicate a similar forms. diagnostically useful radiopharmaceutical. bacteriostat An agent that inhibits the growth of bacteria. dimer A compound formed by thc union of two radicals or basic Having the characteristics of a base, that is, a sub- twomolecules of a simpler compound. Morespecifi- stance which gives hydroxide ion in solution or which cally, a formed irom two molecules of a mono- neutralizes acids, yielding water. mer. biodlstribution The distribution of materialin a biologic electrolysls If a current, i, flows for a time, I, and deposits system, such as an experimental animal. a metal whose electrochemical equivalent is e, the mass, buffer A solution containing large amounts of both a weak wz. of mctaldeposited is m = eit. The value of P is acid and a weak basc that is able to react with added acid usually given for mass in grams, i in amperes, and t in or base, neutralizethe added ions, andrcmain at the seconds. original pH. electron volt (ev) The kinetic energy gained by an electron 179 180 Glossary

after passing through a potential difference of 1 volt. The (same Z and same A) butexisting in differentcncrgy is used to measure the smallamounts of states. energy availahle from individual nuclear reactions. Any one of several nuclides with the same numbcr element A substancccomposed entirely of atoms of the of neutrons in the nucleus but differing in the number of same atomic number. protons. embolus A clot or other plug brought by thc blocd from isotope Onc of a group of nuclides of the same element another vessel and forced into a smaller one so as to ob- (same Z) with the same number of protyns in the nuclcus struct the circulation. but differing in number of ncutrons, resulting in different emulsion A system consisting of a liquid dispersed in an values of A. Sometimes used as a general synonym for immiscible liquid. usually in ciroplcts of largcr than col- nuclide, but this use is not recommended. loid size. kinetics A branch of science that deals with the effects of emulsion (photographlc) A suspcnsion of a sensitive silver forces on thc motions of material bodies or with changcs salt or a mixture of silver halides in a viscous nledium (as in a physical or chctnical systcm. a gelatinsolution) forming a coating on photographic llgand A chemical group, ion, or moleculc courdinatcd tu u plates, film, or paper. central atom or group in a complex or chelate. equlllbrium, chemicalA state of affairs in which a chemical macroaggregatedA particle size of 10 p and up; this size reaction and its reverse reaction are taking place at equal is used for lung scanning. velocities, so that the concentrations of reactingsub- massspectrometer A device for measuring thc mass of stances remain constant. individual particles by passing them through elcctrostatic freeradical A chemicalspecies having onc or more un- and magnctic fields. paired electrons. meantransit tlme The average time for a bolus to pass fritted glass Smitered (ground glass melted into a porous through a particular organ or area. mat) glass uscd in filtration. metabolism The sum of all physical and chemical processes functional imagingor parametric ImagingA derived image by whichliving organized substance is produced atld formed according to some mathcmatical rule, as hy di- maintained and also the transhimation by which energy vision of one image by another. is made available for the uses of the organis-. gel A colloid in a solid or semisolid form. metal A substance posscssing so-called metallic propertics halogens Group 7; the includedelements are Auorinc, such as electricconductivity, heat conductivity, high chlorine, bromine, iodine, and , usuallywith a reflectivity, and luster, properties duc to the high degreo -I charge, that is, C1-. of freedom possessed by electraps of the substance. hmatocrtt (Hct) An expression of the volume of the red micelle A unit of structure built up frnrn complex molecules blood cells per unit volumeof circulating blood. into ct>lloids. HSA Human serum albumin. mlcroaggregatedA particle size of less than 3 p used for hydrolysls A reaction involving the splitting of water into liver scanning; aggregated denatured albumin. its ions and the formation of a weak acid, base, or both. mlcrosphere A sphericalparticle usually I to 3 p or 15 A reaction inwhich water is lost from a complex or to 35 p in diameter and made from heat-denatured strum chelate. albumin. infarcted (infarct) An area of coagulation in a tis- molarity Thc concentration of a solute in a solutionex- sue due to localanemia resulting from obstruction of pressed in molar units, that is, moles ut‘ solute per 1,” circulation to the area. ml of solution. One mole is the weight of a substance In situ (Latin) In the natural or normal placc; confined to in gramsnumerically equal to its molecular weight; a the site of origin without invasion of neighboring tissucs. “gram molecule.” intrathecal Within a shcath. Applied to the cerebrospinal mole Synonym for gram molecular weight. fluid cavity. NBS standard A standardizedand/or intravenous Within a vein or veins. certified by thc National Bureau of Standards. in vitro (Latin) Within a glass; observable in a test tube. neutron activatlon analysisA method of elemental analysis In vivo (Latin) Within the living body. based on identification of ncutron-imdiation prqducts, Ionization The process of knocking electrons from atoms or normality lhc concentration of a solutein solution ex- molecules,thereby creating ions. High temperatures, pressed in gramequivalent weights of eitheracid or electricaldischarges, and nuclear radiation can cause base. One gram equivalent weight is equal to the weight ionization. of substancenecessary to give 1 mole of hydrogel1 or ischemlc () Pertaining to a deficiency of blood in hydroxyl ions in 1,000 ml or solution. a pw because of functional construction or actual ob- nuclear magnetic resonance A method for examining the struction of a blood vessel. electronicmilieu of a nucleus by excitingthe nucleus One of a group of nuclides having the same total with radio frequencies in a magnetic field. number of panicles (ncutrons and protons) in the nucleus nuclide A general term referring to any nucleus (stable or but with these particles so proportioned as to result in radioactive) plus its orbital elcctrons. different values of Z; for example, 3H and ”e. oletion Polymerization by thebonding of metalatoms isomer(nuclear) One of two or morenuclides with the through one or more hydroxyl groups, accomplished by same numberof neutrons and protons in thc nucleus splitting out waters of hydration. organic (as it refers to chemicals) Chemicals composed of a roentgen The quantity of x or ganmma radiation such that carbon skeleton. the