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New myocardial perfusion imaging agents: Description and applications
New myocardial perfusion imaging agents: Description and applications Jaekyeong Heo, M.D., George A. Hermann, M.D., Abdulmassih Alan Askenase, M.D., and Bernard L. Segal, M.D. Philadelphia,
Myocardial perfusion imaging is the most commonly performed procedure in nuclear cardiology. Thallium-201 has been the agent of choice due to its favorable physiologic kinetics: the initial myocardial uptake corresponds to the regional blood flow distribution because of high extraction efficiency during the first transit and the ability to redistribute over time is useful to distinguish scar from ischemia. The physical characteristics of thallium, however, are not ideal for nuclear imaging because of low energy photopeaks, long half-life, and the need for a cyclotron for its production. On the other hand, technetium-99m has very favorable physical characteristics such as a photopeak that has an optimal energy for imaging, a short half-life, and in addition the agent is generator-produced. Thus it is natural to search for technetium-99m-labelled agents for myocardial perfusion imaging to overcome the poor physical characteristics of thallium-201. In this paper, we review the background, technical aspects, clinical application, and future direction. BACKGROUND
INFORMATION
Several nuclear techniques have been used to assess coronary blood flow. Quinn et al.’ used radioiodine-labelled albumin macroaggregates for the successful external visualization of acute myocardial infarction in animals. Subsequent animal and human studies2m5 have documented the safety and efficacy of the technique, with strict quality control on the size and number of particles. The particles may be labelled with technetium-99m, indium-113m, indium-111, iodine-131, or iodine123. The number of particles injected into the coronary circulation varies from 30,000 to 60,000. From the Philadelphia Heart sylvania Medical Center. Received
for publication
Nov.
Institute,
Presbyterian-University
10, 1987; accepted
Reprint requests: A. S. Iskandrian, 39th & Market Streets, Philadelphia,
of Penn-
Dec. 28, 1987.
M.D., Philadelphia PA 19104.
Heart
Institute,
S. Iskandrian,
M.D.,
Pa.
The particle size ranges from 20 to 40 pm?-* A dose of 1 to 2 mCi of radioactive particles is injected directly into one or both coronary arteries during coronary arteriography. Also, left and right coronary arteries can be injected with two different radionuelides, thereby making it possible to evaluate different vascular territories and collateral function.g A different approach was taken by Herd et al.,‘* who used krypton-85 (an inert gas) to measure myocardial blood flow in dogs. Nonimaging detectors, i.e., nuclear probes in early studies, tended to overestimate the washout from the abnormal zone due to contamination by the normal area.“~ I2 With the introduction of imaging detectors, xenon-133 washout curves can now be evaluated from different segments of the myocardium.lss I4 Other radioactive inert gases that may be used include xenon-127 and krypton-81m. However, radioactive particles and inert gas techniques are invasive procedures requiring selective intracoronary injection at the time of diagnostic coronary arteriography. Intravenous injection of radioactive potassium or its analogs such as radioisotopes of potassium (K-42, K-43), rubidium (Rb-81, Rb-84, Rb-86), and cesium (Cs-127, Cs-129, Cs-131, Cs-134)15-20 permit external imaging of myocardial perfusion. Thallium-199 as a potassium analogue was introduced by Kawana et a1.21 in 1970. Lebowitz et alz2 introduced thallium-201, which has more favorable physical characteristics than thallium-199, into clinical use in 1973, and since then thallium-201 has been the agent of choice for myocardial perfusion imaging. Thallium kinetics following intravenous injection have been extensively studied.2”-27 TECHNETIUW99M
The physical characteristics of technetium-99m, the most widely used radionuclide in the nuclear imaging laboratory, are very favorable for nuclear imaging. The element of technetium was first discovered by Perrier and Segre in 1937 by the bom1111
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May 199% American Heart Journal
Heo et al.
bardment of molybdenum with deuterons using a cyclotron. Molybdenum-99, the parent radionuclide of technetium-99m, is packaged in a generator and technetium-99m is eluted as pertechnetate ion. The oxidation state of the technetium ranges from +7 to -1, pertechnetate (TcO,[VII]) being the most stable state in aqueous solution.28 Because technetium by itself has a limited clinical use, formation of different technetium complexes is required. Since the pertechnetate (+7) does not easily participate in chemical reactions, reduction of technetium to lower oxidation states (e.g., +3, +4) is required. The reduction process is carried out by reducing agents (stannous chloride, ferrous chloride, ascorbic acid, hydrochloric acid, etc.) or by electrolytic means. EARLY TC-QQM COMPLEXES
Deutsch et alzg applied the following logic in their search for technetium-99m-labelled myocardial perfusion imaging agents. Since the common feature of all the potassium analogue imaging agents is the fact that they are monovalent cations, then it is possible that cationic technetium-99m compounds can also be used as perfusion imaging agents. These investigators prepared cationic technetium-99m complexes with a +l positive charge. These complexes are technetium-essential in that the technetium center provides the structural framework and the positive charge for the entire complex. Therefore, they are different from technetium-labelled radiopharmaceuticals in which technetium is bound to large molecules such as proteins or particles. Deutsch et al. studied 17 different complexes using four different ligands (DIARS, DAE, PPM, and TETRAPHOS). None of the cationic technetium-99m-DAE, PPM, or TETRAPHOS complexes concentrated in the myocardium. However, DIARS complexes were taken up by the myocardium in dogs and rats. The blood clearance data, biologic distribution, and myocardial uptake in dogs and rats compared favorably with those of thallium-201. Further work resulted in discovery of technetium-99m dichlorobis (1,2dimethylphosphino) ethane (Tc-99m DMPE). This was derived using a Mo-99/Tc-99m generator, an excess DMPE ligand to reduce technetium to the oxidized state of +3, HCl to adjust the pH of the medium, and ethanol/water as a reaction medium. Initial studies in the normal and infarcted myocardium involving dogs showed some promising results.30 Technetium-labelled DMPE has 2.9% uptake within the heart and 21.5% in the liver, whereas thallium accumulates 4.3 % in the heart and 13.6% in the liver. Although the myocardial uptake of DMPE is lower than that of thallium-201, the
