THE UNIVERSITY OF NEW MEXICO COLLEGE OF PHARMACY ALBUQUERQUE, NEW MEXICO

The University of New Mexico

Correspondence Continuing Education Courses for Nuclear Pharmacists and Professionals

VOLUME 111, NUMBER 4

Pulmonary Localization of Non-Solid-Particle : Clinical, Anatomic, Functional, and Therapeutic Implications

By:

John J. Coupal, Ph. D., BCNP

Co-sponsored by: mpi ~armac~ services inc an Amersham company

Tht University of Ncw Mexico College of Phtirmicy is approved by the American Council on Pharmaceutical Educfitinn fis a provider of continuing pharmaceutical education Prugram N{), 1XO-039-93-006. 2.5 Contact Hours or .25 CEU’S m@ Editor and Director of Pharmucy Continuing Education

William B. Hladik III, M.S., R.Ph. College of Pharmacy University of New Mexico

Associate Editor

and Production Specialist

Sharon 1. Ramirez, Staff Assistant College of Pharmacy University of New Mexico

While the tidvice and information in this publictilion arc bclicvcd to be true and accurate at press time, neither the author(s) nor the editor nor the publisher can accept any legal responsibility for any errors or omissions th:it may bc made. The publisher makes no warranty, express or implied, wiih respect to the material con~ined herein.

Copyright 1994 University of New Mexico Pharmacy Continuing Education Albuquerque, New Mexico PULMONARY LOCALIZATION OF NON-SOLID-PARTICLE RADIOPH~ACEUTIC&S: CLINICAL ANATOMIC, FUNCTIONAL, AND THERAPEUTIC IMPL1CATIONS

STATEMENT OF OBJECTIVES

The goal of this correspondence lesson is to inform the reader of several blood-soluble radiopharmaceuticals and their potential applications for diagnosis and treatment of human lung disease. To be discussed are structural aspects of the lung microcirculation, fictional roles of the pulmonary endotheliurn, and major differences in kinetics of retention and washout of endogenous and exogenous soluble compounds after reaching the lungs via the systemic circulation. Unlaheled and various radiolabeled compounds localizing in lung will be compared in terms of their subcellular, tissue, and whole-organ uptake and subsequent kinetics in laboratory animals and in humans with and without disease. Also discussed will he the subtle effects of tobacco smoking, an injurious blood-borne chemical, and external irradiation on the lungs that can be objective y identified and measured, not by , but by . Finally, the optimistic potential for nuclear medicine to out-perform X-ray, CT, MRI, surgery, and “conventional” medications, in diagnosing and treating structural and/or functional diseases of the lungs will bc reviewed.

Upon successful completion of this mteriul, the reader should be able to:

1. Describe the basic structure of the lung capillary vessel.

2, Distinguish between exogenous and endogenous organic and inorganic compounds and elements localized in ● lung from the circulation,

3. Explain the currently-uncertain factors resulting in uptake, retention, and washout of organic compounds (and their metabolizes) from lung tissue.

4. Jdentify several non-malignant and malignant diseases of lung, along with appropriate organic radiopharmaceuticals having potential for diagnosing and/or treating such diseases.

1 COURSE OUTLINE PULMONARY LOCALIZATION Of NON-SOLID-PARTICLE RAD1OPHARMACEUTICALS: CLINICAL I. INTRODUCTION ANATOMIC, FUNCTIONAL, AND ● THERAPEUTIC IMPLICATIONS II. THE LUNG MICROCIRCULATION

III. A COMMON AMINE INHALED INTO THE LUNG By:

IV. CIRCULATION DELIVERY OF BIOGENIC AND EXOGENOUS AMINES TO THE LUNG John J. Coupal, Ph. D., BCNP Nuclear Pharmacist v. RADIOLABELED EXOGENOUS AMINES Veterans Affairs Medical Center Nuclear Medicine Service A. Diarnine and B. Monoamine Associate Professor (Voluntary) Department of Diagnostic VI. RADIOLABELED EXOGENOUS AMIDE Division of Nuclear Medicine University of Kentucky College of Medicine A. Benzamide Derivatives Lexington, Kentucky

VII. TECHNETIUM-99m CHELATES AND THE LUNG

A. ADiamine Bisoxime INTRODUCTION B. Diamine Dithiol Ligands @ c. Isonitriles To date, nuclear medicine has had a limited (although sometimes crucial) role in the diagnosis of VIII. INDIUM-111 LABELED PEPTIDE selected diseases of the lung (e.g., in pulmonary embolism). Ix, NON-MALIGNANT LUNG DISEASE Ironically, due to the constantly improving characteristics of the newer brain imaging radio- A, Respiratory Distress Syndrome pharmaceuticals, those agents have shown potential B. Emphysema applications in lung imaging. The similarity of physiochemical characteristics among these x. MALIGNANT LUNG DISEASE radiopharmaceuticals coupled with similarities between the blood brain barrier (BBB) and the lung endothelium x1. CONCLUSIONS appear to play a major role in such potential. We have come fdr since the days when nucltidr medicine could largely demonstrate only lung ventilation @y inhaled inert gases or aerosols) or perfusion (temporary physical blockage of some smaller lung blood vessels). Since our lungs are constantly exposed to both the ambient gaseolls atmosphere as well as our systemic blood circulation, they are susceptible to assault from external as well as internal forces. Many newer blood-soluble radiopharmaceuticals appear capable of noninvasively demonstrating even subtle structural and functional features of the lungs and subsequent changes thereto; o those features and Ialer changes can range all the way from the harmless to the deadly.

