4- A .1- A r A I Basics of radiopharmacy BUCK A. RHODES, Ph.D. Director of Radiopharmacy, University of New Mexico College of Pharmacy, Albuquerque, New Mexico BARBARA Y. CROFT, Ph.D. Division of Nuclear Medicine, 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. Radiopharmaceuticals. 1. Croft, Barbara Y., 1940- jointauthor. 11. ‘litle.[DNLM: I. Nuclear medicine. 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 pharmacies 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 radiopharmaceutical de- and other nuclides 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 physician. 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 medical specialty 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- physics. Although knowledge of these subjects vide a first-coursetextbook 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 chemistry 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 Cell sequestration, 42 History of radiopharmacy, 7 Active transport, 44 Radiopharmacy compared to pharmacy in Compartmental localization, 47 general, 1 1 Simple or exchange diffusion, 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 angiography, 24 Group 0: thc noble gases, 69 Tracer clearance as a measure of blood Row, 24 Heavy metals and rare earths, 70 Bifunctional compounds designed for use Indicator concentrations and transits as as radiopharnlaceuticals, as 73 ! measures of hlood flow, 26 Absorption, metabolism, and turnover studics, 27 Making radiopharmaceuticals!’ Use of tracers in quantitative microanalysis, safe and effective, 76 27 Isotope 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 General characteristics, 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 phosphate, 91 Radioiodination, 123 Colloids, 9 1 Technetium chemistry, 126 Handling therapy patients, 92 Reduction, 126 Assurance of radioisotope dosage, 92 Ligand exchange, I27 Radiation safety considerations, 92 Chelation, 128 Talking with the patient, 93 F'rotein labeling, 130 Sulfur-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 biology, 95 Biologic synthesis, 133 Review of the properties of radioactive materials and absorption of radiation, 96 Dosimetry 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 radionuclides, Thin-layer chromatography, 136 Gel-columnscanning, 137 105 Sodium pertechnetate 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 Specific activity, 107 Specific activity, 141 Example: lSF from LiCO,, 107 Aluminumbreakthrough, 142 Linear accelerator and cyclotron 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 bone agents, 144 Other cyclotron-produced nuclides, 11 1 99mT~DTPA, 145 Fission production, 11 1 99mTcHSA, 146 9rmT~RBCs, 146 YPmTcWCs, 147 Contents