REVIEW 

Annals of Nuclear Medicine Vol. 7, No. 4, 207-214, 1993 

Rationale for the rational development of new cardiac imaging agents 

D. Douglas MILLER St. Louis University Medical Center, Department of Internal Medicine, Division of Cardiology. St. Louis. Missouri, USA 

There are several prerequisites for the development of new diagnostic cardiovascular radio-pharmaceuticals. Agents which are proposed for clinical use must offer significant advan-tages in one or more of the following categories : I) Radiopharmacy [dosimetry, dose preparation, dose availability] ; II) Imaging characteristics [spatial and temporal resolution, radiotracer biokinetics, patient throughput and acquisition protocols]; and 111) Measure-ment of a previously unmeasurable physiologic or pharmacologic event [metabolic pathways, receptors, neural pathways, preclinical disease]. Technetium-99m-based radio-pharmaceuticals are particularly attractive, in view of their excellent characteristics for imaging with the Anger gamma camera. In addition, the increasing use of tomog-raphic imaging and reconstruction techniques has magnified the importance of developing radiotracers with minimal soft tissue attenuation effects. Technetium-99m and positron emitting radioisotopes offer this advantage. A wide choice of biologically and pharma-cologically relevant ligands are available for complexing with these radiotracers. The clinical studies are underway in order to validate these new agents, and to determine their value in the modern practice of nuclear medicine. Technetium-99m sestamibi is just one example of a novel radiotracer with improved imaging characteristics that has undergone careful pre-clinical and clinical testing, and which has emerged as a usefu] diagnostic imaging agent. Future studies should be directed towards the development of tracers with we]1-defined biokinetic characteristics, which are advantageous for tomographic imaging. The future applications of tracer imaging techniques for the pre-clinical diagnosi_s of cardiovascular, oncologic and other medical conditions are significant and are expanding. Combined diag-nostic and therapeutic approaches may eventua]ly be possible with a single injection of a pharmacologically active radiotracer. 

Key words: myocardial perfusion, radionuclide imaging, positron emission tomography, receptors, atherosclerosis. 

INTRODUCTION

 As WITH OTHER PHARMACEUTICALS, diagnostic radiopharmaceutical research and development is proceeding at a rapid pace.1 A wide range of radio-
pharmaceuticals have been developed for evaluation of myocardial perfusion, ventricular function, myo-cardial viability and substrate metabolism.2 The first era of cardiovascular nuclear medicine has witnessed the experimental and clinical validation of thallium-201 myocardial perfusion imaging and technetium-99m radionuclide angiography, two tech-niques which are widely applied in medical practice for detection and prognostication of cardiac diseases. Planar and tomographic single photon nuclear medicine camera-computer systems have been con-figured to accommodate the physical characteristics and biologic behavior of these two isotopes. Applica-tion of comparable image acquisition protocols, implementation of radiopharmacy preparation for dose preparation and quality control, and dissemina-tion of validated quantitation software and standard-ized normal files have significantly enhanced the diagnostic utility of these radionuclide procedures. 
Despite changing patient referral bases and laboratory utilization profiles, these radionuclide studies have persistently demonstrated high sensi-tivity for disease detection and significant positive predictive accuracy for adverse cardiac events. 
Specificity values vary widely between 50 and 90 %, 
principally due to post-test referral bias, which directs positive test responders to diagnostic cardiac cathe-terization. Collaboration between industry and investigators has led to the development of quantita-tive image analytic techniques which demonstrate excellent transportability between medical centers, and high reproducibility between studies. In this setting, novel cardiovascular radiopharmaceuticals must offer improved dosimetry or image resolution [temporal or spatial], or provide diagnostic infor-mation on a previously unmeasurable but relevant biologic parameter. 