2 THE LUNG MICROCIRCULATION While destruction of lung tissue by tobacco smoke is irreversible, cessation of smoking slows the rate of The capillary blood vessel of the lung appears to decline in pulmonary function so that it begins to play a major role in concentration of certain soluble resemble that of non-smokers after several years (2). radiopharmaceuticals from the blood. The capillary is Mortality of inhalers is greater than that of non- a cylindrical tube (about 8 pm in diameter, the size of inhalers (2). an erythrocyte) lined by endothelial cells forming the Nicotine’s ability to permeate the oral mucosa has semi-permeable endothelium whose main function is been known since 1932 (6). In addition, nicotine is transvascular exchange (1). Surrounding the found to be not only rapidly absorbed across the nasal endothelial cells is a continuous basal lamina, a mucosa from smokeless tobacco snuff placed in the moderately electron-dense band, 50 to 70 nm thick, nasal cavity, but also reported to yield the highest following the contour of the bases of the endothelial plasma nicotine concentration ever reportd in man cells. The capillaries of the lung are characterize as (7,8). “continuous” as are those of skeletal, smooth, and cardiac muscle along with those of the central nervous CIRCULATORY DELIVERY OF BIOGENJC AND system. Capillaries in other tissues and organs are EXOGENOUS AMINES TO LUNG characterized as either “fenestrated” or “discontinuous.” The cytoplasm of the endothel ial cell Endogenous (biogenic) vasoactive amines (e.g., has relatively few mitochondria adjacent to the nucleus, serotonin, norcpinephrinc) are taken up from the blood a sparse endoplasmic reticulum with ribonucleoprotein by the lung by a sodium-dependent carrier-mediated granules, a Golgi complex close to the nucleus, transport system operating at the level of the capillary microtubules, lysosomes, vesicles, and three distinct endothe]ial cell and are then metabolically inactivated types of filaments. The greatest mass of cytoplasm (9). The exogenous soluble compounds preferentially abuts the nucleus. Both acid and alkaline phosphatase localizing in the lung from the blood are basic amines activities are found in the cytoplasrnic vesicles. (p~ > 8) having amphiphilic characteristics [i.e., a molecule having a large hydrophobic group with a side A COMMON AMINE lNHALED INTO THE chain ionized at physiological pH] (10). Lung uptake LUNG of basic amines is saturable, but in contrast to that for o endogenous biogenic amines, does not involve a Nicotine is a tertiary amine derived from tobacco. carrier-mediatd, energy-requiring transport system. Of the two stereoisomers, S(-)-nicotine is the more The lung can efficient y concentrate many active form. Nicotine binds stereoselectively to exogenous basic amine drugs (e.g, imipramine, acetylcholine receptors in the autonomic ganglia, methadone, chlorcyclizine, and propranolol) but, in adrenal medulla, at neuromuscular j~~nctions,and in the contrast, apparently cannot extensively metabolize brain (2), Nicotine from smoking has an e]imination them; it merely stores them in a slowly effluxable pool half-life of one to two hours and a volume of (11). Also in contrast to the biogenic amines, most of distribution of two to three L/kg, which is similar to the exogenous compounds share a sodium- and energy- that from intravenously-administered nicotine. About independent lung uptake mechanism and persist in the 80% to 90% of nicotine from smoking is metabolized lung at cellular binding sites whose nature and location for elimination, mainly in liver, but also in kidney and have not yet been precisely identified (11). lung. A significant fraction of nicotine is metabolized by the lung (3). Major metabolizes are cotinine, trans- RADIOLABELED EXOGENOUS AM INES 3’-hydroxycotinine, and nicotine-1 ‘-N-oxide. More than 20 mctabolites have been identified, all believed Diarninti to be less pharmacologically active than nicotine. One radiolabeled exogenous Diamine, N, N,N’- Importantly, nicotine is a stronger base than its trimethyl-N’ -[2-hydroxy-3 -methyl -5-(1 -l23) rnetabolitcs (4). iodobenzyl]-1 ,3-propanediamine (lnI-HIPDM), was Nicotine is readily absorbed from the respiratory synthesized years ago by Kung et al. (12,13). It was tract, buccal mucosa, and skin (5). In habitual originally employed clinically for cerebral perfusion smokers, it shows systemic bioavailability of 90% by imaging. The high lipid volubility of the diamine that route. Nicotine, suspended on minute particles of (partition coefficient in 1-Octanol/pH 7.0 buffer is 40) ● “tar” in smoking, is quickly absorbed from the lung leads to tirst pass normal brain extraction of 85% to (almost as efficiently as when given intravenously) (2) 95% (14). Iodine- 123 retention within the brain is and reaches the brain within eight seconds of postulatti as partly due to (a) a “pH shift, ” whereby inhalation. the uncharged molecule at blood pH of -7.4 ncounters

3 the intracellular brain pH of -7.0 which protonates Greatest HIPDM specific activity (pmol/mg protein) the molecule (i.e., giving it a positive charge), thereby was in the mitochondrial fraction. HIPDM radioactivity retarding its efflux back through the BBB, and/or (b) (expressed as percent of total lung activity) in each specific or non-specific receptor binding within the fraction changed negligibly over the sacrifice-time brain. In the latter part of the postulate, the amines period evaluated, indicating no redistribution of the ● may interact with neuronal or cellular receptors; diamine among fractions during that period. Overall however, brain uptake and retention of the radiotracer results suggested that HIPDM in lung is bound to have repeatedly been shown to be independent of subcellular organelles, with its relative distribution carrier dose, refuting a criterion for receptor-specific therein indicating that it may be Iysosomotropic. binding. None of the mechanisms proposed to date In isolated, perfused rat lungs, lXI-HIPDM uptake fully accounts for the prolonged retention of the by lungs is reduced by concomitant perfusion of either radiotracer in brain. A similar situation holds true in imipramine, propranolol, or chlorpromazine (all the lung, as we shall see below. lipophilic basic amines), as well as by carrier H1PDh4 Upon intravenous injection in normal human and (17). However, addition of ouabain to perfusate or use animals, rapid and diffuse (homogeneous) uptake of of a sodium-free perfusate has no effect on lung lmI-HIPDM in the lungs occurs. The lung images have uptake. lZSI-HIPDMdoes not appear to localize in lung the appearance of a normal ‘Tc lung perfusion scan. by sodium-dependent active transport. Its uptake In fact, some of the HIPDM entering the brain comes appears similar to that of other basic amines from the lung pool of drug (14). (propranolol or imipramine), known to bind by Pistolesi and colleagues in Italy have ambitiously physiochemical interactions to lung endothelial cell looked at many aspects of radioiodine-labeled HIPDM membranes and reflect pulmonary vascular surface and the lung in human and animals (11,15). For area. example, lung clwdranceof ‘XI-HIPDM in nine normal Using Kung’s HIPDM kit with on-site ‘a31labeling, non-smokers was found to be faster than that in nine we (at W-eVA ‘MedicalCenter in Lexington, Kentucky) asymptomatic smokers of at least 20 cigarettes per day. systematically looked at lung uptake of the drug in A hi-exponential curve described lung clearance of patients referred to us for routine single photon in both groups. The mean time of the first emission computed tomographic (SPECT) brain component(l O + 1.4 min. )(mean & SEM) in smokers imaging. Early-on, we found a case of histologically- did not differ significantly from that in non-smokers confirmed poorly differentiated carcinoma of the lung Q (9.7 + 0.9 rein). But, mean time of the second reflected as a large perfusion defect on the l“1-HIPDM component, 12.9 + 0.6 hr in the smokers, was almost lung image (18, 19). The patient was recommended to twice that in non-smokers, 6.7 + 0.2 hr. The undergo a course of chemotherapy. investigators hypothesized that lung persistence in smokers may reflect either an increased number of Monoamine cellular binding sites or hindered HIPDM Iofetamine HC1 1-123 Injection (SPECTamine, biotransformation (11). Medi-Physics) was available several years ago for As noted above, lung clearance of ‘X1-HIPDM in routine (SPECT) cerebral brain perfusion imaging normal man is slow, compatible with relatively stable (20,21). This agent is a monoamine, lml-N-isopropyl- cellular binding. Normal rabbits receiving lfil-HIPDM p-iodoamphetamine, known also as lnI-IMP. Again, intravenously were sacrificed at intervals from two substantial amounts of intravenous y administered drug minutes up to tlve hours post-injection (PI), with lungs localized diffusely in normal lungs and liver (22). .! excised immediately, weighed, and homogenized. Differential centrifugation of homogenates isolated RADIOLABELED EXOGENOUS AMIDE subcellular fractions (nuclear, mitochondrial, postmitochondrial, and microsomal) and post Benzamide Deriviitivtis microsomal supernatant (16). Radioactivityy and protein A novel group of radioiodinated benzamide concentration were assessed per isolate. The time- derivatives is currently undergoing testing for non- activity clearance curve of l“I in rabbit lung small cell (NSC) lung cancer diagnosis. A prototype homogenates were comparable to that of lZI-tagged designated IPAB ((for 123~-(2-~iperidinyl~minoethyl)-4- drug measured in vivo in humans by external gamma iodo~enzamide)) and tlve relatd compounds bind scintigraph y. The ‘2’1HIPDM was recovered only specifically to sigma receptors on the cell surface of from subcellular fractions of rabbit lung homogenates lung carcinoma cells (23). Normal lung does not● (nucleus and mitochondria containing the bulk of the express such receptors. SPECT imaging with IPAB of compound); the distribution profile mimicked that of laboratory animals bearing tumors from injected human arylsulfatase B, a lysosomal marker hydrolase enzyme. cancer cells can identify both primary tumors and