associated corpuscular enlission per 0.001293 gram oxalation The conversion of a bridging OH group to a of air (i.e., I ml at 0" C and 760 mm) produces, in air, bridging 0 group withthe rclease of hydrogen ions. ions carrying 1 electrostatic unit of quantity of electricity This process produces insoluble forms of chromium, tin, of either sign. tcchnetium, and other metal oxides. saline Consisting of, or containing salt, NaCI. Physiologic oxidation An increase in the oxidation state number of an saline is 0.Y% NaCl by weight. clement; the loss of electrons by an atom or group of self-radiolysis A process in which a compound is damaged atonms . by radioactive decay products originating from an atom pH The common logarithnl of the reciprocal of the hydro- withirl the compound. gen ion concentration in moles per liter. It expresses the sequential Imaging A serics of closely timed images, usu- acidity or alkalinity of a solution, a pH of 7 being neu- allyperformed on a rapidlychanging distribution of radioactivity. tral. p~ = log [A] solute The constituent of a solution that is considcred to be palliation (palliatlve)Affording relicf, but not a cure. dissolved in the other, the solvent. The solvent is usually parenteral Not through the alimentary canal; for example, present in largcr amount than the solute. by subcutaneous,intramuscular, intraarterial, or intra- solvent The constituent of a solutionthat is present in venous injection. larger an~ount,or constituent that is liquid in the pure polymer A chemical ct~rnpoundor tnixturc of compounds state, in the case of solutions of solidsor gases in liquids. formed by puttingtogether individual units and con- speclflc activity (I) The radioactivity or decay rate of a sisting essentially of repcating structural units. radioisotopeper unit of mass of the elementor com- porphyrln Complexcyclic compounds such as the heme pound (e+, microcuries per millimole, disintegrations component of hemoglobin. per second per milligram). (2) The relative activity per psychosomatic Pertaining tu the mind-btdy relationship; unit of mass (counts per minute per milligram). havingbodily symptoms of psychic, emotional, or static imaging One or a set of images, usually perlornmed mental origin. on a fixed or slowly changing distribution of radioac- pyrogen A fever-producingagent usually of bacterial tivity. origin (i.e., bacterial endotoxin). sterlle Aseptic,not prducing microorganisms; frw from qualitative Relating to, or involvingquality or kind. Q. microorganisms. analysis:chemical analysis designed to identifythe stoichlometric Pertaining to weigh! relations in chemical cotnponcnts of a substance or mixture. reactions. quantitative Relating to, or involving the mcasuremenr of subllmation (chemical)Passing from the solid to the vqor quantity or amount. Qu. analysis: chemical analysis de- state by healing. signed to determine the amounts or proportions of the sulfhydryl Sulfur-hydrogen group found in Some proteins components of a substance. ( "SH). R, Symbol for Latin recipe, hence used as a symbol for synthesis A proccss in which a new chcmical ccmmpound therapy; also used to indicate a therapeuticallyuseful is formed in a reaction. radiopharmaceutical. target organ For imaging, the organ intended to receivc rad Radiationabsorbed dose: the basic unit of absorbed thegreatest concentration of a radioactivetracer; for dose of ionizing radiation. One rad is equal to the ab- dosimetry, the organreceiving the largcst cumulated sorption of 100 ergs of radiationenergy per gram of radioactivity or theorgan Tor whichthe dose is being matter. calculated. reactor, nuclear A device for supporting a self-sustained thrombus A plug or clot in a blood vessel or in one of the nuclear chain reaction under controlled conditions. cavities of thc heart, fortncd by coagulation of thc blood, redox A gencralterm describing oxidation-reduction rc- and remaining at the point of its formation. actions. toxicity The quality of being poisonous, especiallythe reduction The opposite of oxidation, decrease in positive degree of virulence of a toxic microbe or of a poison. oxidationnumber; gain in numberof electrons hyan It is expressed by a fraction indicating the ratio bctwern atom or group of atoms. the smallest amount that willcause an animal's death and rem Roentgenequivalent man: a unit of human biologic the weight of that animal. dose as a result of exposure to one or many types of transition metalsThe metallic elcments in the center of the ioniring radiation. It is equalto the absorbed dasc in periodic chart. rads times the RBE (relative biological effectiveness) of the particular type of radiation bcing absorbcd. Index

A Alcohol, methyl, 133 Ablation, thyroid, 3, 8, 91 Alkali tnetals, 64, 65 Absolute uptake of tracer, 61 AI& SCP Alutnina Absorption Alpha counting, 113 photoelectric, 96 Alpha emitters, 96 of radiation, 96-98 Alpha particle. 96 studies, 27 Alumina, 117, 119, 120 Accelcrator, linear, 56, 108 columns, 77, 117, 138 production, 107- 1 1 I Aluminum breakthrough, 142 comparison with reactor productiton, 11 1 Aluminum hydride, lithium, 133 ACD, 131 Arnerican Board of Medical Specialtics, 6 Acetone as solvent, 137, 145 Anwrican Board of Nuclear Mcdicine, 6 Acid ArnericanMedical Association Council onMedical Edu- amino; SPC Amino acids cation, 6 ascorbic, 130, 131, 146 Amino acids, 64 diethylcnetriatnine pcntaacetic; sep DTPA sulfur-bearing, 134 dihydrothioctic, 45. 130 solution, 133 ditnercaptosuccinic. 130 Amtnoniutn hydroxide, 107 N-(2,6-dimethylphcnyIcarbamoylmethyl) iminodiacc- Ammot~iumphosphomolybdate, 122 tic, 45 Amoebocyte,Lirnulus, lysate gelationtest for pyrogens, ethylenediamine tctraacctic, 128 81-83 formic, 133 Arnount or tracer, 61-62 glucoheptonic, 46 Analysis gluconic, 46 activation, 32 glutamic, dehydrogcnase, 133 isotope dilution, 28-29 thiomalic, I30 isotopic equilibrium, 31-32 Acid citrate dcxtrose (ACU), 131 tnultichannel spectral, 120 Activation analysis, 32 ncttlronaclivation, 17-105 neutron, 17, 105 substoichiotnetric, 29-3 1 Activation of stable elements, 105.107 Analyzer,multichannel, 141 Active transport, 14-47, 61 Ancillary drugs and adverse reactions, 89 Activities Anemia and hyperfunctioning spleen, 42 of radiopharmacy, 1-3, 5 Anger camera, 34, 35, 52 troubleshooting. 3, 12 closc and, IS0 Activity, specific; see Specific activity quality control testing, 2 Activity-versus-time curve, 24-26, 99-100 Angiocardiogram, radionuclide, 7 Administration Angiography,nuclear, 147 of oral radioiodine solutions, 1, 34, 93-Y4 dynamic studies and, 24 of radioactive tracers, 10, 89 Antecubital vein, 10 imaging, 50 Antibody-bound thyroxine, 30 Adult human elemental composition, 67 Antigens, labeled, 126 Advantages of tracer techniques, 17- 19 Anlimony: sce Sb isotopes Adverse reactions to rdiopharmaceuticals, 88-89 Apyrogenicity, checking system for, 77-83 Agents Arwries, coronary, flow of blood in, 39 chelating, 128-139 Arthritis, rheumatoid, treatment in, 92 cotnplexing, 127- 128 Ascorbate, ferrous ion with. 127 scanning; see Imaging Ascorhic acid, 130, 131, 146 Airline Pilots Association (ALPA), 151 Assay 142,143 of radiochemical purity, 141 /-Alanine, “N-labeled,synthesis of, 133, 134 radioligand, 3 1 Albunun: SPP Human scnm albumin (HSA) of radionuclidic purity, 140- 141 Index 183