State-of-the-art 
The proceedings of the 38th Annual Meeting of the Society of Nuclear Medicine3 produced an interesting survey of the current international trends in cardio-vascular radiopharmaceutical development. Despite the significant numbers of papers on the use of thallium-201 for coronary disease diagnosis, prog-nosis and viability assessment [7%], and of PET studies of cardiac flow and metabolism with rubid-ium-82, nitrogen-13 ammonia and fiuorine-18 deoxy-glucose [5%], 107 of the 843 general and cardio-vascular papers accepted for this meeting [13%] provided information on the radiochemistry and applications of new tracers for cardiovascular imag-ing. Of these papers, 77% evaluated single photon emitting radionuclides, while 23% presented data on position emitting radiotracers. Studies of then approved myocardial perfusion tracers, Tc-99m sestamibi [24%] and Tc-99m teboroxime [20 %], were most numerous among these new radiopharmaceuticals. Single photon and posi-tron emitting isotope labeled radioligands for receptor binding [alpha and beta adrenergic, cholinergic/muscarinic] also constituted a significant percentage [17%] of "new agent" papers (i.e. iodine-1 25 Iabeled hydroxy- phenyl-ethyl-amino-methyl-tetralone [HEAT] for studies of the alpha-1 receptor, carbon-11 [S] CGP-12177, iodine-125 iodocyano-pindolol and carbon-11 carazolol [for beta-adrenergic receptor studies], carbon-11 epinine [a dobutamine derivative], and 6-[F-18]fluorodopamine [for dopa-minergic receptors], carbon-11 benzovesamicols [for acetylcholine receptors], and iodine-123 3-quinuclidinyl benzilate [QNB] analogs [for mus-carinic receptors]). More established adrenergic neuronal tracers including iodine-123 meta-iodo-benzyl-guanidine [MIBG], and carbon-11 [metaj hydroxyephedrine [MHED] were the subject of further studies. 
Useful clinical applications for antimyosin anti-body imaging of myocardial necrosis were presented [9 %], including molecular modifications of anti-myosin to produce SFV fragments for rapid blood pool clearance, fluorine-18 Iabeling for PET studies and indium-111 Iiposomes for antimyosin delivery. For detection of thrombosis and early atherosclerosis> technetium-99m labeled antifibrin [T2G2] and antiplate]et monoclonal antibodies [S12] were repre-sented. Additional studies of radiolabeled low density lipoprotein [LDL], indium-111 Z2D3 [IgM] anti-body directed against atheromatous ground substance, and a placental anticoagulant protein I ligand for platelet imaging were reported. Overall. single photon agents for plaque and thrombus imag-ing totalled 8% of new studies. 
Single photon labeled modified fatty acid analogs for studies of cardiac metabolism made up 4% of studies, including papers on iodine-123 beta-methyl IPPA and technetium-99m N2S2 derivatized analogs. Fluorine-18 FTHA [fluor0-6-thia-hepadecanoic acidl studies of a modified long chain fatty acid designed to, undergo beta-oxidation and subsequently be metabolically "trapped" in the myocardium were also reported [2%].
Positron-emitting copper-62 PTSM [pyruvalde-hyde-bis-N4-methyl thiosemicarbozone] . A generator-produced PET imaging agent which may be an alternative to cyclotron-produced carbon-1 1 acetate. was the subject of 5% of papers presented. New single photon emitting myocardial flow markers [3%] and potential positron emitting per-fusion tracers [4%] were represented. Including technetium-94, gallium-68 BAT-TECH [a lipid soluble agent], Tc-99m [III] cationic diphosphines [Q12. P53] and Fluorine-18 fluoromisonidazole [FMISO], which concentrates in ischemic tissue. Each of these novel radiotracers fulfills one or more of the specifications for cardiovascular radio-pharmaceutical development. A range of pre-clinical to post-release studies were represented. While a significant percentage of these agents may never achieve widespread clinical utilization, others have already become significant elements of modern cardiovascular nuclear medicine practice. Published studies: 1990-1991 Between August 1990 and July 1991, a total of 30 manuscripts were published in the Journal of Nuclear Medicine dealing with the experimental and clinical validation of novel cardiovascular radioisotopes. Nineteen of these articles (63%) reported studies on single photon radiotracers, while the remaining I l manuscripts (37%) dealt with new positron emitting radiotracers. Significant numbers of both single photon and positron emitting myocardial perfusion imaging radiotracers were studied. In addition to further studies of the technetium-99m perfusion agents sestamibi4-7 and teboroxime,8 iodine-123 9-methyl PPA,9-13 C-11 acetate,14-18 and Ga-68 BAT TECH19,20 were evaluated as myocardial perfusion radiotracers. Fluorine-18 misonidazole uptake was reported to be increased in studies of acute reversible myocardial ischemia associated with ,changes in glycolytic metabolism.52 Several studies ,examined the myocardial uptake of indium-111 antimyosin antibody in previously untested clinical 'subgroups,21-24 including patients with dilated hypertrophic cardiomyopathy, doxorubicin cardiac toxicity, and non-Q wave myocardial infarction. A new technetium-99m based carbohydrate ligand, Tc-99m glucaric acid, demonstrated increased uptake in experimental zones of infarctions, reflecting alter-native cardiac metabolism.53  