4 metas~ases. Jt is also hoped that, eventually, these ratios. compounds could possibly treat sigma-receptor In habitual marijuana smokers, features of containing tumors by delivering anticancer therapies to bronchitis are present. In marijuana smokers with or tumor site(s). without concurrent tobacco smoking, one finds ● increased recovery of neutrophils in bronchoalveolar TECIiNETIUM-99m CHELATES AND THE LUNG lavage (BAL) fluid, histologic changes comprising squamous metaplasia, goblet cell hyperplasia, and Dlaminc Bisoxime intraepithelial inflammation (33). Tc-99m exametazime injection (also known as A 28-yr-old male polysubstance-abusing marijuana ‘mTc-d,l-hexarnethylpropylene amine oxime, or ‘mTc and tobacco smoker had a *Tc exametazime HMPAO) was introduced several years ago for lung/liver uptake ratio of 1.325, the highest value we cerebral perfusion imaging. The ligand and chelate, have encountered (Shih W-J, Carmona JJ, Coupal JJ; first described ten years ago by Troutner et al. (24), unpublished observations). The was heralded a new era in clinical brain perfusion imaging. unremarkable. Delta-9 -tetrahydrocannibinol (THC), an The disadvantages of ‘ZJIfor SPECT brain imaging isomer of tetrah ydrocannibinol, yields most could be avoided with this new agent. The HMPAO psychological effects from marijuana and is reported to Iigand kit is commercially available under the trade accumulate in the lung (34). name Ceretec@from Amersham Health care. Tc-99m examet=ime administerti intravenously to HMPAO is a diamine hisoxime (i.e., 4 nitrogen 18 patients (youngest of age 38 yr; 14 males) with atoms available for coordination/molecule) that cheltites histologically-confirmd primary lung cancer (35) ‘Tc rapidly into a cyclic structure (after stannous yielded promising results. Unfortunately, no mention reduction of ‘mTc-pertechnetate). The oxime structure is made of the patients’ history of tobacco smoking. In is [(RC(H or R) =NOH)]. The resulting chelate is scintigraphic lung images, a region of interest (ROI) lipophilic and has a neutral charge (i.e., non-charged); was created on computer over the focal lesion with a neutrality results from loss of one hydrogen atom from corresponding ROI created over the same location in each of the two amine groups and from one of the the contralateral normal lung. Lung-uptake ratios oxime groups during chelation (25). This so-called (lesion/normal lung) of ‘)mTc radioactivity indicatd “primary Iipophilic complex” is present in the injection significant differences between (a) squamous cell which has a high pH ranging from 9.0 to 9.8 (26) and carcinoma (1.2 + 0.4; mean + SD) and can cross the normal BBB. The extraction e~lciency adenocarcinoma (1.6 + O.1) @< .05), (b) large cell across the BBB is estimated at 0.75 (27). carcinoma (0.9 + 0.1 ) and squamous cell carcinoma Tc-99m exarnetazime biodistribution is not (p< .05), and (c) adenocarcinoma and large cell restricted to the normal adult or neonate brain in carcinoma (p< .01). Most striking arc the relatively humans (28) upon intravenous administration. The homogeneous ratio values (as indicated by low standard excretory routes and miscellaneous organs are seen on deviation values) within the individual histologic types total body scintimages. Focal uptake (]ccurs in a variety of tumors. Three patterns of tumor uptake of *Tc of disease states throughout the body. In 1986, two became evident 1) homogeneous (corresponding to groups (29,30) reported diffuse uptake of radiotracer in tumor), 2) perfusion defect, and 3) ring-like. The the lungs of normal tobacco smokers. Diffuse lung latter two patterns often corresponded to necrotic tissue uptake also occurred in a young man with worsening mostly replacing carcinoma cells of tumor. In contrast memory loss but unremarkable SPECT brain imaging with ‘i7Gacitrate which accumulated in both malignant who had discontinued smoking four days prior to brain cells and necrotic tissue, ‘mTc HMPAO accumulated (and lung) imaging (28). While the mechanism of such in only viable carcinoma cells. Perfusion defects lung uptake (even in the ex-smoker) remains unknown, corresponding to tumor suggested greater possibility of hypotheses center around several effects on pulmonary presence of either squamous. cell or large cell vascular endothelium induced by smoking (31). carcinoma, rather than of adenocarcinoma. The In a group of 55 patients undergoing SPECT brain objective lung uptake ratios (above) tend to support imaging- for ‘neuroloiic reasons, it has been reported that contention. (32) that the lung/liver uptake ratio of *Tc Tc-99m exametazime administered to patients with exametazime (calculated by computer on the lung tumors (histologic type not specified) yielded high corresponding lung/liver images) in 30 smokers (O.805 uptake of ‘mTc in all seven of seven tumors (36). In ● + 0.042; mean ~ SEM) was significantly higher than a variety of other primary and secondary tumors that in the 25 non-smokers (0.408 i 0.019)@< .01). (including bredst, squamous cell, melanoma, sarcoma, Liver uptake of tracer is the same for smokers and lymphoma), the pattern of perfusion showed a high- non-smokers; it was employed for calculating personal activity ring surrounding a low-activity center. In this

5 brief communication, the authors regard the drug to be Diamine Dithiol L~gands useful for detecting tumors in the thorax. In addition, A recent development is a group of diamine dithiol extraction-efficiency of ‘Tc exametazime was greater (DADT) compounds forming coordinate bonds with than that of Rubidium-86 cation (an “ancient,” but ‘mTc (38). The resulting 22 structurally-different effective indicator of regional blood flow) in a tumor chelates are neutral, lipid-soluble, and show varying ● transplanted in a mouse model. These results indicated magnitudes of rapid localization in the lungs of normal greater efficacy of the ‘Tc tracer in showing mice (up to 31% of the injected dose) at five minutes perfusion to (with likely oxygenation of) malignant post intravenous injection. tumors. Crucially, this would reveal relative tumor All are cyclic chelates. The nature and position of radiosensitivity and consequent options for treatment. various alkyl substituent groups appears to play a role Additional evidence exists for potential use of ‘Tc in initial uptake (measurd at five minutes) and examet=ime as a marker for chemical and external subsequent kinetic properties (measurements at 15 irradiation injury to lungs in man and animals in vivo. minutes PI). It appears that partitioning of the In a direct dose-dependent manner, oleic acid given respective chelates into the lipid bilayer is not the sole ‘- intravenously to normal rabbits ld to significantly contributing factor to the observed respective percent increasing bilateral diffuse lung uptake of subsequently of injected dose. Jt is felt that a mechanism of lung intravenously-injected *Tc exametazime (37). While uptake sensitive to variations of chelate structure is the lowest treatment dose of oleic acid (0.05 mL/kg) operating in these living animals. led to a significantly increased pulmonary uptake of Lung/liver “selectivityy ratios” or (“SRS”) compris- ‘Tc in all eight rabbits over that in ten control ing [percent injected dose (ID) in excised lungs/gin animals (which received no oleic acid), it led to no lungs] divided by [percent ID in excised liver/gin corresponding reduced pulmonary perfusion sites after liver], ranged from a high of 15.2 to a low of 0.3 . intravenous *Tc MAA administration. However, in That particular chelate demonstrating the SR of 15.2 all six rabbits receiving either 0.10 mL/oleic acid/kg or showed only a 13% decline in percent ID from that at 0.20 mL/kg, ‘Tc perfusion sites in both lungs were five min to that at 15 rein; among the other chelates, reduced or defective after ‘mTc MAA. Electron the average fall was 40% over the period. Relative microscopy of lungs from all oleic acid-treated animals lipophilicity of the complexes does not appear a major shows morphologic change localized to the contributing factor to biological half-life of the ● microvascular endothelium. chelates. The mechanism of binding and pharmaco- Thirteen patients with lung cancer received a total kinetics of that unique complex of SR 15.2 may be dose of 16 Gy to 50 Gy (1600 Rad to 5000 Rad) (in 2 more involved than that of the others; the authors are Gy increments) during a course of external beam X-ray evaluating this complex further. radiotherapy (37). Only two of the patients (both It is felt that evaluation of patients with one of these receiving 50 Gy) showed abnormal opacity on chest X- complexes may prove fruitfil in clinical pulmonary ray computed (chest CT) due to radiation- diseases such as asthma, emphysema, or lung infection. related pneumonitis in the irradiated lung; in the remaining 11 patients, there was no corresponding Isonitrilw significant opacity in the irradiated lung. All 12 Six isonitrile (-C= N) ligands chelate a *Tc atom patients receiving more than 30 Gy demonstrated, by forming hexakis-2-methoxy-2 -isobutyl isonitrile, SPECT imaging, a higher uptake of subsequently- known as hexamibi. The chelate bears a single administered ‘Tc exametazime in the corresponding positive charge. It is currently available generically as - non-cancerous surrounding irradiated lung than in the ‘mTc sestamibi (Cardiolite@, DuPont Pharma). The contralateral nonirradiated lung. Patients receiving 50 clinical indication for this agent is myocardial perfusion Gy tendd to have higher irradiated/nonirradiated lung imaging. tracer ratios than did those receiving lower doses. The In 11 patients with primary lung cancer, ‘iTc highest lung activity ratios occurred in the two patients sestamibi has localized in the tumors of ten of the showing an infiltrate on chest CT. Thus, a dose- patients as shown by planar imaging (39). Peak dependent effect of external-beam radiation therapy to concentration of radioactivity in tumor was reached lung was shown by ‘mTc exametazime scintigraphy of within the first minute of intravenous injection. lungs; no corresponding sensitivity and specificity were Tumor/normal lung activity ratios on computer demonstrated by chest CT. An objective quantitative remained constant from five to ten minutes PI to 25 to measure of the consequences of irradiation to normal 30 minutes PI, indicating no washout during that time ● lung tissue by non-invasive scintigraphy suggests its frame. Using ‘“Tc sestamibi SPECT imaging, two great diagnostic potential in many clinical, sub-clinical, other groups of investigators reported sensitivity in (and perhaps pre-clinical) disease states. detecting primary lung cancer at 91% and 96%,