Assay - cont'd Bone of total radioactivity, 139-140 cancer, 95 Assurance of radioisotope dosage, 92 nlmow Atomic Energy Comrt~issicm, 6 RE cells in, 40 Atomic mass, 17 in sample dose calculation, 102-103 Atropine, I, 89 scanning,132 '%Au colloid, 40, 70, 91-92 scan, 50 Australia, national radiopharmacy in, 14 agents for, 129 Automation in radiopharmacy, IS I Y9mrc,137, 144-145 Bone-seeking tracers, 61, 65 B Brain-scanningagent, 132, 146 Rreakthrough, 114, 121 I:lTnlBa, 122 aluminum, 142 Bacteria, tcsting for, 79 ""o, 119, 140-141,142 Bacterialsynthesis, 134 "%n. 121 Bacteriostat, 1 IS Bromide,sodium, 122 Ucngal, rose; set Rosc bengal Bromine, 69 Beta emission, 91 Bro~nosulfophthalein (BSP), 13'1, 45 BCtd emitters, 10s Brookhaven rncthod of labeling RBCs, 146 Beta minus decay of 1311, 54 Brookhaven National Laboratory, Beta particles, YG BSP, '>'I, 4S Bifunctional compounds, 72, 73-75 Bureau ol and Kadiopharmaceuticalsof f'ooci and Binding, competitive protein, 31 Drug Administration, 86 Biochemical synthesis, 132- 133 Biodistribution, 5, 65 of iodinated compounds, 69 I'C, 9, 66, 109, 123 studics of, prclirninary, 76-77 compounds, 65 of YamTcpyrophosphate; see 9emlcpyrophosphate, formaldehyde, dis- 133 tribution organicsynthesis, 132-133 01 tracer, 2, 11, 12, I00 "C chlorpromazine synthesis, 132-133 Biologic characteristics of radionuclides, 56-62 "C glucose, 134 Biologic product, radioactive, 3 "C, 3, 66 Biologic synthcsis, 133-134 compounds, 65, 123 Biology. radiation, 95-96 Calcium, 63 Uionuciconics, 7 isotopcs, 65 203, 71 serum, I30 Blockage of capillarics, 3540, 144 Calculation(s) Blocking of thyroid, 62 of pediatric dose, nomogram lor, 149 Blood dosimetry; see Dosimetry, radiation disappearance of colloid from, rate of, 41 of production rates and reactor production, I OS- 1 06 perfusion; see Perfusion of blood of radioactivity in generator, 1 16- 1 17 shunting, 39, 40 of technctium content in pertechnetate solutions, 141 tracer studies (~f,47-48 Calibrator, radiation dose, 139-140, 150 volurnc, 19-21, 47, 131 Camera withdrawal, 89-90 Anger; sep Anger camera Blood cells scintillation; set Anger camera red Cancer labeling, 42-44, 127 bone, 95 with Wr, 42, 48, 131 radiation cxposure and, 95 in vitro,146 thyroid, 8, 69, 91, 95 in vivo,146-147 Capacity of RE systeru tu phagocytize particles, 41 mass,19-21 Capillary blockage, 35-40, 144 sequestration; set Sequestration, cell Capture, elcctron; see Electron capture decay "'"'IC,146-147 Carbinols white dibutyl,133 labeled,134 diethyl,133 98mTc,147 Carhon, 132; SCP ulso C isotopes and compouncls Blood flow Carbon-carbon bond, 132 in coronary arteries, 39 Carbonate.lithium-7. production of fluorine 18 from, indicatorconcentrations and transits as nleasures of, 107 26-27 Carrier, 107 in liver, 24, 41 for syringe, 1, 2 tracer clearance as measure of, 24-26 Carrying cases, 1.53 and traccr localization, 50-5 I Cassen, 33 Blood-poolimaging, 132, 147 Catalysts Blutngan, Herman, 6 in biochetnical synthesis, 133 Bond, carbon-carbon. 132 in organic synthesis, 132 184 lnilKx

Catheters CIO;, 126 indwelling venous, 39. I44 "CO, 1 10, I I I intravcnous, and Wbgenerator, 12 1 "CO,, 132-133. 134 Cavity, peritoneal, effusions, 92 YO, Cells in breath, 3 blood; .see Blood cells in sterility tcsting, 79, 80 Kupffer, 40-41 $?CO,I I I, 134 polygonal, 44. 46 "Cu BIZ,3 1 reticuloendothclial, 40-4 1 4MCo,134 scquestration; see Sequestration, ccll "Co, 120, 134 Central radiophannacies, 14, 151, IS4 Cobalt, 64. 67, 134; see also Co isottopcs Ccrebrospinal fluid (CSF) space, tracer studies of, 47-48 Cohort labeling (11 red hlvod cells, 42 Cesium; set' Cs isotopes Cold spots, 61 C'hwacteristics oi radionuclides; SPC Radionuclidcs. char- Colligative properties of rnolecules, 18 acteristics Collimatcd extcrnal gamma-ray dctcctor, 3 Chard, Swiss, 134 Colloid Chart, periodic; see Periodic chwt of elcrnents IHWAu,40, 70, 91-92 Chccking system for stcrility and apyrogenicity, 77-83 '"1 HSA, 40 Chelates, 128 particlcs; see Particles. colloidal bifunctional, 73, 75 rdtc of disappearance from blood, 41 Chelation, 128-130 sulfur, "ymTc;set' nnmTcsulfur colloid of chromium, 130 Colloids of indium, 131-132 in rdiatiun therapy, 9 1-92 of transition metals, 131 "'"Tc, 142- 144 Chctnical characteristics crf radionuclides, 56-62 Color coding, 150 Chemical scparation: set' Separation, chemical Column Chcmical state, 2 alumina, 77, 117, 138 alteration,107 chromatography,124 Chcrnistry Column generator, 114- I IS chromium, 67 Commercial radiopharmacics, 14 and radiopharrnaceuticaI developmcnt. 72-73 Comparison technetium, 68, 126-131 of radiopharmacy and pharmacy in gcneral, 1 1-14 Chloramine 'I in radioiodination. 124, 125 of reactor and accclerator production of isotopes, 11 I Chlorine, 69 Cotrrparttnental localization, 47-48 in radioiodination, 126 Competitive protein binding, 31 Chlorinc gas, 126 Complexation,I27 Chlormerodrin of chromium, 130 Hg, 70 of indium, 131-132 lwg, 48.72 with technetium, 144 ?&'Hg. 88 of transition metals, 130 Chlorpromazine, 'IC, synthesis,132-133 Compounding, 9, 12 Cholesterol, 50 Compounds Chromate, 67, 68 bifunctional, 72, 73-75 sodium, 20 'IC. 65 Chromatography, I 13 IT, 65, 123 column, 124 iodinated, hidistributions of, 69 gas, 133 labeled, organic, 123 gel-column, 137-138 ssmTc,136 ion-exchangc, 133 Cornpton scattcring, 96 thin-layer, 136-137, 144, 145, 146 Concentrations, indicator, as tneasurcs of blood flow, 26-27 Chromic phosphate, 91-92 Conservation of mattcr, law of. 19 Chromium, 64 Construction of gcnerators, 114- 1 16 chelation and complexation, 130 Contamination chcmistry, 67 by radiochemical impurities, 123, 136: see ulso specific hexavalent, 59 radiochemicals Chromium 5 I; see "Cr in radiopharmacy. 150 Chronic toxicity tests, 86 Contrast in imaging, 61 Cirrhotic liver, 40 Control, quality; see Quality control testing Cisternogram, 47 Control of radioactive materials, 13 Cisternography, 132 Copper, h4 Cl, and radioiodination, 124 Coronary arteries, flow of blood in, 39 Classification of radioactive drugs, 3 Counting Clearance of traccr alpha, I13 from background, h 1 liquid scintillation, 123 as measure of blood flow, 24-26 Wr, 20, 56, 67, 131 Clinical activitics of radiopharmacy, 2-3, 5, 13 decay scheme, Y8 Clinical trials, 87-88 labelingwith, 131 Imkx 185