I. Perfusion imaging agents A new generator produced positron emitting myo-,cardial perfusion agent, copper-62 pyruvaldehyde bis (N4-methythiosemicorbazone) [PTSM] has been extensively studies.25-27 The production of this compound from a zinc-62/copper-62 generator provides a more convenient source of positron radio-pharmaceutical for regional blood flow determi-nations in both the heart and brain. The half life the parent compound (9 hours) and daughter (9 minutes) may limit the clinical utility due to a generator life span of 2 days. Radiochemical com-plexing of Cu-62 with PTSM produces a neutral, lipid soluble compound which passes rapidly through cell membranes and is subsequently trapped intracellularly after interacting with sulfhydril groups. The short physical half life of the Cu-62 daughter permits repeat imaging studies over short time intervals as well as "kit" chemical synthesis of radiopharmaceuticals. Intravenous, Cu-62 PTSM is highly extracted by myocardial tissues, with good myocardial retention and no recognized toxicity. 
Additional copper-62 based radiotracers produced from this generator include Cu-62 benzyl TETA-human serum albumin (HSA) for intravascular blood pool imaging.27 As such, a zinc-62/copper-62 positron generator can produce radionuclide for both blood pool imaging with Cu-62 benzyl TETA-HSA and perfusion studies with Cu-62 PTSM. Subtraction imaging of blood pool and myocardial perfusion phases is possible with Cu-62 benzyl TETA-HSA at laboratories that do not possess an on site cyclotron. PET blood pool images ob-tained with this agent are comparable to those generated with C150. Gated right and left ventricular blood pool function studies can be acquired with this agent in combination with traditional PET perfusion agents (i.e. rubidium-82, nitrogen-13 ammonia, etc.). Another potentially useful positron generator system is the germanium-68/gallium-68 generator. 20,27 The parent compound has a half life of 287 days and is useful for approximately I year, while the daughter has a half life of 68 minutes, making it suitale for complex radiochemical labeling studies. Lipid soluble Ga-68 complexes of potential utility for myocardial perfusion imaging have been investigated. but have significant limitations for this application. 
Other neutral lipid soluble Ga-68 complexes have been studied for cerebral perfusion imaging. Ga-68 BAT TECH is a complex of Ga3+ with bis-amino-ethanethiol-tetra-ethyl-cyclohexyl (BAT TECH) ligand. PET myocardial perfusion imaging studies with this agent have been reported. The percent of the initial dose retained by the rat myocardium 2 minutes following injection of Ga-68 BAT TECH is 1.68%. Rapid myocardial clearance of BAT TECH and other agents limits late image quality, since the rate of radiotracer clearance is likely to be greater in hyperemic than ischemic myocardial regions. Tracer clearance enforces the need for abbreviated imaging acquisition times to assure a constant relationship between tissue counts and relative regional myocardial perfusion, potentially reducing clinical applications. Heart to blood activity ratios obtained 2 minutes following injection of Ga-68 BAT TECH are 3.5, decreasing to 3.1 at 30 minutes and 1.2 at 60 minutes in a rat model. Comparable heart to blood activity ratios for Cu-62 PTSM at I minute, 5 minutes and 120 minutes are 5.9, 9.8 and 9. Thus, Cu-62 PTSM myocardial activity appears better suited to cardiac imaging PET studies. 