image quality was comparable because the lung uptake of DMPE is substantially lower than that of thallium. Technetium-99m DMPE kinetics were also studied in dogs under conditions of varying coronary blood flow produced by regional transient ischemia and reactive hyperemia. In comparison to thallium-201, DMPE showed faster overall kinetics, higher heart-to-lung ratio, equally good correlation with a wide range of regional blood flows, higher liver uptake, and the redistribution phenomenon was incomplete due to a short effective half-life. Although these technetium-labelled myocardial imaging agents showed promising results in the animal studies, the myocardial uptake in the human myocardium was poor, engendering suboptimal imaging quality.31 To produce monocationic technetium complexes, cyclam (1,4, 8,11-tetraazacyclotetradecane) derivatives were also tried. 32 Early experiments with Noctylcyclam and dimethyldiphenyl cyclam showed no significant myocardial uptake in mice; their blood clearance was slow and lung uptake was high. Hexakis (trimethylphosphite) technetium-99m (I) chloride has been tested in animals with limited success.33 [99mT~(POM-POM)3]+, where POM-POM represents 1,2-bis (dimethyl oxyphosphino) ethane, was also examined. Although these various monocationic complexes again showed promising results in animals, their application in clinical studies was disappointing, 34*35 Thus, there appears to be a marked difference in the biodistribution of imaging agents among different animal species; results in animal studies with cats and pigs may be more comparable to human use, since these species also show good myocardial thallium uptake. ISONITRILE
LIGANDS
Jones et a1.36 investigated a new class of cationic Tc complexes containing substituted isonitrile ligands. These materials can be prepared by direct reduction of pertechnetate in aqueous media.37 When injected intravenously into a canine model of pulmonary embolism, clots were visualized. Pendleton et a1.38 produced good myocardial uptake in guinea pigs, cats, and pigs. Biodistribution studies revealed initial heart uptake of 1.3, to 2.2% of injected activity. Imaging and biodistribution data showed significant initial lung uptake, which clears substantially during the first hour after injection. Little or no myocardial washout was observed. In rabbits with ischemia induced by coronary ligation, the complex distributed as a function of regional blood flow. Technetium-QQm
Hexakis
(tertiary-butyl
isonitrile):
vohmle 115 Number 5
TBI. Technetium-labelled TBI is promptly extracted into the myocardial cell in animals after intravenous injection, and the myocardial concentration of the tracer remains stable for several hours. TBI was prepared by ligand exchange from the zinc bromide adduct of t-butyl isonitrile and a standard preparation of technetium-99m glucoheptonate. Three normal subjects and two coronary artery disease patients were studied by Holman et al.,3g using technetium-99m TBI (5 to 10 mCi). Images of excellent technical quality were obtained. In comparison with thallium-201, a substantially higher photon yield is possible because of the higher injected dose and less attenuation. As a result, the quality of the images obtained with technetium-99m TBI was better than those obtained with thallium201 despite the higher lung and liver uptake. The biokinetics of technetium-99m TBI showed high initial uptake and slow clearance from the lungs, which precludes early imaging of the myocardium. Satisfactory images were obtained at 60 minutes post injection and TBI may remain fixed in the myocardium for at least several hours after injection. There may, however, be myocardial uptake from delayed lung washout. Because of the absence of redistribution, two injections will be necessary at rest and peak exercise to distinguish transient exercise-induced ischemia from irreversible myocardial damage.
Tc-QQm
Technetium-QQm carbomethoxy isopropyl isonitrile (CPI): Tc-QQm CPI. Technetium-labelled CPI was pre-
pared by adding pertechnetate solution to a glucosan kit followed by zinc bromide solution from a thawed kit. Animal studies by Kronauge et al.*O showed that CPI has favorable biologic characteristics with good myocardial uptake and rapid clearance from the lung and liver. Holman et a1.41reported the first application of CPI in three normal volunteers and six coronary artery disease patients. Technetium-labelled CPI has more favorable biologic characteristics than TBI. In normals, CPI cleared quickly from the lungs and accumulated in the liver and the heart. Liver activity peaked at 10 to 15 minutes and cleared through the hepatobiliary system. High myocardium-to-background ratios were achieved as early as 10 minutes after injection, resulting in good quality images. In six patients with coronary artery disease, myocardial defects were present up to 2 hours after injection.
Myocardial
perfusion,
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1113
the agent was rapid, with low lung uptake and low peak liver activity. The myocardial extraction of this agent during the first transit is approximately 65%. There is no significant redistribution involving the myocardial concentration of Tc-99m MIBI. Clinical application of Tc-99m MIBI in humans showed little lung background activity and little interference from liver activity. McKusick et al.43 compared three Tc-99m isonitriles (TBI, CPI, MIBI) for detecting ischemic heart disease in humans. Liver uptake obscured the heart in 6 of 40 TBI, but in none of CPI or MIBI. All three agents were able to detect the presence of ischemic heart disease; MIBI had good agreement with perfusion segments analyzed by thallium-201. MIBI showed the highest initial image contrast due to better myocardial uptake and less lung and liver activity.43,44 MIBI is now undergoing extensive trials in this country (Figs. 1 and 2). The initial results suggest that single photon emission computed tomography (SPECT) imaging provides better results than planar imaging. The dose may have an important effect on the image qualit,y. Separate rest and exercise studies on consecutive days are necessary, and the optimal imaging time is t to 2 hours after injection. This permits the use of this agent outside the nuclear medicine facility and even in community hospitals when patients with acute myocardial infarction are first seen. These patients may then be transferred to institions with imaging facilities. This agent may also be useful in interventional studies in patients with acute myocardial infarction. Bolus injection of Tc-99m MIBI permit assessment of global and regional functions of both ventricles using the first-pass technique. Thus, simultaneous analysis of function and perfusion is possible. BISARENE
COMPLEXES
A series of bis-a-arene technetium (I) complexes have shown substantial myocardial uptake.¶” These cationic complexes appear to have reasonable myocardial uptake, especially when methyl substitutions on the benzene ring increase. Imaging studies in dogs using the trimethyl or tetramethyl benzene derivatives (MP-724) showed excellent myocardial images after 10 minutes. Studies involving normal volunteers have demonstrated rapid blood pool clearance and relatively low plasma binding, with excellent myocardial uptake.