6 respectively (40). On a subcellular level, it has been serotonin) was observed in patients with ARDS shown that ‘Tc sestamibi binds to a small protein compared to that in controls [normal volunteers and (- 10000 daltons) in the cell lvsosome. patients positive for human immunodeficiency virus (HIV), but without chest symptoms or signs] (45). o INDIUM-111 LABELED PE~IDE Notably, subjects “at risk” for ARDS had a 6,2% reduction (p< .005) in lung extraction of 5-HT. Peptides for scintimaging are prepared from However, those results had been obtained by invasive hypervariable regions of binding to specific techniques. Similarly, first-pass pulmonary extraction cell surface receptor regions (41). Hypervariability of a synthetic amine analog (“31- indicates that the peptides have antigen specificity metaiodobenzylguanidine or MIBG) in sheep receiving similar to that of parent , but reduced affinity endotoxin infusion decredsed (p< .05) by 27.8% at for receptor sites, compared with intact antibody (41). seven hours and by 42.3% at 24 hours, compard with Somatostatin, a neurotransmitter hormone baseline. comprising 14 amino acid residues, occurs in human Relevant non-invasive diagnostic techniques, tumors, primarily those displaying amine precursor nevertheless, are necessary to ensure widespread uptake and decarboxylation (APUD), such as small cell clinical acceptance. For example, BLM therapy is (SC) lung cancers. known to damage the pulmonary endotheliurn. Verma [Iridium-l 11-DTPA-D-Phe’]-octreotide is a et al. (45) sequential y injected intravenous y ‘mTc- radiolabeled somatostatin analog. It is presently labeled autologous erythrocytes (as a reference vascular available as l*lIn-pentetreotide under the trade name tracer) and *~1-IMP (as an endothelial cell marker) in Octrti)Scan@(Mallinckrodt Mdical). Its normal tissue four patients receiving BLM treatment and in four localization does not include lung. However, lung normal subjects. A mean reduction (p< .05) of 28.8% uptake may occur after surgery, after external beam in lung extraction of ‘Zsl occurred in the patients, radiotherapyy to lung, after bleomycin (BLM) treatment, compared with that in the controls. The authors had or after upper respiratory tract infections (latter, previously shown that lmI-JMP is extracted from the primarily in pulmonary hilum)(41). In various clinical blood by lung endothelium through a receptor-mediatd trials, this has detected SC lung mechanism. Imaging by gamma camera over lungs and cancer with frequencies ranging from 63% to 100% superior vena cava led to a pulmonary-extraction- (41). fraction curve for radiotracer including first pass of tracer bolus and sequentially thereafter. Verma et al. NON-MALIGNANT LUNG DISEASE believe that such pilot data on first-pass l“l-lMP pulmonary extraction will lead to similar non-invasive Rwpiratory Distrms Syndrome nuclear medicine techniques to evaluate pulmonary Diffuse alveolar infiltrates are seen on chest X-rays endothelial integrity using radiolabeled amine markers in adult respiratory distress syndrome (ARDS), a for endothelium. clinical disorder of parenchymal inflammation, permeability, pulmonary edema, severe dyspnea, and Emphysema refractory hypoxemia. The chest X-ray shows Emphysema is often characterized by disruption of progressively increasing lung-tissue density, as alvalar walls at some site within the acinus, which is accumulation of fluid in the extravascular space the lung division distal to the terminal bronchiole. The replaces gas density with a water-equivalent density. acinus includes respiratory bronchioles, alvmlar ducts, To evaluate lung edema in ARDS best, direct and terminal alveoli. measurement of extravascular lung water is needed Sixteen adult patients of a group of 125 referred for (42). However, neither invasive indicator-dilution SPECT brain imaging also showed signs of chronic techniques nor bedside pulmonary or obstructive pulmonary disease (COPD) on their lung radionuclide perfusion lung imaging is ideal. PET images after receiving 1’31HIPDM intravenously (46). imaging is a more sophisticated method for lung water Decreased radioactivity in the upper one-half or one- quantitation (43,44). The chest X-ray is now the only third of the lungs indicated so-called mild COPD in ten practical means of evaluating pulmonary edema in of the patients, and moderate-to-severe COPD in six. critically ill patients (42). Both anterior and posterior lung images correlated well Damage to pulmonary endothelium is currently with changes due to COPD on respective chest o thought to be the first step in evolution of ARDS in radiographs. It is felt that lmI HIPDM lung images may patients with sepsis (45). Using noninvasive methods, be an ideal diagnostic tool for diffuse pulmonary a 12.8% to 18.8% reduction (p< .05) in pulmonary disedse processes. extraction of 1’C-5-hydroxytryptamine (5-HT or Current thought on causation of emphysema zeroes