II. Metabolic imaging Iodinated fatty acid molecules have been evaluated over the last decade for detection of myocardial metabolism rates and viability with single photon imaging systems.9~13 Analogs of phenyl pentade-canoic acid (PPA) have demonstrated the capacity for perfusion assessment based on initial uptake, and fatty acid metabolism based on differential myo-cardial clearance. Limited iodine-123 availability for labeling to this moiety have reduced its clinical application. The desire to provide cardiac metabolic information without the need for expensive PET detector systems and cyclotrons has fueled con-tinued investigation. Recently, iodine-131 ortho-PPA has demonstrated a reasonable correlation with FDG data (r=0.51) for detection of viability in "fixed" thallium-201 defects.13 Additional studies have correlated modified 9-methyl iodine-123 PPA with thallium-201 uptake in patients with coronary artery disease induced myocardial ischemia. 12 Ortho-PPA is another compound which binds to co-enzyme A and remains principally within the free fatty acid pool, while para-PPA enters mitochondrial beta oxidation.9 The implications of these metabolic path-ways for detection of myocardial viability, and the relationship to myocardial ATP content have been evaluated in further basic studies.ro The search for a single photon emitting fatty acid metabolic tracer for the detection of viability continues. PET imaging studies utilizing carbon-11 acetate as a marker of aerobic metabolism via the tri-carboxylic acid (TCA) cycle metabolism have increased.14-18 The myocardial uptake of this agent at steady state is proportional to the cellular gen-eration of carbon dioxide. The agent is avidly extracted by the myocardium in response to increased myocardial oxygen consumption; mitochondria con-vert it to carbon-11 acetyl-CO-A prior to entering the TCA cycle. As compared to carbon-11 palmitate, C-11 acetate is rapidly and completely oxidatively metabolized. Its experimental myocardial clearance is closely related to myocardial oxygen consumption over a range of physiologic conditions and cardiac workloads. The metabolism of carbon-11 acetate is not significantly affected by circulating levels of other competitive substrates, as opposed to carbon-1 palmitate and fluorine-18 FDG. Modeling of C-1 1 acetate clearance kinetics should permit absolute quantification of myocardial oxygen consumption using PET imaging. In addition to the value of clearance data following injection of this agent, preliminary studies indicate a direct proportionality between initial uptake and myocardial blood flow in coronary artery disease patients. Despite its rela-tively complex radiochemistry, carbon-ll acetate is being widely evaluated as a clinical diagnostic tool. 

III. Neuro-humoral imaging agents Cardiac adrenergic and muscarinic receptor radio-tracers continue to be the focus of new studies.30-34 The myocardial beta adrenergic receptor can be characterized by PET imaging with C-1 1 CGP 12177 and C-1 1 metahydroxyephedrine (MHED). Fluorine-18 Iabeling of the norepinephrine analog, meta-raminol, provides an indirect approximation of tissue NE Ievels from PET images. C-11 CGP 12177 is a potent high affinity hydrophilic beta adrenergic receptor ligand which couples to adenylate cyclase,33 and has significant image advantages over C-11 propranolol, which is confounded by excessive back-ground lung uptake. C-ll MHED can detect myo-cardial denervation in response to a variety of insults including myocardial infarction, congestive heart failure and chronic hypoxia.30,34 This sympathetic nervous system probe provides for competitive up-take between the radiolabeled drug (carbon-11 MHED) and the endogenous neurotransmitter, norepinephrine (NE). Mathematical modeling has been developed for quantification of the uptake of this agent. 
Another radiolabeled catecholamine analog, fluo-rine-18 metaraminol (FMR), is used to assess the sympathetic nervous system responses to regional myocardial ischemia.31 Transient disturbances of sympathetic neuronal function may occur in response to ischemia, and may be dynamically assessed by FMR imaging. Experimental studies have demon-strated significantly reduced F-18 metaraminol activity in post occlusive zones with 87% flow reduction and 18% reduction of tissue NE concen-tration. Pharmacologic blocking studies of this agent in vivo confirm neuronal localization by the uptake I carrier system and subsequent vesicular storage. The relationship between regionally depressed post-ischemic FMR concentrations derived by PET imaging and electrophysiologic instability and ar-rhythmogenesis remains unconfirmed. 
Muscarinic receptor binding agents including 4-iodine- 125-iododexetimide32 and carbon- 11 MQNB have been studied. The potential for single photon or PET imaging of muscarinic cholinergic (ACH) receptors may be valuable in the assessment of cardiac dysfunction due to diabetes, aging, congestive heart failure and anti-arrhythmic therapy. Fluorine-l 8 fiurodopamine can experimentally assess cardiac sympathetic innervation in animals.51 Cardiac uptake of this positron emitting neuronal radiotracer is significantly diminished by pre-treatment with the competitive antagonist, desipramine. Clinical studies with these and other radioisotope markers of neuronal function are proceeding with the goal of defining the cardiac response to pharmacologic interventions and diseases. 