Technetium-QQm-Hexakis-2-methoxy-2-isobutyl-isonitrile:Tc-QQm MIBI. Further refinement of the isonitrile
BORONIC
complex resulted in Tc-99m MIBI. Initial animal studies42 showed 2 % of the injected dose to accumulate in the heart of rodents. The blood clearance of
Neutral technetium-99m complexes appear to show promise for myocardial imaging. Among these, SQ-30217, the hepta-coordinate technetium-99m
ACID TECHNETIUM
OXIME COMPLEX
(BATO)
1114
He0 et al.
American
May 1988 Heart .Journa,
of exercise thallium-201 images Cleft panel) and exercise Tc-99m MIBI images (right subject. The top two panel images are in the anterior projection, the middle two images are in the left anterior oblique, and the lower panel images are in the left lateral projection. (Courtesy of DuPont Diagnostic Imaging Division, N. Billerica, Mass.) Fig.
1. Comparison
panel) in a normal
complex, has been introduced by Nunn et a1.46and preclinical testing in dogs demonstrated good images of the myocardium from 2 to 20 minutes after injection. The tracer cleared rapidly from the lungs and peak activity was seen in the liver 5 to 7 minutes after injection. In the canine infarct model, areas of myocardial infarction were clearly delineated in all studies. In clinical studies, the myocardium was visualized as early as 1 minute after injection, with good visualization continuing through about 15 to 20 minutes. This agent exhibits a biphasic washout pattern with about half the
radiotracer clearing with a 3 to 4-minute half-life and the remainder clearing with a half-life of about 2 hours. In contrast to the isonitrile complex, the BAT0 complex requires that imaging be performed virtually immediately after injection. Repeat imaging at rest or after an acute intervention in as short as 30 to 45 minutes is possible. BAT0 complexes with longer retention time are under investigation. FATTY
ACID MYOCARDIAL
PERFUSION
IMAGING
Free fatty acid is the primary energy source for the normal myocardium. During an ischemic condi-
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Fig. 2. Exercise tomographic images with Tc-99m MIBI are shown in upper panels and rest images are show in the lower panels. The left two panels are short-axis slices, the middle two panels are horizontal long-axis slices, and the right two panels are vertical long-axis slices. During exercise, there are perfusion abnormalities involving the anteroseptal area, while rest images appear normal. (Courtesy of DuPont Diagnostic Imaging Division, N. Billerica, Mass.)
tion, cardiac metabolism relies on glucose, so that fatty acid utilization and clearance are diminished. Two different kinds of radionuclides can be used to label fatty acids: positron emitters and single photon emitters. Carbon-11 labelled palmitate has been used with positron emission tomography.47 This, however, requires an onsite cyclotron facility because of the short half-life of positron emitters. Thus only a few large research centers can apply this approach. Radioiodine-labelled fatty acids have attracted interest as cardiac agents to localize ischemia and infarction in patients with coronary artery disease.48-52Initially, radioactive iodine labelling was achieved with I-131, which has unfavorable physical characteristics such as P-radiation, high energy photons, and a long half-life. In contrast, I-123 has several desirable nuclear properties, i.e., optimal y-ray of 159 keV and 13.3 hour half-life. Its disadvantage, however, is the fact that it is cyclotronproduced, thus causing limited availability and high cost. Iodine-123 hexadecanoic and heptadecanoic acid have been extensively studied in animals and humans. A major limitation of these compounds has been rapid deiodination by beta oxidation and subsequent development of significant blood pool activity. Consequently, alternative free fatty acids have been developed and iodine-123 pentadecanoic acid (IPPA) has been shown to have excellent imaging characteristics. IPPA has a myocardial half-life of 70
minutes and does not release free iodine into the blood pool following beta oxidation. IPPA has been demonstrated to be useful for SPECT and planar imaging. Normal, ischemic, and infarcted myocardiurn can be identified by IPPA imaging. Normal myocardium demonstrates uniform uptake and clearance of IPPA. Ischemic myocardium demonstrates decreased clearance of IPPA with diminished or normal uptake, whereas infarcted myocardium demonstrates decreased IPPA uptake. Clinical experience with the use of IPPA in normal volunteers and patients with coronary artery disease has been encouraging. By means of the planar technique and IPPA, Kennedy et a1.53studied 15 normal volunteers and 18 patients with coronary artery disease during exercise. They demonstrated that regions of myocardial ischemia were identified as areas of increased uptake and/or delayed clearance of IPPA. These regions corresponded to the areas of reduced thallium uptake. Using SPECT imaging, Hansen et a1.54compared IPPA to thallium-201 in patients with chronic ischemic heart disease. The patients underwent exercise thallium-201 imaging and exercise IPPA imaging. The two exercise tests were comparable in maximum heart rate and double product. Image abnormalities were identified as abnormality in initial uptake and/or clearance of IPPA. The results
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Heo et al.
with IPPA and thallium-201 were comparable. IPPA imaging may provide information not only on coronary flow but on metabolic activity of myocardiurn and may thus be useful in identification of hibernating myocardium. The authors wish to thank Brian M. Gallagher, Ph.D., at DuPont Corporation for supplying a summary overview of Cardiolite Development (Tc-99m-MIBI), and Phyllis L. Hartsfield for secretarial assistance in the preparation of the manuscript.