j’Cr-cont’d Dilution - cont’d red cells labeled with, 42, 48, 131 isotope Cr(llI), I3 I analysis, 28-29 Criteria, design, for radiclpharmaceuticals, 52-75 double, 28 for radiation therapy, Y I rcversc, 28 ‘34Cs. 120 Dilnercaptosuccinic acid, 130 137cs Dimerized proteins, 123 gamma-ray cnegy, 53 Dimethylformatnide,133 source, 140 N-(2,6-DimethyIphenylcarbarnoyImethyl) irninodiacetic 137Cs/137mBagenerator, 122 acid, 45 Cumulated whole-body radiation dose, maximum, 95 Disappearance of colloid from blood, rate of, 41 Cup, lead-shielded, 93 Disease rinsing, 94 Paget’s, SO Curve thyroid, history of tracer diagnosis of, 33-35 activity-versus-time, 24-26, 99- I00 Dispensing aclivities of radiophartnacy, 1-2,5, 13, 148-150 decay, 100, I01 Distribution dose-response, 84, 85, 95 particle size, of colloid, 143-144 Cyclotron of radiopharmaceuticah in New Mexico, 1s productirm, 107-111 volumcs of, 2 1-23 schematic. 109 Diverticulum, Meckel’s, 44 Cyclotron-produccd nuclides, I1 1 DMSA, 130 in organic synthesis, 132- 133 lemTc, 146 Cystine,134 Dosage of radiopharlnaceuticdl, I, 2, 84-85 assurance of, 92 n calculation; see Dosimetry, radiation, calculations D,, 3, 11 Dose Daily preparations and quality control, 136-147 dispensing, 1-2, 5, 13, 148-150 Data tables, MIRD, 97-98 drawn, labeling, I50 Daughter nuclides, I13 pediatric, nomogram for calculating, 149 Decay radiation, maximum cumulated whole-body, 95 curvc, 100, 101 Dose calibrator, radiation, 139-140 electron capture; see Electron capture decay Dose-response curve, 84, 85, 95 of nucleus, 96 Dosimetry. radiation, 95-104 Decay schemc calculations, 98- I03 of “Cr, 98 sample, 102- 103 of‘ generators of radiopharmaceuticals, 122 tor *@lnTcsulfur colloid, 97 of PTJl, 70 Double isotope dilution, 28 of 1:y 54 Drug history, 1 I, 13 of **&. s4, 102 Drug state of patient, 62 Deficits, perlusion, 37-38 Drugs Definitions ancillary, and advcrse reactions, 89 drug, 3 definition, 3 nuclear medicinc, 6 diagnostic, 1 I radiopharmaceuticals, 3, S nonradiWactiVe, 1 radiopharmacists, 5-6 radioactive; see Kadiopharrnaceuticals radiopharmacy, 1-3 rcgular, labeled with radioactive tracer, 5 Dehydrogenasc, 133 therapeutic, 1 I glutanic acid. 133, 134 DTPA, 65, 68, 72, 128-129 Denland for radiopharmaceuticals, 1 13-1 14 In, 132 Denaturcd albumin, 144 ”“‘Tc, 34, 48, 73, 137, 145-146 Department of Transportation (DOT), 14, 151 lUuYb,hO Depyrogenation, 77-78 Dual-head rectilinear scanner, 34 Derivative dilution, 28 Dyes, 17 Design criteria for radiopharmaceuticals, 52-75 gallbladder, 33 for radiation therapy, 91 intravenous (IVP), 33 Detector, gamma-ray; srr Gamma-ray detector Dynamic studies, 23 DHTA, 130 and nuclear angiography, 24 Diagnostic procedures, nuclear, 6 Diagnostic radiopharmaceuticals, 3 E Dibutyl carbinols, 133 Early trbservations of radiation effects, YS Diethyl carbinols, 133 Earths, rare, 70-73 Diethylenetriamincpentaacetic (DTPA);acid wt Economics of radiopharmacy operation, 150- 151 DTPA Edctate,128 Diffusion, simple or exchange, 48, 61 EDTA,128 Dihydrothioctio acid, 45, 130 Effect, Tyndall, 57 Dilution Effective half-lifc, 60, 91 derivative, 28 Effective, making radiopharmaceuticals, 76-90 Effects, radiation, early observations or, 95 Ferrous ion with ascorbate, 127 Effisions, treatment of, 91-92 Fetus and iodine therapy, 91 EHDP, 73, 129 Fibrinogen, 69 Electrolysis, 126, 127 1251, 60 Electron capture decay, 55 Field flood tcst source, 2 of Tr,98 carrying casc, I53 of '9,70 Filling of prescription, I, 5 Elcments; we also specific elements and isotopes Filters, 78 in adult human, 67 First National Symposium on Radiclpharmaccuticals, 3 essential trace, 66-68 Fission nnMogenerators, 119, I20 by groups in periodic chart, 62-73 Fission production, 11 1-112 stablc. activation of, 105- 107 Flocs of ferrous hydroxide labeled with '!'"'Tc, 36, 89 substitution, 134 Flow of blood; we Rlood flow transition, 66, I26 Flow hood, larninar, 78, 79 Eluate, evaluation of Fluid thioglycolate medium, 79 of RRMo/RRmTcgenerator, 119-121 E1uc)rine 18; .we I*P of 113Sn/113t"lngeneratw, 121 Food and Drug Administration (FDA) and IND, 86-87 of X'Sr/R2Rbgenerator, 122 Formaldehyde "C, 133 Elution, 114-115 Frrrnmic acid, 133 in HYMo/YY"mTcgenerator, 119, 138-139 hnctional image, 24, 25 volume, 139 Functional imaging, 6 Emboli, pulmonary, 37 Emittcrs G alpha, 96 "Ga, 59, 11 I beta, 105 KMGa,61 gamma, 3, 55, 62-64, 123 Gallhladder positron, 55, 56, 63, 109, 111, 123 dyes, 33 Emulsions of water, 58 visuali~ation, 44 Endotoxins, 79 Galliun~,61, 65, 131; see nlso Ga isotopes Energy Gamrna emitters, 3, 55, 6244, 123 of radionuclide, 52 Gamma radiation, 96 gamma-ray, 52, 53 Gamma-ray detector recoil, 107 collimated external, 3 Enrichment of %Mo, I06 Ge(Li), 119-120 Enteropathy, protein-losing, diagnosis, 13 1 Gamma-ray energy, 52, 53 Enzymes Gamma-ray spectrometry, 140, 14 1 in biochemical synthesis. 133 multichannel,141 in organic synthesis, 132 Gases Equilibrium analysis, isotopic, 31-32 inert, 69-70 Equilibrium in generator systems, 117 noble, 69-70 Equiprntnt in radiopharmacy, 148 Gastrointestinal (GI) tract, tracer studies of, 47-48 Erythrocytes, 67 Gelatin,142 Essential trace elements, 66-68 Gel-column scanning, 137-138 Ethyl iodide, irradiation of, 107 Ge(Li) detector, 119.120 Ethylenediamine tetraacetic acid (ED'TA). 128 Generator systems, 1 13- I22 Evaluation of eluate; SPP Eluate, evaluation of colu rnn, 1 14- 1 15 Examinations and half-lives of radionuclides, 55-56 construction, 114-1 16 Exchange diffusion, 48 L37Cs/137tnBa,122 Exchange, ligand, 127- 128 ideal,114 Excitation labeling, 124 liquid-liquid extraction, 115 ExOgGnollS idinc, 62 "YMo/wmT~;.see '"Mo/'""'Tc generator Exposure to radiation, 18-19, 52, 92-93, 123 operation, I 16- 117 and cancer, 95 of radiopharmaceuticals. 122 Extraction of radionuclide, 107 ulRb/"'mKr, 122 liquid-liquid,115 rubidium 82, 121 MEK, 119, 120 1'3Sn/1'"In, 121 R2Sr/82Rb,122 F "TC, 9 F-, hY for ultrashort-lived nuclides, 121-122 F,, 69 lasXc/lesl, recoil labeling in, 125 ISF, 9, 69 Glands; see spccific glands pnxluction from LiCO,,, 107 multifortne, 49 Factor, intrinsic, 1, 31 Globulin, serum. 59 kt2, 127 Clucoheptonatc, "Tc, 146 Fe"$, 143 Glucoheptonic acid, 46 "e, 36, 89, 64, 67, 74, 127, 134, 143, 146 Gluconic acid, 46 Ferrous hydroxide, flocs of, labeled with numTc, 36,89 Glucose, "C, 134 Index 187