IV. Myocardia/ perfusion imaging with technetium based radionuclides The relative advantages and disadvantages of thallium-201 and technetium-99m sestamibi (Car-dioliteR) and Tc-99m teboroxime (CardiotecR) have been extensively reviewed.35 Prior approval of the technetium-based perfusion compounds by licensing bodies in Europe and Canada was followed by approval in the United States. Insufficient time has elapsed to determine what impact these novel perfusion agents will have on the day-to-day practice of clinical nuclear cardiology. Whether these agents will completely replace thallium-201 for the detec-tion and assessment of patients with known or sus-pected coronary artery disease is unclear. 
Tc-99m sestamibi (CardioliteR) offers significant advantages for SPECT imaging over results achieved with thallium-201, with improved diagnostic accu-racy in most clinical validation trials. Thallium-201 activity distribution over time, in particular detection of defect "redistribution" by thallium-201 reinjection or delayed (18-24 hour) imaging, is highly cor-related with myocardial viability. The relationship between technetium-99m perfusion agent distribution and perfusion is better validated than is the dis-tribution of these agents to tissue viability.36 PET imaging and dual isotope imaging studies with in-dium-111 antimyosin and thallium-201 may c]arify this unresolved aspect of technetium-99m perfusion agent imaging. Software for reconstruction and quantitative analysis of Tc-99m sestamibi images have been developed by extrapolation from tech-niques of thallium-201 image analysis.4 
Despite the rapid myocardial clearance of tech-netium-99m teboroxime, it appears that planar and tomographic images can be generated with this perfusion agent. Differential clearance from ischemic and normal myocardial zones may permit detection of early perfusion defect "redistribution" within 10 minutes of stress injection.37,38 The evolution of thallium-201 myocardial per-fusion imaging from its inception in 197739 to the tomographic description of persistent fluorine-18 deoxyglucose uptake in persistent thallium perfusion defects40 and delayed (8-24 hour) tomographic defect redistribution41 required a decade of intensive experimental and clinical evaluation. Despite tremen-dous interest and enthusiasm, a full understanding of the scope and importance of myocardial per-fusion imaging with technetium-99m isonitrile42 and teboroxime43 may not be achieved without a similar duration of intensive investigation and validation. 

V. Indicators of atherosclerotic plaque instability A significant future challenge for cardiovascular radionuclide imaging is the detection of insipient subclinical atherosclerotic plaque instability. The local metabolic activity of atheroma and activated platelets can now be assessed in vivo using radio-labeled plaque components and monoclonal anti-bodies. For example, monoclonal antibodies specific for the platelet surface membrane glycoprotein IIB-IIIA, indium-11 1 P256 antibody, has been utilized to image canine vascular thrombi. Another monoclonal antibody within this cluster of differentiation with specificity for translocated ce-granule membrane proteins, iodine-123 anti-PADGEM, has been utilized to detect baboon deep venous thrombi.44 A novel technetium-99m monoclonal antibody with specificity for the ce-granule GMP-140 membrane glycoprotein expressed on the surface of activated platelets, Tc-99m S12, has been successfully imaged in animals and man following arterial angioplasty injury.45,46 These highly specific radiolabeled mono-clonal antibodies demonstrate favorable biodis-tribution and imaging characteristics with minimal contamination of blood pool usually associated with autologous platelet imaging studies. Other components of atherosclerotic lesions47 and 10cal thrombi48 can be directly imaged following technetium-99m labeling of low density lipoproteins and thrombus-specific monoclonal antibodies. Thrombus components including recombinant tissue plasminogen activator (t-PA) and factor-XIII have also been radiolabeled for non-invasive in vivo imaging studies of experimental thrombi.49,50 The incorporation of various thrombus components has been studied in vivo with radiotracers including indium-111 antifibrin monoclonal antibody (for deep venous thrombosis)28 and indium-111 "inhibited" recombinant tissue plasminogen activator (rt-PA).29 The role of cardiovascular nuclear medicine studies of thrombotic and thrombolytic proteins is being evaluated during the pre-clinical and therapeutic phases of thrombogenesis and fibrinolysis. 