7 in on the possibility that elastolytic enzymes are NSC lung carcinomas in 20 patients (52). In that released in the lung and, fidiling to be neutralized, study, six of the patients received 1 mg labeled Mab digest the elastic framework (i.e., the protein elastin) plus 19 mg unlabeled Mab (total 20 mg), while 14 of the lung parenchyma (47). Emphysema is almost patients received 1 mg labeled Mab plus 39 mg invariably present in pwple severely deficient in the unlabeled Mab (total 40 mg). That difference was ● globulin known as alpha- 1-antitrypsin (alpha-1- intended to assess if a larger dose of unlabeled Mab proteinase inhibitor, or alpha-l-Pi) which is a potent would result in higher sensitivity for tumor detection inhibitor of proteol ytic enzymes (such as trypsin and and localization. Clinically, it was learned that there elastase). It is felt that elastase, found in neutrophils was no difference in tumor detection rate sensitivity and alveolar macrophages, is released therefrom on a between patients receiving either 19 mg or 39 mg more or less continuing basis, to digest the lung unlabeled Mab. Importantly, non-localization of parenchyma. When alpha-l-Pi is present, elastase is radiotracer in three of four patients with benign inactivated in its proteinase activity. Strikingly, the conditions suggested its specificity for tumor. vast majority of patients with emphysema have normal Originally described by Haskell et al. in 1983 (53), serum levels of alpha-1-Pi. But, the concept of that ZCE-025 is a complete lgG, with a molecular weight enzyme-inhibitor balance is still strongly considered to of 160,000 daltons. It has been evaluated for colorectal play a role in some cases of emphysema. cancer imaging as Hybri-CEAker (Hybritech Emphysema-like disorders can be induced in Incorporated); unfortunately, it elicits considerable animals by intrapulmonary instillation of elastase, human anti-mouse antibody (HAMA) production (in > papain, or leukocyte homogenates. Intravenous 40% of patients) (54). Levine (55) has succinctly administration of alpha-1-Pi in people natural]y enumerated the negatives of HAMA induction: (a) deficient in the inhibitor restores the inhibitor- adverse reactions and possibly death, (b) HAMA proteinase balance in alvmli. Oxidants(including interaction with tagged MAb possibly leading to components of cigarette smoke) can inactivate alpha-1- rduced image quality from a HA MA-MAb complex Pi, rendering it inactive for inhibition of elastase and localizing in the liver, thereby also decreasing the other protml ytic enzymes. amount of desired tagged MAb available for tumor Shih et al. administered elastase intratracheall y in detection, and (c) HAMA interference witi some anesthetized normal adult rats (48). Four weeks later, diagnostic tests (e.g., CEA radioimrnunoassay). treated and control animals (no elastase) received, In a separate study of 66 patients with primary lung @ sequentially, ‘“Tc albumin aggregated (MAA) cancer, ‘l’In-labeled F~db’)zfragments of another anti- injection and l“1-HJPDM intravenously 48 hr apart. CEA antibody (F023C5) produced diagnostic images in Elastase-treated animals had a significant decrease in 57 of 63 patients (90% sensitivity) with histological y- both HIPDM and MAA radioactivity /excisd-lung- confirmed bronchocarcinoma (56). However, radio- volume ratios. That suggested a decrease in both tracer localization in non-cancerous lung diseases functioning pulmonary vascular endothelium and in reduced specificity to 45%. While there were many number of pulmonary capillary vessels caused by more lung cancer patients with NSC than with SC enzyme insufflation. The authors suggested a potential studied, lesion scintigraphic detection rates were found for ‘mI-HIPDM as a diagnostic aid in pulmonary to be comparable. A high fdlse-positive rate, coupled emphysema. with inability to reveal centrally-located lesions smaller than 2 cm (the latter difficulty likely resulting from MALIGNANT LUNG DISEASE high background ‘“In radioactivity) partly led to the limitti c1inical usefulness of th 1s tracer. Clinically, radiolabeled monoclinal antibodies Harwood and Abdel-Nabi (57) have recently (MAb) against the oncofetal protein CEA, against suggested that smaller MAb fragments tagged with human milk fat globulin (HMFG), and against ‘mTc are more likely to yield improvd sensitivity and glycoprotein expressed by SC or NSC lung cancers specificity in imaging of lung cancers. NR-LU-1O is a have been evaluated. Around the time that tumor- murine antibody of IgGt~ subclass that recognizes a associated CEA was shown to be expressed in primary glycoprotein expressed on SC lung cancers. In a group lung cancer (49), Goldenberg et al. showed that lung of six male patients with pathologically-confirmed SC cancer could be imaged by 1311-anti-CEAMAbs (50), lung cancer, seven lung lesions were detected (58). the work being done here at the VA Medical Center Relative success in localizing metastatic disease and the University of Kentucky at Lexington. depended on site (i.e., spread into lymph nodes, bone, ● Iridium Jn-111 altumomab pentetate ~d mouse and liver was well detected, while that into adrenals monoclinal ZCE-025 anti-human antigen CEA and brain was not). antibody (51) has detected 12 of 16 known primary Using the same antibody, Lamki et al. detected 22

8 of 25 lung lesions (sensitivity 88%) (59). Additionally, fragments tagged with other (57). two of the patients had pleural effusions, and Deletion of the Fc fragment of antibody markedly radiotracer was localized in the fluid. Three occult diminishes induction in the patient of HAMAs and the lesions, later confirmed orIfollow-up, were also found. disadvantages thereof. The prolonged biological half- In studies conducted by Abdel-Nabi et al. and Lamki life of intact MAbs causes delays of two to three days et al. (58,59), some of the patients received re-injection after injection for imaging. Shortened biological half- of ‘mTc-NR-LU- 10 later to assess chemotherapeutic lives of MAh fragments coupled with the higher photon response. In four out of four patients, disappearance flux of ‘mTc permit rapid diagnostically-efficient of, or a suhsrdntial reduction in, lesion radioactivity visualization of mediastinal and hilar regions. One-day post treatment reflected fdvorable clinical and imaging regimens become possible. Harwood and radiographic response to chemotherapy. Thus, *Tc- Abdel-Nabi (57) recently evaluated a ‘~Tc-labeled anti- NR-LU-1O appears to not on]y identify and stage CEA MAb fragment (OncoScint-NSC lung, or Tc- patients newly diagnosed with SC lung cancer, but also CYT-380 fragment, Cytogen Corporation) in three effective y monitor response to chemotherapy (57). patients having NSC lung cancers; both primary and A multi-center trial (21 sites) employed *Tc-NR- mediastinal lesions were detected in all three. LU-10 to s~age SC lung cancer in 96 patients (60). Currently in Phase I investigation for NSC lung cancer The ‘Tc tracer yielded a positive predictive value of detection and staging, Tc-CYT-380 fragment is 95 to 100% compared with 96% using the standard tentatively targeted to receive FDA approval in 1997 battery of tests (e.g., chest X-ray, CT, radionuclide (62). bone scan, hone marrow aspirates, etc.). Fifteen In the long run, radioimmunoscintigraphy with patients initially thought to have disease limited to one- antibody fragments (particularly those tagged with half the chest were upstaged due to detection by ‘mTc) seems ready to play a dominant role in radiotracer of previously unsuspected lesions. As a evaluating people with newly diagnosed lung cancer. single, non-invasive staging test for SC lung cancer, Safety, increased sensitivity and specificity, and the *Tc MAb fragment had a positive predictive value (probably) cost-effectiveness of such Iabeld fragments of 95 %, superior to that of any other single test (61). (though nominally expensive to discover and develop) ‘“Tc-NR-LU-10 has also shown considerable will prove superior to the present grab-bag of tests promise detecting the more-ubiquitous NSC lung needed to assess disease extent. cancers. In 44 patients with histological diagnosis of tiither adenocarcinoma (20 patients), squamous cell CONCLUSIONS carcinoma (13 patients), undifferentiated carcinoma (10 patients), or alvalar cell carcinoma (1 patient) While ventilator function and blood vessel patency receiving the radiopharmaceutical, images correct]y of lung have been classic nuclear medicine procedures identified 21 of 21 lung lesions, and 10 of 10 for decades, an exciting array of new radiopharma- mediastinal lesions. Distant metastasis were detected ceuticals offer potential for our entry into finding and with variable efficacy. The radiotracer was found to managing lung diseases where nuclear medicine played be more accurate than CT scans in detecting extent of no effective role in the past. disease, with a positive predictive value of 75% to With a vast surface area that conducts a massive 100% in patients with metastasis in ipsilateral and/or flow of blood, the pulmonary endothelium efficiently subcoronal lymph nodes and an encouraging negative metabolizes and/or stores blood solutes in a manner predictive value of 92% (60). Moreover, as a single still not well understood. The endothelial cellular and agent, ‘Tc-NR-LU- 10 is superior to other subcellular structures must he examined thoroughly for conventional methods in staging patients with newly us to understand their ability to quickly remove diagnosed lung cancer. It also stratifies lung cancer radiolabeled amines, amine-ox imes, amine-thiols, patients well into the appropriate therapeutic regimens amides, etc., from blood. Mechanisms of subsequent which differ qualitatively depending on the histologic retention, possible biotransformation, and efflux of the diagnosis. As an added benefit, a very low incidence radiotracers remain speculative, while our knowledge of HAMA formation elicited by NR-LU-1O permits of lung ultrastructure is minimal. repwdted administration of the radiotracer to measure The sensitivity of Tc-99m examet~ime, for response to therapy. In all, the radiopharmaceutical example, to detect subclinical (preclinical?) insult (even shows high sensitivity in imaging primary lung lesions long past) to lung in the form of tobacco smoking, ●and mediastinal involvement. chemotherapyy, and external bwdm irradiation offers Accurate imaging of primary lung cancer probably dramatic diagnostic potential. The possibility of will be achieved by a ‘mTc-labeled MAb fragment finding and quantitating damage to lung from rather than by either whole antibody or F(ab’)~ environmental sources (e.g., radon, “the sick building