/-Glutamic acid, 13NN-lahcleti,synthesis 01, 133, 134 Hydrogen, 17 Glutamic acid dehydrogenase, 133, 134 Hydrolysis, 145 Glutamic-pyruvictransaminase, 133 Hydrolyzed technetium, 137 Clycinc. 132 Hydroxide Gold 198; see lg8Au colloid ammonium, 107 Graphic log-prohit method, X5 ferrous, flocs of, labcled with symTc,36, 89 Group 0 elements, 69-70 indium, 40 Group I elemcnts, 64, 65 iron, particles labeled with indium, 132 Group 2 elements, 65 Hydroxyapatitc crystal, 69 Group 3 clements, 65 I-Hydroxyethylidene- I, 1-disodium phosphonate (IiHDP), Croup 4 elemcnts, 66 73 Group 5 elements, 66 Hydroxyproline, 145 Group 6 elements, 66 Hypersplenism, 42 Group 7 elements, 68-69 Hypertension, pulmonary, 89 Groups 01 clements in periodic chart, 62-73 Hyperthyroidism, 8, 69, 91 Hypochlorite, 126 H 'H, 17 1 ", 3, 17, 107. 112, 123 I-; see Iodide tIall-life, IX-19, 52, 53 I,, 123 biologic, control of-,59-60 1~31,69, 1 I I, 123 effectivc, 60, 91 decay scheme, 70 in generator system, 1 13, I17 production, 110, I I I, 124, 125 physical, 59 rBBIorthoicldohippurate, 46 Halogens, 68-69, II1 i241, 123 Handling therapy patients, 92-Y4 impurity, 11 1 HCI, 121, 122, 142 la31, 69, 91, 111, 123, 124 4He, 96 gamma-ray energy, 53 Head, positron tornograms 01, 110 lZ3I tibrinogen, 60 Heavy metals, 70-73, 126 laRlproduction, 107 Helium; .see 4He 1311, 3, 8, 56, 69, 111, 119, 120, 123 Heme, 67, 74 decay scheme, 54 Hcnwglobin, 67, 74 therapy with, 91 Hcptasullide,technetium, 143 thyroid hormone labeled with, 2Y, 30 Hevesy, George de, 6, 33 1311 , 134 Hexavalent chromium, 59 L311 albumin, 48 '%Hg, 70 r311 bromosulfophthalein, 45 "h?Hg, 70 IS1J HSA, 59, 146 Hg chlortnerodrin, 70 colloid, 40 Ig7Hg chlormerodrin, 48, 72 "'1 MAA, 36, 88, 89 pORHgchlormerodrin, 88 l3II rose hengal, 44 IR'Hg mercurihydroxypropane (MHP), 42 lsll thyroxine, 31 HIDA, 46 I:Y, 119, 123 !'HmT~, 26 contamination with, 141 History lC1, 124-126 drug, 11, 13 Ideal generator system, 1 14 ol radiophartnacy, 7-9, I1 IDP, 129 of traccr diagnosis of thyroid disease, 33-35 Image, functional, 24, 25 H,O, 128 Imaging H20, in radioiodination, 124 blood-pool, 132 Hood, laminar flow, 78, 79 bone; we Bone, scan Hormones, thyroid; SPP Thyroid hormones hone marrow, 132 Hospital brain, agent fur, 132, 146 accreditation, 6 contrast, 61 paficnt in, 92-93 functiotd, 6 Hospital radiopharmacies, 14 gel-column, 137-138 HSA we Human serum albumin (HSA) of kidneys, 70, 131 Human, adult, elemental composition of, 67 liver; see Liver, imaging Human serum albunun (HSA), 36, 59, 130, 146 lung; see Lungs, imaging denatured, 144 of pancreas, 46 I'll, 59, 146 radioisotope, devices fur, 34 labeled with Wr, 13 I sequential, 6 macroaggregated; .see Macroaggregated albumin (MAA) spleen, 132 microaggrcgated; we Microaggregated albumin static, 6, 75 tnicrospheres; see Microspheres of albumin, yHmTc lnlpurities minimicrospheres,RRiiiTc, 134, 147 radiochemical, 123, 136 snmTc,59, 146 rddionuclidic; see specific generators 188 Index

”‘In, 40, 65, Ill, 132 K In UTPA, 132 K‘, 59, 63 lilln DTPA, 47, 48 4UK*total-body, 32 ‘l31n, 121 42K,65 ‘ramJn, 40, 65, 76, 89, 132 Kcthoxal-bis, 45 production, 12 1 Ketone, methylethyl, llS, 119 toxicity, 76, 86 Kidneys In vitro labeling of RBCs, 146 filtering by, 46 In vitro tracer studies, 6, 75 imaging, 70, 131 In vivo labeling of RBCs, 146-147 and uYm’TcDTPA, 34 In vivo performance of lsmTc bone agents, 145 Kinetics, traccr, nonimaging, in vivo studies of, 28 In vivo stability, 59-61, 76 Kit In vivo tracer kinetic studies, nonimaging, 28 NDA-approved,136 In vivo tracer study, 6, 7 for *“‘TC SC preparation, 142 of thyroid. 34 PYP, Mallinckrodt, 146 InCI,,132 wl’nKr,122 113mInC1,,85, 86 Kupffcr cclls, 40-4 I IND, 86-87 Indicator concentrations asmcasures of blood flow, 26- L 27 Labeled compounds, organic, I23 Indium,65, 67; see also In isotopes andcompounds Labeling chelation and complexation, 131- 132 of antigens, 126 trivalent, 59 of blood sample, 42, 44 Indium hydroxidc, 40 cohort, 42 Indium phosphate, 40 of drawn dose, 150 Indwelling vcnous , 39, 144 of proteins, 124 Incrt gases, 69-70 with technetium, 130 Injection problems, 89-90 random, 42, 44 Intcrnational Atomic Energy Agency, 7, 14 recoil, 124 Intravenous pyelogram (IVP) dyes, 33 of red blood cells; sec Blood cells, red, labeling Intrinsic factor, I, 31 of vial, 142 Introducing new radiopharmaceuticals, 86-88 of whitc blood cells, 134, 147 Investigational New Drug Application (TND), 86-87 Lactoperoxidase,124 Idide, 75, 126 Laminar flow hood, 2,79, 157 ethyl, irradiation of, 107 LAMPF accelerator, 108 ion, 63 Law of consmvation of matter. 19 potassium, saturated solution of, 60 Lawrencc, E. O.,6 reduction to iodine, 123 Lead 203, 70 solution, I Lcad-shielded cup, 93 and thyroid, 44 Lead-shielded vial, 1, 138, 140 Iodinated compounds, hiodistribution of, 69 Lesions Iodine,64, 69, 123; see nlso I isotopesand com- metastatic. 51 pounds vascular, 41 exogenous, 52 Lethal dose, 76, 84-8s isotopcs, 17, 68, 123 Leukemia, 9 1 radioactive, 34 Leukocytes, 67 and active transport, 44 Licensure, 15 1 reduction from iodide, 123 LiC03, prtduction of IUFfrom, 107 lodocholesterol, 50 Ligand exchange, 127-128 lodofibrinogen, 69 Ligands,127 Todohippurate, sodium, 8 Limulus amoebocyte lysate gelation test for pyrogens, 81- Iodomethylnorcholesterol, SO x3 Ionization, 96 Lincar accelerator; see Accelerator, linear Ionizing radiation, 95-96 Lipid solubility, 58 Iron; see “Fe Liposomes, 73 Iron hydroxide particles, 132 Liquid-liquid extraction generator, 1 15 Irradiation of ethyl iodide, 107 Liquid scintillation counting, 123 Isomeric transition of nsmTc.54, 55, 102 Lithium aluminum hydride, 133 Isotope dilution analysis, 28-29 Lithium-7 carbonate, production of iRFfrom, 107 Isotope vcnopm, 38 Liver Isotopes, 17; see ulso specific isotclpes blood flow, 24, 41 Isotopic cquilihrium analysis, 31-32 cirrhotic, 40 1V catheter anti R’Rb gencrator, 121 as filtcr, 44 IVP dyes, 33 radiation dose to, calculation of, 102-103 RE cells in, 40 J imaging, 45, 132 Joint Conmission for Accreditation of Hospitals, 5 agents for, 62, 102-103 Liver-ccont'd MHP, 42 imaging-cont'd Mice, biodistribution in, of OnmTcpyrophosphate, 77 radioactivity in lungs during, 143 Microaggregatcd albumin transmcthylaticln,134 colloid, 40 Localization, tracer labeling, 130 blood flow and, 50-51 Microanalysis, quantitative, use of tracers in, 27-32 compartmenral. 