ACKNOWLEDGMENTS

 I would like to thank Ms. Lori Gallini Meeker for her secretarial assistance. 

REFERENCES

1. Miller DD, Gill JB, Fischman AJ, et al : New radio-nuclides for cardiac imaging. Prog Cardiovasc Dis 28: 419-434, 1986 
2. Miller DD, Elmaleh DR. McKusick KA, et al : Radio-pharmaceuticals for cardiac imaging. Radiol Clinics of N Am 23 : 765-781, 1985 
3. Proceedings of the 38th Annual Meeting, Society of Nuclear Medicine. J Nucl Med 32 (5) : 909-1 108, 1991 
4. Koster K, Wackers FJ Th, Mattera JA, et al : Quanti-tative analysis of planar technetium-99m sestamibi myocardiai perfusion images using modified back-ground subtraction. J Nuc/ Med 31 : 1400-1408, 1990 
5. Pellikka PA, Behrenbeck T, Verani MS, et al : Serial changes in myocardial perfusion using tomographic technetium-99m-hexakis-2 - methoxy - 2 - methylpro pyl-isonitrile imaging following reperfusion therapy of myocardial infarction. J Nuc/ Med 31: 1269-1275 1990 
6. Tartagni F, Dondi M, Limonetii P, et al : Dipyrida-mole technetium-99m-methoxy isobutyl isonitrile tomoscintigraphic imaging for identifying diseased coronary vessels: comparison with thallium-201 stress-rest study vessels: comparison with thallium-201 stress-rest study. J Nuc/ Med 32: 369-376, 1991 
7. De Puey EG, Jones ME, Garcia EV : Evaluation of right ventricular regional perfusion with a techne-tium-99m-sestamibi SPECT. 
8. Naka.jima K, Taki J. Bunko H, et al : Dynamic acqui-sition with a three-headed SPECT system : application to technetium-99m-SQ30217 myocardial imaging. J Nucl Med 32: 1273-1277, 1991 
9. Kaiser KP. Geuting B, GroBmann, et al : Tracer kinetics of 1 5-(orth0-123/1311-phenyl)-pentadecanoic acid (oPPA) and 15-(para-123/1311-phenyl)-pentade-canoic acid (pPPA) in animals and man. J Nucl Med 3: 1608-1616, 1990 
10. Fujibayashi Y, Yonekura Y. Takemura Y, et al : Myocardial accumulation of iodinated beta-methyl branched fatty acid analogue, iodine-125-15-(p-iodo-phynyl)-3-(R,S)methylpentadecanoic acid (BMIPP), in relation to ATP concentration. J Nucl Med 31: 1818-1822, 1990 
11. Fink GD, Montgomery. David F, et al : Metabolism fi-methyl-heptadecanoic acid in the perfused rat heart and liver. J Nucl Med 31 : 1823-1830, 1990 
12. Chouraqui P, Maddahi J. Henkin R, et al : Compari-son of myocardial imaging with iodine-123-iodo-phenyl-9-methyl pentadecanoic acid and thallium-201-chloride for assessment of patients with exercise-induced myocardial ischemia. J Nucl Med 32: 447~,52, 1991 
13. Heinrich MM, Vester E, von der Lohe E, et al : The comparison of a 2-18F-2-deoxyglucose and 1 5-(orth0-1311-pheny])-pentadecanoic acid uptake in per-sisting defects on thallium-201 tomography in myo-cardial infarction. J Nucl Med 32: 1353-1357, 1991 
14. Hicks RJ, Herman WH, Kalff V, et al: Quantitative evaluation of regional 41 substrate metabolism in the human heart by positron emission tomography. J Am Coll Cardiol 18: 101-111 1991 
15. Kotzerke J. Hicks RJ, Wolfe E, et al : Three-dimen-sional assessment of myocardial oxidative metabo-lism : a new approach for regional determination of PET-dervied C-1 1 acetate kinetics. 
16. Gropler RJ. Siegel BA, Geltman EM: Myocardial uptake of carbon-1 1 acetate as an indirect estimate of regional myocardial blood fiow. J Nucl Med 32: 245-251, 1991 
17. Schwaiger M, Hicks R : The clinical role of metabolic imaging of the heart by positron emission tomog-raphy. J Nucl Med 32: 565-578, 1991 