9 syndrome, ” passive smoking, etc.) holds great 11. Pistolesi M, Minitili M, Pctruzxelli S, Carroz~i L, Giani promise. With growing acceptance by health physicists L, Bellina CR, ct al. Pulmontiry retention of iodobcnzyl- of the lung as a radiosensitive organ, our ability to propanediamine in humans: effect of cigarette smokin~. quantify even minimal damage there offers hope. Am Rev Resp Dis 1988; 138:1429-33. ● The radiolabeled peptides, antibodies, and 12. Kung HF, Trtimposch KM,Blau M. A ncw brain fragments now being evaluated offer greater sensitivity perfusion imaging agent: [1-l~3]HIPDM:N, N, N,. and specificity for receptor binding. Radiolabeling lrimcthyl-N ‘-[2 -hydroxy-3-methy l-5-iodobenxyl]- 1,3- with *Tc promotes world-wide acceptance of such propancdiamine. J Nuc[ Med 1983;24:66.72. products. 13. Kung HF, Blau M. Regional intracellular pH shift: a We have moved past the concept of the lungs as pmposcd newmcchanistn forradio-pilarmacelltical uutake merely “the plumbing in the chest. ” We have accepted in brtiin and other tissues. J NUC1Med 1980;21: 14?-52. the fact that the newer radiopharmaceuticals permit us much more scientific and clinical expertise in managing 14. Kung HF. Iodine kibeled brain perfusion imaging agents. the many structural and/or functional maladies of the In: Nunn AD, cditt]r, Radiophurrnaceulicak-Che?nistty human lung which are not now being managed and Phat-maco(ogy. Ncw York, Marcel Dckker, 1992:141-65. optimally. 15. Minitili M, Cocci F, Paci A, Giani L, Pistolcsi M. Evaluation of non-respiratory function of the human lung Referencm by HIPDM lung scanning. Clin Physiol 1992;12:303-11.

16. Miniati M, Paci A, Ciarimboli F, Cocci, Giani L, 1 McCuskey RS, Krasovich MA. Anatomy of the Microvascular Systcm. In: Mortillaro NA, Taylor AE, Pistolesi M. Lung subccllultir distribution of the ditors. The fathophysiulo~ of Ihe Microcirculution. pnellmophilic compound HIPDM [abstract]. Fed Am Soc Boca Raton:CRC Press,1994: 1-18. fip Biol J 1989;3:A1 147.

2. Chicn YW. R~ent advances in noninvasivc syslemic 17. Slosman DO, Brill AB, Polli BS, Aldcrson PO. delivery of pharmaceuticals and hiopharmaceuticals. Evaluatirm of [Iodine- 125]N ,N,N’-trimethyl-N ‘.[2. Drug Development & Industrial Phurmacy 1994;20:417- hydroxy-3-m~yl-5-iodobemzyl]-l ,3-pmpanediamhc lung 68, uptake using an isolated-perfused lung model. J Nucl Med 1987;28:203-8. 3. Turner DM, Armitage AK, Briant RH, Dollcry CT. Metabolism of nicotine by the isolated perfused dog lung. 18, Coupal JJ, Shih W-J, Brandenburg S. iodine-123 Xenobiotica 1975;5:539-51. H IPDM in ncoplastic disease of lung: a case report [abstract]. Abs~racts of American Pharmacenlical 4. Pichini S, Zuccaro P, Pacifici R. Drugs in semen. C/in Association 133rd Annual Meeting, San Francisco, Pharrrracokineric.~1994;26:356-73. 1986:92.

5. Benowitz NL. Clinical pharmacology of nicotine. Arm 19. Shih W-J, Coupal JJ, DeLand FH, Domstad PA, Rev Med 1986; 37:21-32, Brandenburg S, Dillon ML, et al. Dcmonslration of pulmonary mass defect by iodine-123 N, N, N’-trimct}~yl 6. Franke FE, Thomas JE. A note on the minimal fatal -N’-[2-hyd roxy-3-melllyl- 5-iodobenzyl]-l ,3- dose of nicotin for unanesthctized dogs. Proc soc EXp propancdiamine lung imaging. C[in Nucl Med Biol Med 1932;29:1 177-9. 1986; 11:632-3,

7. Temple DJ. The absorption of nicotine from tobacco 20. Hill TC, Holmtin BL, Lovctt R, O’Leary DH, Front D, snuff through the nasal mucosa. Arch Pharm fW~irrheitn) Mtigistrctti P, et al. Inititil experience with SPECT 1976;309:9 S4-7. (single-photon computerized tomography) of the brain using N-isopropyl 1-123 p-iodoamphetamine: concisc 8. Russell MAH, Jarvis MJ, DcVilt G, Feyerabend C. communication. J Nucl Med 1982;23: 191-5. Nicotine in~ke by snuff use. Brit MedJ 1981 ;283:814-7. 21. Kuhl DE,Barrio JR, Huang S-C, Selin C, Ackerman 9, Alabaster VA. Inactivation nf endogenous amines in the RF,Lear JL, et il. Quantifying local cerebral blood flow lungs, In: Bakhlc YS, Vane JR, editors. Metabolic hy N-isopropyl-p- [1231-]iodotitnptlctam inc (IMP) Funcfions of the Lung, New York; Marcel Dckker, tomography. J NI/cl Med 1982; 23: 196-203. 1977:3-31. 22, Bushnell DL, Eastman G, Btirncs WE. Coml>arison of-. IMP and HMPAO for SPECT brain imaging. J NUC1 10. Philpot RM, Anderson MW, Eling TE. Uptakc, accumulation, and metabolism of chemicals by the lungs. Med Tech 1991; 19:70-4. ● In: Bakhle YS, Vane JR, editors. M#tabolic Functions oj’ /he Lung, New York; Marcel Dekkcr; 1977:123-71.