47-48 Microspheres of albumin, 09mTc, 36, 37, 57, 59, 60, 89, mechanisms of, 33-51 144 Low-energy gamma radiation, 98 labeling, 130 Lugol's solution, 60, 89 Millipore filters, 78, 133 Lungs Minitnicrosphcres, albumin, OomTc-labeled, 134, 147 capillaries, 35-36 MIRD data tables, 97-98 imaging MIRD reference man, 98-99 perfusion,36-38, 132, 144 MnO,, 126 agents lor, 62, 90 "o, 105-106, 119 ITi, 144 carrier, 1 19 ventilation, 69, 122 enrichment, 106 radioactivity in, during liver scan, 143 YYMo,X, 64, loti, 111, 117, 119, 138 Lysatc, Limulus amoebocyte, gclatiuntest forpyrogens, breakthrough, I 19, 140- I4 1, 142 8 1-83 decay; sce o'Mo/RR"lT~gcnerator fision, 119, 120 M as molybdate, 1 19 MAA; see Macroaggregated albumin (MAA) reactor, 119 Macroaggregated albumin (MAA), 36, 37, 144 YHMomolybdate, 117, I19 l3ll, 88, 89 "M~/~~Tcgenerator,8, 9, 111, 115, 117-120, 126, 138 labeling, 130 elution, 119,138-139 9yml'c, XY, 144 NDA,136 Magic bullet approach versus tracer concept, 33-35 rechargeable, 115-1 16 , 64 Model for organ, 100-101 Making radiophwmaceuticak safe and effective, 76-90 Molecular weight, 58 Mallinckrdt PYP kit, 146 Molybdate, YYMo,117, 119 Man, reference, 98-99 Molybdenum, 106; see ulw Mo isotopes and compounds Manganese, 64, 126 targets, 106- 107 , 105 Molybden~lm99; we "Mo Marrow, bone; see Bone, marrow Moo,, 117 Mass Multichannel analyzcr, 141 atomic,I7 Multichannel gamma-ray spectrometry, 141 red cell, 19-21 Multichannel spectral analysis, 120 use of tracers 10 determine, 19-23 Myocardium, ions in, 48, 49 Mass spectrometer, 17 Matter, law of conservation of, 19 N Maximum cumulated whole-body radiation dose, 95 I3N, 66, 111, 123 MDP, 129 organic synthesis, 132 Measures of blood Row, 24-27 NaBH,,127 Mechanisms of localization, 33-51 NaI,107 Meckel's diverticulum, 44 NAOH, 119 Medical Internal Radiation Dose Committee of Society of solution, 133 Nuclear Mcdicine, Inc., 98 National Bureau of Standards, 113 Medicine, nuclear National radiopharmacies, 14 definition, 6 National Radiophartnacy of Denmark, 14 physicians, 6 NDA, 86, 88 tracer techniques in, 17-32 NDA Yyml'cgenerator, 136 MEK, extraction by, 119, 120 NDA-approved kit, 136 Mercurihydroxypropane (MHP), 'O'Hg, 42 lor preparation of YOmTcSC, 142 Mercury, 67; see also Hg isotopes and cornpounds Needles,150 Metabolism studies, 27 analysis, 17, 105 Metals, 123 Neutrons, 105 alkali, 64, 65 New Drug Application (NDA), 86, 88 heavy, 70-73, 126 New Mexico, distribution of radiopharmaceuticals in, 15 nonessential transition, 66-68 New radiopharmaceuticals, introducing, 86-88 transition, chelation and complexation, 13 I I3NH,, 11 1, 133 Metastatic lesions, 51 Nitrogen 13; see 13N Methanol , 14 1 rJN-l-alanine synthesis, 133, 134 Methionine, 63, h4,67, 134;seealso 7iSe selenornethionine '3NN-l-glutamicacid synthesis, 133, 134 Methyl alcohol, 133 Noble gases, 69-70 Methylene diphosphonate, ggmTc, 50 Nomogram for calculation of pediatric dose, 149 Methylethyl ketone (MEK), 115, 119 Nonessential transition metals, 66-68 Nonimdging in vivo tracer kinetic studies, 28 Patient- cont'd Noninvasive tracer techniques, I X talking with, 93-94 Nonradioactive drugs, 1 therapy, handling, 92-94 Nonradioisotopic tracers, 32 Penicillamine, 130 Norchlorpromazine, 133 nwmTc,146 239Np, 120 Percent tag, 2, 20 Nuclear angiography: see Angiography, nuclear and bicdistribution, 65 Nuclear tnagnetic resonance spectrometry, 17 Perchlorate, 1, 89, 126 Nuclear medicinc; .see Medicine, nuclear Perfusion imaging of lungs; see Lungs, imaging, perrusion Nuclear pharmacies, 15 Perfusion of blood, 36 Nuclear reactors; .see Reactors, nuclear deficits, 37-38 Nuclear Regulatory Commission (NRC), 14, 151 Periodic chart of elements, 63 Nucleus, decay of, 96 groups in, 62-73 Nuclides; see Radionuclides Peritoneal cavity effusions, 92 Number of radioactive particles, 37 Permanganate, 126 Perrhenate, 126 0 Pertechnetate, 40, 59, 68, 75,126 '"0,66, 111, 123 free, 137, 146 organic synthesis, 132 ion, 63 Oak Ridge National Laboratory, 7 reduction, 126- 127 Observations, early, of radiation effects, 9s sodium; src "mTcO; OH-,128 in sulfur-based reactions, 130-131 Olation reaction or chromium complex, 13 1, 132 "Tc, 119 Old radiopharmaccuticals, rcplacing, 88 HH"Tc; see """'TcO; Oldendorf procedure, X? PEIT IV Scanner, 55 Operation Phagocytosis, 40-41 of generators, 116-1 17 Phantom, 100 of radiopharmacy, 148- IS4 thyroid, 102 quality controls, 154 Pharmacies,nuclear, I5 Opsonin, 40 Pharmacyin general, radiopharmacy compared to, 11-14 Oral radioiodine solutions, administering, 93-94 Phosphate Organ chromic, 91-92 radiation dose to, calculation of, 98-103 indium, 40 source, 98-99 sodium, 91 target, 61, 98-99 , 120 uptake of ys'nTc,77 cotnplexes of, with technetium, 144-145 Organic synthesis, 132-133 Phosphomolybdate, ammonium, 122 Organic labeled compounds, 123 Phosphonates, 129 Orthoicdohippuratc, InsI, 46 Phosphorus 32; see snP Overdosing, 89 Photoelectric absorption, 96 Oxidation states of chromium, 131 Photons, 96 Oxygen 15; see 150 Physical characteristics of radionuclides, 52-56 Physical setup of radiopharmacy, 148 P Physician, nuclear medicine, 6 JaP, 3, 91-92 Phytate, 129, 130 colloid, 91-92 sodium, 58 compounds, 123 'l'c, complex, 130 "P stdium phosphate, 9 I ""'Tc, 40, 144 Paget's disease, 50 Plasma citrate, 59 Painters, radium-watch dial, 95, 96 Plasma labeling with "Cr, 13 I Pancreas imaging, 46 Platclets, 67 Particles, radioactive Poisoning, radiation, 89 alpha, 96 Polycythemia vera, 91 beta, 96 Polygonal cells, 44, 46 colloidal, 57 Polyphosphate, 129 capacity of RE systcm to phagocytize, 41 Positron emitters, 55, 56, 63, 109,111, 123 and capillary blockage, 36-38, 56 Positron-emission transaxial tomograph, 55, 56 number, 36-37 Positron tomograms of head, 110 size, 36-31, 57 Potassium, 63-64, 65; see also K isotopcs of wmTcX's, 143-144 ions, 63, 64 properties, 96-98 specific activity in body, 32 Pathways , saturated solution of, 60 decay, 55; see also Decay scheme and iodine therapy, 91 use of tracers to determine, 23-27 Preliminary bicdistribution studies, 76-77 Patient Preparations, daily, and quality control, 136-147 contwt with, 13 Prescriptions drug state, 62 filling, 1, S Index 191

'rcscriptions - cont'd Radiation- cont'd transportation, 13, 14, 153.154 ellkcts, early observations of, 95 'roblems of injection, 89-90 exposure to, 18-19, 52, 92-93, 123 Voccdure, Oldcndorf, 89 and cancer, 95 'roduction gamma, 96-98 comparison of reactor and accelerator, 1 1 I low-encrgy, 98 cyclotron, 107-1 1 I ioniiing, 9596 of lMFfrom I.iCO,, 107 poisoning, 89 fission. I1 1-1 12 Radiation biology, 95-96 of '231, 1 IO Radiation dose calibrator, 139-140, 150 linear accelerator, 107-1 I I Radiation safety, 13, 92-93, 95, 148 of radiochemicals, 123- 135 Radiation therapy; .we Therapy, radiation of radionuclides, 105- 112 Radioactive biologic product. 