REFERENCES
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myocardial infarction by photoscanning after administration of cesium-131. AM HEART J 1964;68:627. Love WD, Ishihara Y, Lyon LD, Smith RO. Differences in the relationship between coronary blood flow and myocardial clearance of isotopes of potassium, rubidium, and cesium. AM HEART J 1968;76:353. Watson A. Cyclotron production of the radionuclides 81-Rb, 82m-Rb, and Cs [Abstract]. J Nucl Med 1970;11:378. Yano Y, Van Dyke D, Budinger T, Anger HO, Chu P. Myocardial uptake studies with 129-Cs and the scintillation camera. J Nucl Med 19’70:11:663. Strauss HW, Zaret BL, Martin ND, Wells HP, Flamm MD. Noninvasive evaluation of regional myocardial perfusion with potassium-43. Radiology 1973;108:85. Kawana M, Krizek H, Porter J, Lathrop KA, Charleston D, Harper PV. Use of Tl-199 as a potassium analog in scanning. J Nucl Med 1970;11:333. Lebowitz E, Greene MW, Bradley-Moore P, Atkins HL, Ansari AN, Richards P, Belgrave E. Tl-201 for medical use. J Nucl Med 1973;14:421. Bradley-Moore PR, Lebowitz E, Greene MW, Atkins HL, Ansari AN. Tl-201 for medical use. II. Bioloeic behavior. ,J Nucl Med 1975;16:156. Strauss HW, Harrison K, Langan JK, Lebowitz E, Pitt B. Thallium-201 for myocardial imaging: relation of thallium201 to regional myocardial perfusion. Circulation 1975; 51:641. Wackers FJT, Schoot JB, Sokole EB, Samson G, Nitrik GJC, Lie KI, Durrer D, Wellens HJJ. Noninvasive visualization of acute myocardial infarction in man with thallium-201. Br Heart J 1975;37:741. Hamilton GW, Trobaugh GB, Ritchie JL, Williams DL, Weaver WD, Gould KL. Myocardial imaging with intravenously injected thallium-201 in patients with suspected coronary artery disease: analysis of technique and correlation with electrocardiographic findings. Am J Cardiol 1977; 39:347. Pohost GM, Zir LM, Moore RH, McKusick KA, Guiney TE, Beller GA. Differentiation of transiently ischemic from infarcted myocardium by serial imaging after a single dose of Tl-201. .-Circulation 1977;55:294. Jones AC;, Davison A. ‘I’he relevance of basic technetium chemistry to nuclear medicine. J Nucl Med 1982;23:1041. Deutsch E, Glavan KA, Sodd VJ, Nishiyama H, Ferguson DL, Lukes SJ. Cationic Tc-99m complexes as potential myocardial imaging agents. J Nucl Med 1981;22:897. Nishiyama H, Deutsch E, Adolph RJ, Sodd VJ, Libson K, Saenger EL, Gerson MC, Gabel M, Lukes SJ, Vanderheyden J, Fortman DL, Scholz KL, Grossman LW, Williams CC. Basal kinetics studies of Tc-99m DMPE as a mvocardial imaging agent in the dog. J Nucl Med 1982;23:1093: Dudczak R, Angelberger P, Homan R, Kletter K, Schmoliner R, Frischanf H. Evaluation of 9YmTc-dichlorobis (1,2-dimethylphosphino) ethane (99”‘Tc-DMPE) for myocardial scintigraphy in man. Eur J Nucl Med 1983;8:513. Ketring AR, Troutner DE, Volkert WA, Holmes RA. Tc-99m complexes of lipophilic cyclam derivatives; assessment of potential myocardial imaging agents. J Nucl Med 1982; 23:117. Robbins MS, Adams MD. Myocardial kinetics of hexakis (trimethylphosphite) technetium-99m (I) chloride (Tc-TMP) in rats, rabbits, dogs, cats and pigs [Abstract]. J Nucl Med 1984;25:P15. Gerundini P, Savi A, Gilardi MC, Margonato A, Vicedomini G, Zecca L, Hirth W, Lihson K, Bhatia JC, Fazio F, Deutsch E. Evaluation in dogs and humans of three potential technetium-99m myocardial perfusion agents. J Nucl Med 1986; 27:409. Ketring AR, Deutsch E, Libson K, Vanderheyden JL. The Noah’s Ark experiment. A search for a suitable animal model for the evaluation of cationic Tc-99m myocardial imaging agents [Abstract]. J Nucl Med 1983;24:P9.
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A, Abrams MJ, Brodack JW, Kassis AI, 36. Jones AG, Davison Goldhaber SZ, Holman BL, Stemp L, Manning T, Hetchman HB. Investigations on a new class of technetium cations [Abstract]. J Nucl Med 1982;23:P16. MJ, Davison A, Jones AG. Synthesis and character37. Abrams ization of hexakis (alkyl isocyanide) and hexakis (arylisocyanide complexes of technetium(I). Inorganic Chem 1983;22:2798. 38. Pendleton DB, Delano ML, Sands H, Gallagher BM, Liteplo MP, Canin LL, Subramanyan V. Pharmacological characterization of Tc-99m (CN-t-butyl)* A potential heart agent [Abstract]. J Nucl Med 1984;25:P15. 39. Holman BL, Jones AG, Lister-James J, Davison A, Abrams MJ, Kirshenbaum JM, Tumeh SS, English RJ. A new Tc-99m-labelled myocardial imaging agent, hexakis (t-butylisonitrile) technetium(I) (Tc-99m TBI): initial experience in the human. J Nucl Med 1984;25:1350. 40. Kronauge JF, Jones AG, Davison A, Lister-James J, Williams SJ, Mousa SA. Isonitrile ester complexes of technetium. J Nucl Med 1986;27:894. 41. Holman BL, Sporn V, Jones AG, Sia STB, Balino NP, Davison A, List&-James J, Kronauge JF, Mitta AEA, Camin LL. Camobell S. Williams SJ. Carnenter AT. Mvocardial imaging with Tc-99rn CPI: initial exderience in the human. J Nucl Med 1987;28:13. 42. Williams SJ, Mousa SA, Morgan RA, Carroll TR, Maheu LJ. Pharmacology of Tc-99m-isonitriles: agents with favorable characteristics for heart imaging [Abstract]. J Nucl Med 1986;27:877. 43. McKusick K, Holman BL, Jones AG, Davison A, Rigo P, Vosberg H, Moretti J. Comparison of 3 Tc-99m-isonitriles for detection of ischemic heart disease in humans [Abstract]. J Nucl Med 1986;27:878. 44. Sia STB, Holman BL. Dynamic myocardial imaging in ischemic heart disease: use of technetium-99m isonitriles. Am J Cardiac Imaging 1987;1:125. 45. Wester DW, Nosco DL, Coveney JR, Dean RT, Gerundini P, Zecca L, Saci A, Fazio F. New Tc-99m myocardial agent with low plasma binding and fast blood clearance. J Nucl Med 1986;27:894.