18. Chan SY, Brunken RC, Phelps ME, et al : Use of the metabolic tracer carbon-11-acetate for evaluation of regional myocardial perfusion. J Nucl Med 32: 665-672, 1991 
19. Kung HF, Liu BL, Mankoff D, et al: A new myo-cardial imaging agent : synthesis, characterization, and biodistribution of gallium-68-BAT-TEC.H. J Nucl Med 31 : 1635-1640, 1990 
20. Green MA. Editorial : The potential for generator-based PET perfusion tracers. J Nucl Med 31 : 1 641-1645, 1990 
21. Hendel RC, McSherry BA, Leppo JA : Myocardial uptake of indium-111-labeled antimyosin in acute subendocardial and autoradiographic correlation of myocardial necrosis. J Nuc/ Med 31 : 1851-1 853, 1990 
22. Estorch M. Carrio I. Berna L, et al: Indium-111-antimyosin scintigraphy after doxorubicin therapy in patients with advanced breast cancer. J Nucl Med 31 : 1965-1969, 1990 
23. Nakata T, Sakakibara T, Noto T, et al : Myocardial distribution of indium-111-antimyosin fab in acute inferior and right ventricular infarction : comparison with technetium-99m-pyrophosphate imaging and histologic examination. J Nuc/ Med 32: 865-866. 1991 
24. Nishimura T, Nagata S, Uehara T, et al : Assessment of myocardial darnage in dilated-phase hypertrophic cardiomyopathy by using indium-111-antimyosin fab myocardial scintigraphy. J Nucl Med 32: 1 333-1337, 1991 
25. Green MA, Mathias CJ, Welch MJ, et al : Copper-62-labeled pyruvaldehyde Bis (N4-methylthio-semi-carbazonato) copper (II) : synthesis and evaluation as a positron emission tomography tracer for cerebral and myocardial perfusion. J Nucl Med 31 : 1989-1996, 1990 
26. Mathias CJ, Welch MJ, Green MA, et al : In vivo comparison of copper blood-pool agents : potential radiopharmaceuticals for use with copper-62. J Nucl Med 32: 475-479, 1991 27. Subramanian KM. Editorial : Cardiac b]ood-pool tracers. J Nucl Med 32: 480-482, 1991 
28. DeFaucal P, Peltier P, Planchon B, et al : Evaluation of indium-111-labe]ed antifibrin monoclonal antibody 
for the diagnosis of venous thrombotic disease. J Nucl Med 32: 785-790, 1991 
29. Butler SP, Kadar KL, Owen J, et al : Rapid localiza-tion of indium-111-labeled inhibited recombinant tissue plasminogen activator in a rabbit thombosis mode]. J Nucl Med 32: 461-467, 1991 
30. Rosenspire KC, Haka MS, Van Dort ME, et al: Synthesis and preliminary evaluation of carbon-11-meta-hydroxyephedrine : a false transmitter agent for heart neuronal imaging. J Nuc/ Med 31 : 1328-1334, l 990 
31. Schwaiger M. Guibourg H. Rosenspire K, et al : Effect of regional myocardial ischemia on sympathetic nerv-ous system as assessed by fiuorine-18-metaraminol. J Nucl Med 31 : 1352-1357, 1990 
32. Matsumura K, Uno Y, Scheffel U, et al : In vitro and in vivo characteristics of 4-[125l]lododexetimide bind-ing to muscarinic cholinergic receptors in the rat heart. J Nucl Med 32: 76-80, 1 991 
33. Delforge J, Syrota A, Lamcon JP, et al : Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177, and a graphical method. J Nucl Med 32: 739-748, 1991 34. Schwaiger M, Kalff V, Rosenspire K, et al : Non-invasive evaluation of sympathetic nervous system in human heart by positron emission tomography. Circ 82: 457-464, 1990 
35. Berman DS (Ed.) A symposium : Technetium-99m myocardial perfusion imaging agents and their rela-tionship to thallium-201. Am J Cardiol 66 : IE-96E. 1 990 