10 23. (Anonymous). Imaging agent for lung cancer and 36. McRcady VR, Tatc D, Keeling F, Hammcrsley PAG, melanom~ (RCT Project No. 076B- 1646). Research Dwvidson T, Ott RJ, ct al. Technetium-99m HMPAO for Corporation Technologies, Tucson, AZ, July 1993:1-4. the detection of tumours and measurement of blood flow [abstracl]. Brit J Rad 1988;60:734. 24. Troutncr DE, Volkert WA, Hoffmtin TJ, Holmes RA. 0 A tctradendate amine oxime complex of Tc-99m 37. Suga K, Uchisako H, Nishigauchi K, Shimizu K, Kume [abstract]. J Nucl Med 1983 ;24:P10. N, Yamada N, et al. Tecnhetium-99m-HMPAO as a marker of chemical and irradiation lung injury: 25, Sah~ GB. Fundamental of Nuclear Pharmacy. 3rd ed. experimenbl and clinical investigations. J NUClMed New York: Springer-Verltig, 1992:119-21. 1994:35:1520-7.

26, Amcrsham Corporation. Ccrctec package insert. 38. Lever SZ, Sun S-Y, Scheffcl UA, Ktiltovich FA, Baidoo Arlington Heights, IL, 1990. KE, Goldfarb H, el al. Pulmonary accumulation of neutral diamine dithinl complexes of Technetium-99m. 27. Chiltort HM, Thrall JH. Radiopharmacculictils for J Phurm Sci 1994;83 :802-9. central nervous system imaging: blood-brain barrier, function, receptor-binding, ccrcbral spinal fluid kinetics. 39. Hassan IM, Sahweil A, Constantinides C, Mahmoud A, In: Swtinson DP, Chillon HM, Thrall JH, editors. Nair M, Omtir W, etal. Upbke and kinetics of Tc-99m Pharmaceulicuh in Medicu[ Imaging. New York: hcxakis 2-methoxy isobutyl isonitrilc in benign and Mticmillan, 1990:305-42. malignant lesions in the lung. Clin Nucl Med 1989;14:333-40. 28. Shih W-J, Coupal J, Magoun S. The biodistribulion of technetium-99 m-hcxamethylpropy lenc amine oxime. 40. Abdel-Dtiycm HM, Scott AM, M~capinlac HA, El- Semin Nucl Me(i 1994;24: 180-3. Gaz~ar AH, Larson SM. Role of ‘n’Tl chloride and “TC scstamibi in tumor imaging. In: Freeman LM, editor. 29. Sharp PF, Smidl FW, Gemell HG. Tc-99m HM-PAO Nuclear Medicine Annual 1994. New York, Raven stereoisomers as potential agcnls for imaging rcgiontil Press, 1994:181-234. blood flow: human volunteer studies. J Nucl Med 1986; 27:171-7. 41. Paptithco fan is FJ, Munson L. Pcptide radiophar- maccutical imaging, Appl Radio/ 1994 June;23 (6): 11-7. 30. Cosk DC, Ell PJ, Cullum ID, Jarritt PH. The in vivo distribution of “’Tc-HM-PAO in normal min. Nuc h4ed 42. Bombino M, Gattinoni L, Pescnti A, Pistolcsi M, Miniati Comm 1986; 7:647-58. M. The value of potihle chest roentgcnogrtiphy in adult 0 respiratory distresss yndrome; comparison with computed 31, Shih W-J, Coup~l JJ, Grunwald F, Dillon ML, Bicrsack nomography. Che.rl 1991 ;100:762-9. HJ. Tc-99m HMPAO lung uptake and cigarette smoking. In: Shih W-J, editor. Proceedings qflhe World 43. Shustcr DP, Marklin GF, Mintun MA. Regional changes Chinese Conference of Nuclear Medicine, Wuxi, China, in cxlravascular lung water dctectcd by positron emission Chinese American Socicly of Nucletir Medicine, June tomography J Appl Physiol 1986;60: 1170-8, 1994:189-94. 44. Calandrino Jr FS, Anderson DJ, Mintun MA, Shuster 32. Shih W-J, Rchm SR, Grunwtild F, Coupal JJ, Biersack DP. Pulmonary vascular permcabiliLy during the tidult HJ, Berger R, ct al. Lung uptake of Tc-99m HMPAO in respiratory distress syndrome: a positron emission study. cigarette smokers expressed by lung/liver activity ratio. Am Rev Respir Di.s 1988;138:421-8. Clin Nucl Med 1993 ;18:227-30. 45, Verma RC, Can M, Bennett L, Lin K, Schiepers C, 33. Floreani AA, Buchaltcr SE, Sisson JH, Thompson AB, Basic M, et al. First-pass pulmontiry cxtraclicm studies Rennard S1. Chronic bronchitis. In: Penningtcm JE, in humans [abstract]. C/in Nucl Med 1993; 18:926. editor. Respirato~ ln~eclious - Dia~nosis and Manugemenl. 3rd ed. Ncw York, Raven Press, 46. Shih W-J, Lai YL, Coupal JJ, Pulmano C, Wierzbinski 1994:149-92, B, Dillon M. Dctcctab]c chronic obstructive pulmonary (emphysema) disease by 1-123 HIPDM lung scinligraphy: 34. Hollinger MA. Respiraluy P/tarmticology and animtil and human study [abstract]. I IVucl Med Toxicology. Philadelphia, W,B. Saunders, 1985:37-58. 1988:29:905.

35 Oshima M, ltoh K, Okfie S, Tadororo M, Kodama U, 47. Moser KM, Bordow RA. Chronic obstructive pulmonary Sakuma S. Evaluation of primary lung carcinoma using disease: definition, cpiderniology, and pathology. In: technetium 99m-hcxamethyl propylene amine oxime: Bordow RA, Moser KM, editors. Manual o~ Clinical preliminary clinical experience. Ei~r J Nucl Med Problems in Pulmunuq Medicine, 3rd cd., Boston, Little, 1990;16:859-64. Brown Co., 1991:219-23,

48. Shih W-J, Lai Y-L, Coupal JJ, Simmons G. [l“I]HIPDM pulmnnary imaging demonstrates clastase-induce.d pulmonary emphysema. LI/ng 1993;171:3 1-41.

11 49. Said JW, Nash G, Tepper G, Banks-Schlegel S. Kcratin 62. Grant KL. Investigational drug tracking: phases 1-111and proteins and carcinoembryonic antigen in lung carcinoma: NDA submissions - part 11. Hospital Pharmacy an immunoperoxidase study of fihy-four cases, with 1994;29:900-34. ultrastructural correlations. Human Pathology 1983;14:70-6.

50. Goldenberg DM, Kim EE, DeLand FH, Bennett S, Primus FJ. Radioimmunodctection of cancer with QUESTIONS radioactive antibodies to carcinoembryrmic antigen. Cancer Research 1980;40:2984-92.