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Nunn AD, Treher EN, Feld T. Boronic acid adduct.s of technetium oxine complexes (BATOs): a new class of neutral complexes with myocardial imaging capabilities. J Nucl Med 1986;27:893. Weiss ES, Ahmed SA, Welch MJ, Williamson JR, TerPoeossian MM. Sobel BE. Quantification of infarction in cross sections of canine myocardium in vivo with positron emission transaxial tomography and “C-palmitate. Circulation 1977;55:66. Evans JR, Gunton RW, Baker RG, Beaulands DE, Spears JC. Use of radioiodinated fatty acid for photoscans of the heart. Circ Res 1965;16:1. Robinson GD Jr, Lee AW. Radioiodinated fatty acids for heart imaging: iodine monochloride addition compared with iodide realacement labeling. J Nucl Med 1975:16:17. Poe ND: Robinson GD 5, Graham LS, M&Donald NS. Experimental basis for myocardial imaging with “jI-labeled hexadecanoic acid. J Nucl Med 1976;17:1077. Machulla H-J, Stocklin G, Kupfernagel C, Hock FA, Vyska K, Feinendegen LE. Comparative evaluation of fatty acids labeled with C-11, Cl-34m, Br-77, and I-123 for metabolic studies of the myocardium: concise commimication. J Nucl Med 1978;19:298. Jansen DE, Pippin J, Hansen C, Henderson E, Kulkarni P, Ugolini V, Corbett JR. Use of radioactive iodine-labeled fatty acids for myocardial imaging. Am .I Cardiac Imaging 1987;1:132. Kennedy PL, Corbett JR, Kulkarni PV, Wolfe CL, Jansen DE, Hansen CL, Buja LM, Parkey RW, Willerson dT. Iodine-123 phenypentadecanoic acid myocardial scintigraphy: usefulness in the identification of my>cardial ischemia. Circulation 1986;74:1007. Hansen CL, Corbett JR, Ugolini V, Kulkarni l?, Kennedy PL, Jansen DE, Buja LM, Parkey RW, Willerson JT. Comparison of exercise iodine-123 phenylpentadecanoic acid with thallium scintigraphy in patients with chronic ischemic heart disease [Abstract]. Circulation 1986;74:21!
Myocardial perfusion imaging is the most commonly performed procedure in nuclear cardiology. Thallium-201 has been the agent of choice due to its favorable physiologic kinetics: the initial myocardial uptake corresponds to the regional blood flow distribution because of high extraction efficiency during the first transit and the ability to redistribute over time is useful to distinguish scar from ischemia. The physical characteristics of thallium, however, are not ideal for nuclear imaging because of low energy photopeaks, long half-life, and the need for a cyclotron for its production. On the other hand, technetium-99m has very favorable physical characteristics such as a photopeak that has an optimal energy for imaging, a short half-life, and in addition the agent is generator-produced. Thus it is natural to search for technetium-99m-labelled agents for myocardial perfusion imaging to overcome the poor physical characteristics of thallium-201. In this paper, we review the background, technical aspects, clinical application, and future direction. BACKGROUND
INFORMATION
Several nuclear techniques have been used to assess coronary blood flow. Quinn et al.’ used radioiodine-labelled albumin macroaggregates for the successful external visualization of acute myocardial infarction in animals. Subsequent animal and human studies2m5 have documented the safety and efficacy of the technique, with strict quality control on the size and number of particles. The particles may be labelled with technetium-99m, indium-113m, indium-111, iodine-131, or iodine123. The number of particles injected into the coronary circulation varies from 30,000 to 60,000. From the Philadelphia Heart sylvania Medical Center. Received
for publication
Nov.
Institute,
Presbyterian-University
10, 1987; accepted
Reprint requests: A. S. Iskandrian, 39th & Market Streets, Philadelphia,
of Penn-
Dec. 28, 1987.
M.D., Philadelphia PA 19104.
Heart
Institute,
S. Iskandrian,
M.D.,
Pa.
The particle size ranges from 20 to 40 pm?-* A dose of 1 to 2 mCi of radioactive particles is injected directly into one or both coronary arteries during coronary arteriography. Also, left and right coronary arteries can be injected with two different radionuelides, thereby making it possible to evaluate different vascular territories and collateral function.g A different approach was taken by Herd et al.,‘* who used krypton-85 (an inert gas) to measure myocardial blood flow in dogs. Nonimaging detectors, i.e., nuclear probes in early studies, tended to overestimate the washout from the abnormal zone due to contamination by the normal area.“~ I2 With the introduction of imaging detectors, xenon-133 washout curves can now be evaluated from different segments of the myocardium.lss I4 Other radioactive inert gases that may be used include xenon-127 and krypton-81m. However, radioactive particles and inert gas techniques are invasive procedures requiring selective intracoronary injection at the time of diagnostic coronary arteriography. Intravenous injection of radioactive potassium or its analogs such as radioisotopes of potassium (K-42, K-43), rubidium (Rb-81, Rb-84, Rb-86), and cesium (Cs-127, Cs-129, Cs-131, Cs-134)15-20 permit external imaging of myocardial perfusion. Thallium-199 as a potassium analogue was introduced by Kawana et a1.21 in 1970. Lebowitz et alz2 introduced thallium-201, which has more favorable physical characteristics than thallium-199, into clinical use in 1973, and since then thallium-201 has been the agent of choice for myocardial perfusion imaging. Thallium kinetics following intravenous injection have been extensively studied.2”-27 TECHNETIUW99M
The physical characteristics of technetium-99m, the most widely used radionuclide in the nuclear imaging laboratory, are very favorable for nuclear imaging. The element of technetium was first discovered by Perrier and Segre in 1937 by the bom1111
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May 199% American Heart Journal
Heo et al.