36. DeCoster PM, Wijns W, Cauwe F, et al : Area-at-risk determination by technetium-99m-Hexakis-2-methoxyisobutyl isonitrile in experimental reperfused myocardial infarction. Circ 82: 2152-2162, 1990 
37. Hendel RC, McSherry B, Karimeddini M, et al : Diagnostic value of a new myocardial perfusion agent, teboroxime (SQ30,217), utilizing a rapid planar imaging protocol : Preliminary results. J Am Coll Cardiol 16: 855-861, 1990 
38. Stewart RE. Heyl B. O'Rourke RA, et al : Demon-stration of differential post-teboroxime clearance kinetics after experimental ischemia and hyperemic stress. J Nucl Med 1991 (in press) 
39. Strauss HW, Pitt B : Thallium-201 as a myocardial imaging agent. Semin Nucl Med 7 : 49-58, 1977 
40. Brunken R. Schwaiger M, Grover-McKay M, et al : Positron emission tomography detects tissue metabo-lic activity in myocardial segments with persistent thallium perfusion defects. J Am Coll Cardiol 10: 557-567, 1987 
41. Cloninger KG, DePuey EG, Garcia EV, et al : In-complete redistribution in delayed thallium-201 SPECT images : An overestimation of myocardial scarring. J Am Coll Cardiol 12: 955-963, 1987 
42. Jones AG, Davison A, Abrams MJ, et al : Bio-logical studies of a new class of technetium com-plexes : The hexakis (alkyl/isonitrile) technetium (1) cations. Int J Nucl Biol 11 : 225-234, 1984 
43. Treher EN, Gougoutas J, Malley M, et al : New technetium radiopharmaceuticals: boronic acid ad-ducts of vicinal. dioxime complexes. J Label Comp Radiopharm 23 : 118-120, 1986 
44. Palabrica TM, Furie BC, Konstam MA, et al : Thrombus imaging in a primate model with anti-bodies specific for an external membrane protein of activated platelets. Proc Natl Acad Sci USA 86: 1036-1040, 1989 
45. Miller DD, Boulet AJ, Tio FO, et al : In vivo techne-tium-99m S12 antibody imaging of platelets ??-granules in rabbit endothelial neointimal proliferation after angioplasty. Circ 83: 221-236, 1991 
46. Miller DD. Palmaz JC, Garcia OJ, et al : Platelet activation at human angioplasty sites : Noninvasive detection by specific S12 monoclonal antibody imag-ing. Circ 82 (Suppl 111) : 111-650, 1990 
47. Lees AM, Lees RS, Schoen FJ, et al : Imaging human atherosclerosis with Tc-99m labelled low-density lipo-proteins. Arteriosclerosis 8 : 461~70, 1988 
48. Rosebrough SF, McAfee JG, Grossman ZD, et al : Thrombus imaging : a comparison of radiolabeled GC4 and T'_Gls fibrin-specific monoclonal anti-
bodies. J Nucl Med 31 : 1048-1054, 1990 
49. Ord JM, Daugherty A, Thorpe SR, et al : Detection of thrombi with modified t-PA coupled to a residual-izing radiolabeled. Cir 82 (Suppl 111) : 111-320, 1990 
50. Cergueira MD, Edwards M, Bishop P, et al : In vivo arterial thrombus labeling with recombinant factor-XIII. Circ 82 (Suppl 111) : 111-650, 1990 
51. Goldstein DS, Chang PC, Eisenhofer G, et al : Posi-tron emission tomographic imaging of cardiac sym-pathetic innervation and function. Circ 81: 1606-1621, 1990 
52. Shelton ME, Dence CS, Hwang DR, et al: In vivo delineation of myocardial hypoxia during coronary occlusion using F-18 misonidazole and positron emission tomography : a potential approach for identification of jeopardized myocardium. J Am Coll Cardiol 16: 477-485, 1990 
53. Orlandi C, Crane PD, Edwards S, et al : Early scin-tigraphic detection of experimental myocardial infarc-tion in dogs with technetium-99m-glucaric acid. J Nucl Med 32: 263-268, 1991