3 rates, calculation of, 105- 106 and active transport, 44 reactor, 105- 106 Radioactive materials of radiophamaccuticals, gcnerators for, 122 control of, 13 ?roperties of radioactive materials, 96-98 properties, 96-98 Propylthiouracil, 62 Radioactivc particles; see Particles, radioactive Protein binding, compctitive, 3 I Radioactivc prescriptions; sre Prescriptions Protcin-losing enteropathy diagnosis, 13 I Radioactive tracer; sre Radiopharmaceuticals; Tracers, ra- Protein synthesis, 64, 134 dioactive Proteins, 67 Radioactive wastes, 13, 92-93 ditncrized, 123 Radioactivity labeledwith *'"'l'c, 137 calculation of, in gcnerator, 116-117 labeling, 124 total, assay of, 139-140 with technetium, I30 Radiochemicalimpurities, 123, 136 as stahilizcrs, I42 Radiochemical purity, assay of, 141 Protocol for prevention of radioiodine uptake into thyroid, Radiochemicals, production of, 123- 135 60 Hadioirnmunoassay (RIA), 3 I, 124, 126 Pulmonary emboli, 37 Radioiodinatcd serum albumin (RTSA), 59 Pulmonary hypertension, 89 Radioiodination, 123- 126 Purity Radioisotope imaging devices, 34 radiochemical, assay 01-, 141 Radioligand assay, 3 I radionuclidic, assay of, 140-141 Radiomctric methods of sterility testing, 79 Pyridoxyhkneglutalnate, 45, 46 Radionuclide angiocardiogram, 7 Programs in radiopharmacy, training, 9, 11, IS Radionuclides; ser ulso Radiopharmaceuticals PYP kit, Mallinckrodt, 146 charactcristics Pyrogens, 79 biologic, 56-62 contamination with, 89 chcmical, 56-62 rcsponse, 79 physical, 52-56 testing, 79-83 cyclotron-produced, I1 1 Pyrophosphate,129 daughter, 113 stannous,146 dosage, assurance of, 92 uumTc., .sPe YymTcpyrophosphate gamma-emitting, 55, 62, 123 positron-emitting, 55, 56 Q production; see Production of radionuclides Quality control testing as tracers, 18 01 Anger camera, 2 ultrashort-lived, generators for, 121-122 of daily preparations, 136- 147 Radionuclidic impurities; SPU specific generators of radiopharmaceuticals, 2 Radionuclidic punty, assay of, 140-141 of radiopharmacy system, I54 Radiopharmaceuticals routine,136-138 adverse reactions to, 88-89 Quantitative microanalysis, use of tracers in, 27-32 bifunctional cc)mpounds as, 73-75 classification, 3 R definition, 3, 5 R,, 3, I1 design criteria, S2-75 22eRa,113. 117 diagnostic, 3 Rabbit, bicxlistribution of '*"'Tc pyrophosphate in, scinti- distribution in New Mexico, 15 gram of, 145 establishment of term, 9 Rabbit test fur pyrogens, 79, 8 1 generators of, 122 ""RaCI,, 113, 114 new, introducing, 86-88 Rad, 98 old, replacing, 88 Radiation orders for, 148 absorption, 96-98 quality control, 2 beta, 98 radiation therapy with, 91-94 dosc, n~axirnurn cumulated whole-btxly, 95 research, 3, 5 dosimetry; see Dosimetry, radiation safe and effective, making. 76-90 192 Index

Radiophannaceuticals- cont'd Resin-asbestos, 122 therapeutic, 3, 5 Response, pyrogen, 79 Radiopharmacists Reticuloendothelial cells, 40-41 definition, 5-6 Reverse isotope dilution, 28 training, 14- 15 Rhenium, 126 Radiopharmacy Rheumatoid arthritis, treatment in, 92 central, 14, 151, 154 Richards, Powell, 8, 9 compared to pharmacy in general, 11-14 Rinsing of cup in oral doses, Y4 definitions, 1-3 RISA, 59 history, 7-9, 11 er2Rn, 113, 114, 117 hospital, 14 Roentgen, 98 operation, 148-154 Rose bengal, 8, 46 staffing, 148 1311, 44 types, 14 Routine quality control, 136-138 Radium 226; see a2GRa lnsRu, 119, 120 Radium-watch dial painters, 95-96 Rubidium; see Rb isotopes Radon 222; see 222Rn Rules regarding radiopharmacy, 151-152 Random labeling of red blood cells, 42, 44 Rare earths, 70-73 S Rate of disappearance of colloid from blood, 41 134 Rates compounds, 123 production, calculation of, 10.5-106 Safe, making radiopharmaceuticals, 76-90 use of tracers to determine, 23-27 Safety, radiation, 13, 92-93, 95, 148 Ratio, target-to-target, 61, 91 Safety test for toxicity, 85-86 "Rh,122 Saline as solvent, 137, 138, 145 RBCs: see Blood cells, red Sample dose calculation, 102-103 RIRb/W1mKrgenerator, 122 Samples, 3 82Rb,122 biodistribution, 66 R'Rb generator, 121 blood, labcling, 42 8GRb,120 for dose calculations, 100 RE cells. 40-41 Saturatedsolution of potassiumiodide (SSKI), RE system, capacity to phagocytize particles, 41 60 Reaction(s) Sb as radionuclidic impurity, 121 adverse, to radiopharmaceuticals, 88-89 I%b, 120 olation, of chromium complex, 13 I, 132 Scan; see Scintigram Szilard-Chalmers, 107 Scanner, rectilinear; see Rectilinear scanner tagging, 58-59 Scanning; see Imaging Reactors, nuclear, 6, 7, 105 Scattering, Compton, 96 production, 105-106 Scintigram comparison with accelerator production, 11 1 bone, 50 Rechargeable "HMO/~~~TCgenerator, 115-1 I6 brain, 49 Recoil energy, 107 CSF spacc, 47 Recoil labeling, 124 liver in 1r3Xe/1z9 gencrator, 125 '''1 rose bengal, 45 Record keeping, 142, 152.153 ""'Tc sulfur colloid, 41 Rectilinear scan, 42 lung Rectilinear scanner, 33, 52 lair MAA, 37 dose and, 1 50 "mTc HSA microspheres, 39 dual-head, 34 myocardium, 49 Red blood cells; see Blood cells, red pig skin, gamma, 26 Red cell mass, 19-21 rabbit, YymTc pyrophosphate,145 Reduction spleen, 42 by organic thiols, 127, 130 Scintillation camera; set Anger camera of pertechnetate, 126-127 Scintillation counting, liquid, 123 stannous, 40, 127, 130, 144 75Se, 134 sulfur-based, products of, 130- 13 1 selenomethionine, 46, 63, 64, 134 of =rco-. 4, see RR"T~O,,reduction 75Se(CH,),, 134 Reference man, 98-99 75seo,,134 Registered pharmacist, 6 Secular equilibrium, 117 Registry of Adverse Reactions, 89 Seleniunr, fi4, 67, 134; see ahso 75Se compounds Regular drugs labeled with radioactive tracer, 5 Self-radiolysis, 120 Regulation of radiopharmacy, 13-14 Sensitivity test, up-and-down, 84-85 Regulations regarding radiopharrnacy, 151- 152 Separation, chemical Rem, 98 in generator systems, 113; see also specific generator Renal function stvdies, 146 techniques,1Of-107 Replacing old radiopharmaceuticals, 88 Sequential images, 24, 25 Research radiopharmaceuticals, 3, 5 Sequential imaging, 6 Index 193

Sequestration, cell, 42-44 Stannuus chloride, 144 site, 40 Stannous ion; see SnI2 splenic. 42. 44 Stannous pyrophosphate,146 Serum albumin; see Human serum albunlin (HSA) Stannous reduction, 40, 127, 130, 144 Serum calcium, 130 Statewide radiopharmacies, 14 Serum globulin, 59 Static imaging, 6, 75 Setup, physical, of radiopharmacy. 