51. USAN Council. Monoclomil antibodies - list no. 351. 1. An element present in many blood-soluble Clinical Phurmacolo~ & ~~erapeutics 1993;54: 114-6. radiopharmaceuticals showing affinity for lung tissue is: 52. Krishnamurthy S, Morris JF, Antonovic R, Ahmed A, Galey WT, Duncan C, ct al. Evaluation of primary lung A. bromine cancer with Iridium-l 11anti-carcinoembry onic antigen (type ZCE-025) monoclinal antibody scintigraphy. B. cadmium Cancer 1990;65:458-65. c. nitrogen D. lead 53. Haskell CM, Bucheggcr F, Schreycr M, Carrel S, Mach J-P. Monoclinal antibodies to carcino-embryonic 2. A normal never-smoking human would antigen: ionic strength is a factor in sccrelion of probably show no lung radioactivity on a antibodies for immunoscintigraphy. Cancer Research 1983;43:3857-64. scintimage of the chest after receiving which one of the following intravenously? 54. Patt YZ. Radioactive immunodiagnosis (RAID) in patients with and rising serum CEA. A. Tc-99m albumin aggregatd New Perspectives in Cancer Diagnosis ad Management B. Tc-99m exametazime 1993;1:33-9. c. 1-123 iofetarnine 55. Levine G. Investigational radioimmunopharrnaceuticals: D. 1-123 HIPDM pharmaceutical care responsibilities and opportunities. ~ @ Pharm Pratt 1994;7:117-23. 3. An endogenous amine localized in the lungs from blood is: 56, Biggi A, Buchcri G, Ferrigno D, Viglictti A, Farinclli MC, Comino A, et al. Detection of suspcc(ed primary lung cancer by scintigraphy with Iridium-111 anti- A. HIPDM carcinoembryonic antigen monoclinal antibodies (type B. serotonin F023c5). J Nucl Med 1991;32:2064-8. c. IMP D. imipramine 57. f-tarwood SJ, Abdel-Nabi H. The use of monoclinal antibodies for radioscintigraphic detection of cancer. J In a person with mild COPD receiving 1-123 Pharm Pratt 1994;7:93-116. 4. HIPDM intravenously, the lung images would 58. Abdcl-Nabi H, Abrams P, Ackerhalt R, Farrell E, probably show: Faubirm C, Gona J, et al. Tc-99m-labeled monoclinal antibody imtiging of small cell carcinoma of the lung A. intense focal activity at disedse site(s) [abstract]. J Nucl Med 1989;30:818-9. B. intense diffuse activity throughout both 59. Lamki LM, Glisson B, Murray JL, Podoloff D, lungs Bhadkamkar V, Salk D, et al. Radioimmuno- c. a perfusion defect at disease site(s) scintigraphy of small cell lung carcinoma (SCC) using the D. no radioactivity present in either lung Tc-99m Iabelcd rnonoclonal antibody fragment [abstrtict], J NUCIMed 1989;30:819. 5. In normal human cigarette smokers compared with non-smokers, the overall lung clearance 60. Friedman S, Sullivan K, Stilk D. Staging non-small cell carcinoma of the lung using Technetium-99m labeled rate of the exogenous diamine I-123 HIPDM monoclinal antibodies. Hematofo~ Oncology Clinics is: North America 1990;4:1069-78, A. equal 61. Brictz HB, Sullivan K, Nclp WB. Imaging lung cancer B. faster with radiolabelcd antibodies. Semin N~t~.1 Med 1993 ;23:127-32. c. slower D. zero 6. 1-123 IPAB binds specificallyy to which one of 12. The site of uptake of radiolabeled basic the cell surface receptors on NSC lung diarnines in the lungs is believed to be in the: cancers? A. muscular layer around each blood ● A. epsilon vessel B. kappa B. blood pool circulating through the c. sigma lungs D. zeta c. the epithelial cells of the arterioles D. the inner wall of the blood vessel 7. No lung uptake of Tc-99m exametazime would (endothelium) be expected in a: 13. The one study cited investigating subcellular A. current marijuana and cigarette smoker localization of a radioiodinated basic diamine B. current cigarette smoker in lungs of normal rabbits demonstrated: c. former cigarette smoker D. never smoker A, considerable redistribution over time of radioactivity from one structure to 8. Relative degree of blood perfusion of Tc-99m another exametazime to a tumor would likely indicate: B, greatest diamine specific activity in the mitochondria A. relative tumor radiosensitivity c. faster clearance of radiolabel from B. relative oxygenation of tumor homogenate fractions in vitro than c. choice of treatment option(s) from the different isotopic-labeled D. all of the above compound in lungs of humans in vivo D. no localization of radiotracer in the 9. After which one of the following intravenous nucleus doses of the liquid oleic acid to normal rabbits ● were there no reduced or defective arwas of 14. Lung extraction from the blood of the lung perfusion following subsequent radiolabeled endogenous amine serotonin in intravenous injection of Tc-99m MAA? patients with ARDS is that in patients without: A. 0.05 mL/kg B. 0.10 mL/kg A. greater than c. 0.20 mL/kg B. equal to D. 0.25 mL/kg c. less than D. virtually undetectable compard with 10. After which one of the following intravenous doses of the liquid oleic acid to normal rabbits, 15. After intravenous injection, 1-123 labeled basic was there the least lung uptake of subsequent amines usd as cerebral perfusion (brain) intravenous injection of Tc-99m exametuime? imaging agents tend to localize in normal human lungs: A. O mL/kg B. 0.05 mL/kg A, never c. 0.10 mL/kg B. focally D. 0.20 mJ./kg c. late D. homogeneous] y 11. HAMA production in patients sometimes occurs after the patient receives:

A. an 1-123 Iabeld basic diarnine B. Tc-99m labeled diamine dithiol @ (DADT) compound c. an In-11 1 labeled antibody D. an 1-123 labeled neutral diamine

13 16. A common quantitative measurement on 21. Which of the following statements is true? scintimage of uptake of Tc-99m exametazime in lung tumors may be determined on A. All lipophilic neutral amine computer by deriving a “region of interest” radiopharmaceuticals concentrate in ● activity ratio of tumor-to-: normal and in disedsed human lungs. B. Pulmonary uptake of Iipophilic neutral A, normal brain radiopharmaceuticals, when it occurs, B. blood pool (heart) is usually rapid. c. contralateral normal lung c, Endogenous (biogenic) amines taken D. thigh up by the lungs are not metabolized there, but S1OW1y efflux. 17. The HMPAO molecule contains: D. Exogenous amines are readily metabolized by the lungs with profuse A. 2 sulfur and 2 nitrogen atoms release of metabolizes into the blood. B. 4 sulfir atoms c. 4 nitrogen atoms 22. Elastase, which may play a role in damaging D. 4 carbon atoms the structural framework of the lungs, is found in: 18. Intratracheal insufflation of the proteolytic enzyme elastase has been used in an animal A. leukocyte homogenates model in viva for study of B. alveolar macrophages c. neutrophils A. lung cancer D. all of the above B. respiratory distress syndrome c. black lung disedse 23. Iridium-l 11 pentetrmtide is likely to show D. emphysema greatest diagnostic efficacy for which disease of the lung? 19. An organ frequently present as the denominator in “activity ratios” or “selectivity A, emphysema ratios” describing lung uptake of blood-soluble B. non-small cell cancer radiopharmaceuticals is the: c. ARDS D. small cell cancer A. liver B. kidney 24. Which one of the following statements is true c. spleen about Tc-99m NR-LU- 10? D. heart A. It has shown promise for detecting 20. Therapy with which one of the following drugs both NSC and SC lung cancer. describ~ herein has been shown to reduce B. It elicits significant HAMA production pulmonary Iocalizationof subsequently-injected in patients receiving it. 1-123 IMP? c. The Tc-99m label yields poorer quality images than the corresponding I-123 A. acetylsalicylic acid label. B. arnoxicillin D. As for OncoScint CR/OV, only one c. dipyridamole injection per patient is recommended. D. bleomycin 25. Enhanced uptake of Tc-99m exametazime may be expected in which of the following lung cancer histologies?

A. squamous cell carcinoma B. adenocarcinoma ● c. large cell carcinoma D. equally among the three above

14