bardment of molybdenum with deuterons using a cyclotron. Molybdenum-99, the parent radionuclide of technetium-99m, is packaged in a generator and technetium-99m is eluted as pertechnetate ion. The oxidation state of the technetium ranges from +7 to -1, pertechnetate (TcO,[VII]) being the most stable state in aqueous solution.28 Because technetium by itself has a limited clinical use, formation of different technetium complexes is required. Since the pertechnetate (+7) does not easily participate in chemical reactions, reduction of technetium to lower oxidation states (e.g., +3, +4) is required. The reduction process is carried out by reducing agents (stannous chloride, ferrous chloride, ascorbic acid, hydrochloric acid, etc.) or by electrolytic means. EARLY TC-QQM COMPLEXES
Deutsch et alzg applied the following logic in their search for technetium-99m-labelled myocardial perfusion imaging agents. Since the common feature of all the potassium analogue imaging agents is the fact that they are monovalent cations, then it is possible that cationic technetium-99m compounds can also be used as perfusion imaging agents. These investigators prepared cationic technetium-99m complexes with a +l positive charge. These complexes are technetium-essential in that the technetium center provides the structural framework and the positive charge for the entire complex. Therefore, they are different from technetium-labelled radiopharmaceuticals in which technetium is bound to large molecules such as proteins or particles. Deutsch et al. studied 17 different complexes using four different ligands (DIARS, DAE, PPM, and TETRAPHOS). None of the cationic technetium-99m-DAE, PPM, or TETRAPHOS complexes concentrated in the myocardium. However, DIARS complexes were taken up by the myocardium in dogs and rats. The blood clearance data, biologic distribution, and myocardial uptake in dogs and rats compared favorably with those of thallium-201. Further work resulted in discovery of technetium-99m dichlorobis (1,2dimethylphosphino) ethane (Tc-99m DMPE). This was derived using a Mo-99/Tc-99m generator, an excess DMPE ligand to reduce technetium to the oxidized state of +3, HCl to adjust the pH of the medium, and ethanol/water as a reaction medium. Initial studies in the normal and infarcted myocardium involving dogs showed some promising results.30 Technetium-labelled DMPE has 2.9% uptake within the heart and 21.5% in the liver, whereas thallium accumulates 4.3 % in the heart and 13.6% in the liver. Although the myocardial uptake of DMPE is lower than that of thallium-201, the
image quality was comparable because the lung uptake of DMPE is substantially lower than that of thallium. Technetium-99m DMPE kinetics were also studied in dogs under conditions of varying coronary blood flow produced by regional transient ischemia and reactive hyperemia. In comparison to thallium-201, DMPE showed faster overall kinetics, higher heart-to-lung ratio, equally good correlation with a wide range of regional blood flows, higher liver uptake, and the redistribution phenomenon was incomplete due to a short effective half-life. Although these technetium-labelled myocardial imaging agents showed promising results in the animal studies, the myocardial uptake in the human myocardium was poor, engendering suboptimal imaging quality.31 To produce monocationic technetium complexes, cyclam (1,4, 8,11-tetraazacyclotetradecane) derivatives were also tried. 32 Early experiments with Noctylcyclam and dimethyldiphenyl cyclam showed no significant myocardial uptake in mice; their blood clearance was slow and lung uptake was high. Hexakis (trimethylphosphite) technetium-99m (I) chloride has been tested in animals with limited success.33 [99mT~(POM-POM)3]+, where POM-POM represents 1,2-bis (dimethyl oxyphosphino) ethane, was also examined. Although these various monocationic complexes again showed promising results in animals, their application in clinical studies was disappointing, 34*35 Thus, there appears to be a marked difference in the biodistribution of imaging agents among different animal species; results in animal studies with cats and pigs may be more comparable to human use, since these species also show good myocardial thallium uptake. ISONITRILE
LIGANDS
Jones et a1.36 investigated a new class of cationic Tc complexes containing substituted isonitrile ligands. These materials can be prepared by direct reduction of pertechnetate in aqueous media.37 When injected intravenously into a canine model of pulmonary embolism, clots were visualized. Pendleton et a1.38 produced good myocardial uptake in guinea pigs, cats, and pigs. Biodistribution studies revealed initial heart uptake of 1.3, to 2.2% of injected activity. Imaging and biodistribution data showed significant initial lung uptake, which clears substantially during the first hour after injection. Little or no myocardial washout was observed. In rabbits with ischemia induced by coronary ligation, the complex distributed as a function of regional blood flow. Technetium-QQm
Hexakis
(tertiary-butyl
isonitrile):
vohmle 115 Number 5
TBI. Technetium-labelled TBI is promptly extracted into the myocardial cell in animals after intravenous injection, and the myocardial concentration of the tracer remains stable for several hours. TBI was prepared by ligand exchange from the zinc bromide adduct of t-butyl isonitrile and a standard preparation of technetium-99m glucoheptonate. Three normal subjects and two coronary artery disease patients were studied by Holman et al.,3g using technetium-99m TBI (5 to 10 mCi). Images of excellent technical quality were obtained. In comparison with thallium-201, a substantially higher photon yield is possible because of the higher injected dose and less attenuation. As a result, the quality of the images obtained with technetium-99m TBI was better than those obtained with thallium201 despite the higher lung and liver uptake. The biokinetics of technetium-99m TBI showed high initial uptake and slow clearance from the lungs, which precludes early imaging of the myocardium. Satisfactory images were obtained at 60 minutes post injection and TBI may remain fixed in the myocardium for at least several hours after injection. There may, however, be myocardial uptake from delayed lung washout. Because of the absence of redistribution, two injections will be necessary at rest and peak exercise to distinguish transient exercise-induced ischemia from irreversible myocardial damage.