148 Sterility Shclf-life, 52, 58, 59, 76 checking systcm for, 77-83 Shield testing, 78-79 for assay of ""Mo, 140 Sterilization, 78, I IS for syringe, 1 Stoichiometry, 29-30 Shunting of blood, 39, 40 Strrptornyces griseus, 134 Simple diffusion, 4X Struntiurn, &I; see also U2Sr Size isotopes, 65 distribution in symTcSC's, 143-144 Sublimation, I 15, 120 of lung perfusion imaging particles, 37, 144 Substitution of elements, I34 of radioactive colloidal particles, 36-37, 40, 57 Substoichiomctric analysis, 29-3 I Sn+2 Sulfur; SCP also 35S in cell sequestration, 42 in biologic synthesis, 134 reductionby, 40, 127, 130, 144 cornpounds containing, 67, 130-131 Sn",145 Sulfur colloid, ""'"Tc; see """'Tc sulfur colloid "3Sn, 121 Sulfur-based reduction products, 130- 131 SnCI,, 144 Sulfur-bearing amino acids, 134 ii3Sn/113mln generator,121 Swiss chard, 134 SO;, 134 Synovial membrane effusions, 92 S,OT, 127,134 Synthesis Sodium, 64 bacterial, 134 Sodium bromide, 122 biochemical, 132- 133 Sodium chromate, 20 biologic, 133- I34 Sodium iodohippurate, 8 organic, 132.133 Sodium pertechnetate; see yymTcO; protcin, 64, 134 Sudiurn phosphate, 32P, 91 Syringe, 1 Sodium phytate, 58 camer for, I Soluhility of tracer, 5X labcling, 1, 150 Solution shield for, 1 ACD,131 System, checking for sterility and apyrogenicity, 77-83 ammonia, 133 System, generator; ,see Generator systems Lu~oI's,60, X9 Szilard-Chalmcrs reaction, 107 oral radioitdine, administering, 93-94 saturated, of potassium iodidc, 60 '1. sdium pcrtechnetate, 138- 142 Tables, MIRI), 97-98 Source organ, 98-99 Tagging rcactions, 58-59 Soybean-casein digest medium, 79 Talking with patient, 93-94 Space, usc of tracers to determine, 19-23 Target-to-nontarget ratio, 61, 91 Specific activity, 31-32, 107 Target organ, 6f, 98-99 of potassium in body, 32 "Tc, 117, 141 of technetium, 141 "OTc generator, 9 Spectral analysis, multichanncl, 120 sHmTc,8-9, 55, 61, 107, 119, 126, 138, 141, 144 Spectrometer,17, 140 bifunctional compounds with, 73 mass,17 chemistry, 68, 126-131 Spectrometry, 17 compounds,136 gamma-ray,140, 141 decay scheme, 54, 102 multichannel, 141 and flocs of ferrous hydroxidc, 36, X9 nuclear magnetic resonance, I7 gamma-ray energy, 53 Spleen hydrolyzed,137, 145 cell sequestration in, 42-44 labeling pruteins with, 130 RE cells in, 40-41 organ uptakes, 77 in sample dose calculation, 102-103 specific activity, 141 imaging, 132 HH'"Tc bonc agents, 137, 144-145 Splcnic sequestration, 42, 44 ssmTc colloids, 142- 144 Squibb Gamma Flu" system, 30 HnrtlTcDMSA, 146 %r, 122 RDmTcDTPA, 34, 48, 73, 137, 145-146 R2Sr/HzRb generator,122 gs'nTc-Fe(OH3)focs, 36, 89 SSKI, 59, 60 @OrnTcgenerators; see ssMo/m"Tc generator Stability, in vivo, 59-61, 76 sYmTcglucoheptonate, 146 Stable elements, activation of, 105-107 uHmTcHIDA, 26 Staffing of radiophllrmacy, 148 sn"tTcHSA, 59, 146 onlnTclung agents, 36, 88, 144 Thyroid - cont'd Sn'"lc MAA, 89. 144 phantom, 102 "Tc methylene diphosphonate. 50 radioiodinc uptake into, prevcntion of', 59. 60 !'"'"Tc microsphcres, 89, 144 study, 34 ""'"Tc tninimicrosphcrcs,134, 147 therapy, 91, 92 oomTcpenicillamine, 146 Thyroid hortnones, 44, 134 HHmT~pertechnetate, 48 determination, 30-31 oonlTcphytatc, 40, 144 '"1-labeled, 29, 30 symTcproteins, 137 'Thyroxine nn'"l'cpyrophosphate, 48 antibody-bound, 30 hiodistributiotl dctcrmination, 29 in tnicc, 77 "'I, 31 in rabbit, scintigram of, 145 Tin; sw dso Sn isotopes BB1l'T~SC; see ""'"Tc sulfur colloid stable, 12 I rr'nTcsulfur colloid, 40, 41. 42,92, 127,142-144, 147 TI+, 59, 63, 65 dosimetry calculations, 97 in myocardium, 48, 49 preparation, 142- 143 "'1'11, 70, 11 I yymTctin colloid, 144 TLC, 136-137, 144, 145.146 RRml~WBCs, 147 TMA, 130 TcO,,128 'l'otnograms, positron, of head, 1 10 ""'"TcU,,145 Tomograph, positron-emission transaxid, 55, 56 TcO,, ; see Pertechnetate T(>tal-bodypoVassiuI11, 32 RR'I'cO; , 119 Total radioactivity, assay of, 139-140 ""'"TcO;, 2, 48, 61, 89, 119, 127, 138-142 Toxic dose, 84, 85 free, 143, 144 Toxicity of tracers, lack of, 76 in preparation of lslnTc sulfur colloid, 142 Toxicity studies, 83" reduction with DTPA and Sn", 145- 146 Toxins, retnoval of, 44 Tc,O,, 119 Trace elements, essential, 66-68 'l'cS, , I43 Tracer concept, magic bullet approach versus, 33-35 TcS,, 143 Tracer depot methud, 24 '"Te, 119 Tracer kinetic studics, nonimaging in vivo, 28 Tcchnetium; see eol"Tc;"'"Tc compounds Tracer study Technetium hcptasulfide, 143 in vitro, 6 'Iechnctium phosphate complexes, 144- I45 in vivo, 6, 7 Tcchnetium phytatc complex, 130 or thyroid, 34 Techniques Tracer techniques separation, 106- I07 advantages,17-19 tracer; see Tracer techniques in mcdicine, 17-32 Test uses, 17-19 safety, for toxicity, 85-86 Tracers, 11, 17 up-and-down sensitivity, 84-85 nonradioisotopic, 32 Testing radioactivc; see ulso Radiophartnaceuticals pyrogen, 79-83 administration, 10, 89 quality control: see Quality control testing amount, 6 1-62 sterility, 78-79 biodistribution, 2, 11, 12,100 Thallium 201; see "'TI clearance; SYC Clearance of tracer Therapeutic drugs, 11 in compartmental localization, 47-48 Therapeutic radiophatnlaceuticals, 3, 5 diagnosis of thyroid disease with, history of, 33-35 'Therapy, radiation excreted into bile, 44, 46 patient for, handling, 92-94 localization; see Localization, traccr with radiopharmaceuticals, 91-94 positron-emitting, of C, N, and 0, 109 thyroid, 91, 92 regular drugs labeled with, 5 Thin-layer chromatogmphy ('LC)* 136-137, 144, 145, 146 toxicity, lack of, 76 Thioglycolate, fluid, 79 use Thiols, organic, reductiorl by, 127, 130 to determine mass and space, 19-23 'l'hiomalic acid, 130 tu determinc rates and pathways, 23-27 Thiosetnicarbazone, 45 in quantitative tnicroanalysis, 27-32 'l'hiosulfate, 40, 127, 130,142-143 Training progran~sin radiophannacy, 9, 11 IS Thorium dioxide, 96 Training of radiopharmacists, 14- 15 Thorotrast, 96 Transaminase,glutamic-pyruvic, 133 Thrombogenesis.130 Transferrin. 59, 86, 132 Thrombolysis, 130 Transient equilibriurn, I 17 Thyroid Transition, isomeric, of ""'"TC, 54, 55, 102 ablation, 3, 8, 91 Transition elements, 66, 126 blocking, 62 Transition metals cancer, 8, 69, 9 I, 95 chclation and complexation, 131 disease, history of tracer diagnosis of, 33-35 nonessential, 66-68 Index 195

Transits as rneasures of blood flow, 26-27 Visualization, optinrum, tirrre of, h I Transmethylation, livcr, 134 Vitamin BIZ,31, 67 Transport, active, 44-47 radiwctive, 134 'Transportation ofradioactive prescriptions, 13, 14, 153.154 synthesis, 133-134 Trials, clinical, 87-88 Volume(s) 'Tritium, 3, 17, 107 blood, 19-21, 47, 131 Trivalent indium, 59 01 distribution, 21-23 'Troubleshooting activities, 3, 12 elution, 139 Tungsten, 106 W Turnover studies, 21 . 'l'yndall effect, 57 Wagner, H. N., Jr., 9 Types of radiopharrnacies, 14 Washout of tracer, 24-26 Tyrosine, 69 Wastes, radioactive, 13, 92-93 WRCs; SPE Blood cells, white U Weight, molecular, 58 2351J, I11 Well-counting device, 52 Ultrashort-lived nuclides, generators for, 121-122 White hlmi cells; sw Blood cells, white IJnderdosing, 89 Whole-body radiation dose, maximum cumulated, 95 IJnivcrsity radiopharnlacics, 14 Up-and-down sensitivity test, 84-85 X Uptake "3Xe decay, 1 1 I, 124 absolute, 61 123Xc/'231generator, recoil labeling in. 125 organ, of YsmTc,77 'SsXe, 11 1 of radioitdine into thyroid, prevention 01, 60 Xenon, 69-70 U.S.P. methods of sterility testing, 78-79 Y V W'b DTPA, 60 , 64 Yterrhium 196, 71 Vascular lesions, 4 1 Vein, antecubital, 10 z Venogram, isotope, 38 , 64 Vcnous catheters, indwelling, 39 Zirconium oxide, I2 1 Ventilation inlngirrg of lungs, 69, 122 "Zn, 120 Vesicles, 73, 74 R5ik. 120 Vial labeling,142 lead-shielded, 1, 138, 140