Tc-QQm
Technetium-QQm carbomethoxy isopropyl isonitrile (CPI): Tc-QQm CPI. Technetium-labelled CPI was pre-
pared by adding pertechnetate solution to a glucosan kit followed by zinc bromide solution from a thawed kit. Animal studies by Kronauge et al.*O showed that CPI has favorable biologic characteristics with good myocardial uptake and rapid clearance from the lung and liver. Holman et a1.41reported the first application of CPI in three normal volunteers and six coronary artery disease patients. Technetium-labelled CPI has more favorable biologic characteristics than TBI. In normals, CPI cleared quickly from the lungs and accumulated in the liver and the heart. Liver activity peaked at 10 to 15 minutes and cleared through the hepatobiliary system. High myocardium-to-background ratios were achieved as early as 10 minutes after injection, resulting in good quality images. In six patients with coronary artery disease, myocardial defects were present up to 2 hours after injection.
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the agent was rapid, with low lung uptake and low peak liver activity. The myocardial extraction of this agent during the first transit is approximately 65%. There is no significant redistribution involving the myocardial concentration of Tc-99m MIBI. Clinical application of Tc-99m MIBI in humans showed little lung background activity and little interference from liver activity. McKusick et al.43 compared three Tc-99m isonitriles (TBI, CPI, MIBI) for detecting ischemic heart disease in humans. Liver uptake obscured the heart in 6 of 40 TBI, but in none of CPI or MIBI. All three agents were able to detect the presence of ischemic heart disease; MIBI had good agreement with perfusion segments analyzed by thallium-201. MIBI showed the highest initial image contrast due to better myocardial uptake and less lung and liver activity.43,44 MIBI is now undergoing extensive trials in this country (Figs. 1 and 2). The initial results suggest that single photon emission computed tomography (SPECT) imaging provides better results than planar imaging. The dose may have an important effect on the image qualit,y. Separate rest and exercise studies on consecutive days are necessary, and the optimal imaging time is t to 2 hours after injection. This permits the use of this agent outside the nuclear medicine facility and even in community hospitals when patients with acute myocardial infarction are first seen. These patients may then be transferred to institions with imaging facilities. This agent may also be useful in interventional studies in patients with acute myocardial infarction. Bolus injection of Tc-99m MIBI permit assessment of global and regional functions of both ventricles using the first-pass technique. Thus, simultaneous analysis of function and perfusion is possible. BISARENE
COMPLEXES
A series of bis-a-arene technetium (I) complexes have shown substantial myocardial uptake.¶” These cationic complexes appear to have reasonable myocardial uptake, especially when methyl substitutions on the benzene ring increase. Imaging studies in dogs using the trimethyl or tetramethyl benzene derivatives (MP-724) showed excellent myocardial images after 10 minutes. Studies involving normal volunteers have demonstrated rapid blood pool clearance and relatively low plasma binding, with excellent myocardial uptake.
Technetium-QQm-Hexakis-2-methoxy-2-isobutyl-isonitrile:Tc-QQm MIBI. Further refinement of the isonitrile
BORONIC
complex resulted in Tc-99m MIBI. Initial animal studies42 showed 2 % of the injected dose to accumulate in the heart of rodents. The blood clearance of
Neutral technetium-99m complexes appear to show promise for myocardial imaging. Among these, SQ-30217, the hepta-coordinate technetium-99m
ACID TECHNETIUM
OXIME COMPLEX
(BATO)
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He0 et al.
American
May 1988 Heart .Journa,
of exercise thallium-201 images Cleft panel) and exercise Tc-99m MIBI images (right subject. The top two panel images are in the anterior projection, the middle two images are in the left anterior oblique, and the lower panel images are in the left lateral projection. (Courtesy of DuPont Diagnostic Imaging Division, N. Billerica, Mass.) Fig.
1. Comparison
panel) in a normal
complex, has been introduced by Nunn et a1.46and preclinical testing in dogs demonstrated good images of the myocardium from 2 to 20 minutes after injection. The tracer cleared rapidly from the lungs and peak activity was seen in the liver 5 to 7 minutes after injection. In the canine infarct model, areas of myocardial infarction were clearly delineated in all studies. In clinical studies, the myocardium was visualized as early as 1 minute after injection, with good visualization continuing through about 15 to 20 minutes. This agent exhibits a biphasic washout pattern with about half the
radiotracer clearing with a 3 to 4-minute half-life and the remainder clearing with a half-life of about 2 hours. In contrast to the isonitrile complex, the BAT0 complex requires that imaging be performed virtually immediately after injection. Repeat imaging at rest or after an acute intervention in as short as 30 to 45 minutes is possible. BAT0 complexes with longer retention time are under investigation. FATTY
ACID MYOCARDIAL
PERFUSION
IMAGING
Free fatty acid is the primary energy source for the normal myocardium. During an ischemic condi-
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Fig. 2. Exercise tomographic images with Tc-99m MIBI are shown in upper panels and rest images are show in the lower panels. The left two panels are short-axis slices, the middle two panels are horizontal long-axis slices, and the right two panels are vertical long-axis slices. During exercise, there are perfusion abnormalities involving the anteroseptal area, while rest images appear normal. (Courtesy of DuPont Diagnostic Imaging Division, N. Billerica, Mass.)
tion, cardiac metabolism relies on glucose, so that fatty acid utilization and clearance are diminished. Two different kinds of radionuclides can be used to label fatty acids: positron emitters and single photon emitters. Carbon-11 labelled palmitate has been used with positron emission tomography.47 This, however, requires an onsite cyclotron facility because of the short half-life of positron emitters. Thus only a few large research centers can apply this approach. Radioiodine-labelled fatty acids have attracted interest as cardiac agents to localize ischemia and infarction in patients with coronary artery disease.48-52Initially, radioactive iodine labelling was achieved with I-131, which has unfavorable physical characteristics such as P-radiation, high energy photons, and a long half-life. In contrast, I-123 has several desirable nuclear properties, i.e., optimal y-ray of 159 keV and 13.3 hour half-life. Its disadvantage, however, is the fact that it is cyclotronproduced, thus causing limited availability and high cost. Iodine-123 hexadecanoic and heptadecanoic acid have been extensively studied in animals and humans. A major limitation of these compounds has been rapid deiodination by beta oxidation and subsequent development of significant blood pool activity. Consequently, alternative free fatty acids have been developed and iodine-123 pentadecanoic acid (IPPA) has been shown to have excellent imaging characteristics. IPPA has a myocardial half-life of 70
minutes and does not release free iodine into the blood pool following beta oxidation. IPPA has been demonstrated to be useful for SPECT and planar imaging. Normal, ischemic, and infarcted myocardiurn can be identified by IPPA imaging. Normal myocardium demonstrates uniform uptake and clearance of IPPA. Ischemic myocardium demonstrates decreased clearance of IPPA with diminished or normal uptake, whereas infarcted myocardium demonstrates decreased IPPA uptake. Clinical experience with the use of IPPA in normal volunteers and patients with coronary artery disease has been encouraging. By means of the planar technique and IPPA, Kennedy et a1.53studied 15 normal volunteers and 18 patients with coronary artery disease during exercise. They demonstrated that regions of myocardial ischemia were identified as areas of increased uptake and/or delayed clearance of IPPA. These regions corresponded to the areas of reduced thallium uptake. Using SPECT imaging, Hansen et a1.54compared IPPA to thallium-201 in patients with chronic ischemic heart disease. The patients underwent exercise thallium-201 imaging and exercise IPPA imaging. The two exercise tests were comparable in maximum heart rate and double product. Image abnormalities were identified as abnormality in initial uptake and/or clearance of IPPA. The results
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Heo et al.
with IPPA and thallium-201 were comparable. IPPA imaging may provide information not only on coronary flow but on metabolic activity of myocardiurn and may thus be useful in identification of hibernating myocardium. The authors wish to thank Brian M. Gallagher, Ph.D., at DuPont Corporation for supplying a summary overview of Cardiolite Development (Tc-99m-MIBI), and Phyllis L. Hartsfield for secretarial assistance in the preparation of the manuscript.
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A, Abrams MJ, Brodack JW, Kassis AI, 36. Jones AG, Davison Goldhaber SZ, Holman BL, Stemp L, Manning T, Hetchman HB. Investigations on a new class of technetium cations [Abstract]. J Nucl Med 1982;23:P16. MJ, Davison A, Jones AG. Synthesis and character37. Abrams ization of hexakis (alkyl isocyanide) and hexakis (arylisocyanide complexes of technetium(I). Inorganic Chem 1983;22:2798. 38. Pendleton DB, Delano ML, Sands H, Gallagher BM, Liteplo MP, Canin LL, Subramanyan V. Pharmacological characterization of Tc-99m (CN-t-butyl)* A potential heart agent [Abstract]. J Nucl Med 1984;25:P15. 39. Holman BL, Jones AG, Lister-James J, Davison A, Abrams MJ, Kirshenbaum JM, Tumeh SS, English RJ. A new Tc-99m-labelled myocardial imaging agent, hexakis (t-butylisonitrile) technetium(I) (Tc-99m TBI): initial experience in the human. J Nucl Med 1984;25:1350. 40. Kronauge JF, Jones AG, Davison A, Lister-James J, Williams SJ, Mousa SA. Isonitrile ester complexes of technetium. J Nucl Med 1986;27:894. 41. Holman BL, Sporn V, Jones AG, Sia STB, Balino NP, Davison A, List&-James J, Kronauge JF, Mitta AEA, Camin LL. Camobell S. Williams SJ. Carnenter AT. Mvocardial imaging with Tc-99rn CPI: initial exderience in the human. J Nucl Med 1987;28:13. 42. Williams SJ, Mousa SA, Morgan RA, Carroll TR, Maheu LJ. Pharmacology of Tc-99m-isonitriles: agents with favorable characteristics for heart imaging [Abstract]. J Nucl Med 1986;27:877. 43. McKusick K, Holman BL, Jones AG, Davison A, Rigo P, Vosberg H, Moretti J. Comparison of 3 Tc-99m-isonitriles for detection of ischemic heart disease in humans [Abstract]. J Nucl Med 1986;27:878. 44. Sia STB, Holman BL. Dynamic myocardial imaging in ischemic heart disease: use of technetium-99m isonitriles. Am J Cardiac Imaging 1987;1:125. 45. Wester DW, Nosco DL, Coveney JR, Dean RT, Gerundini P, Zecca L, Saci A, Fazio F. New Tc-99m myocardial agent with low plasma binding and fast blood clearance. J Nucl Med 1986;27:894.
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Nunn AD, Treher EN, Feld T. Boronic acid adduct.s of technetium oxine complexes (BATOs): a new class of neutral complexes with myocardial imaging capabilities. J Nucl Med 1986;27:893. Weiss ES, Ahmed SA, Welch MJ, Williamson JR, TerPoeossian MM. Sobel BE. Quantification of infarction in cross sections of canine myocardium in vivo with positron emission transaxial tomography and “C-palmitate. Circulation 1977;55:66. Evans JR, Gunton RW, Baker RG, Beaulands DE, Spears JC. Use of radioiodinated fatty acid for photoscans of the heart. Circ Res 1965;16:1. Robinson GD Jr, Lee AW. Radioiodinated fatty acids for heart imaging: iodine monochloride addition compared with iodide realacement labeling. J Nucl Med 1975:16:17. Poe ND: Robinson GD 5, Graham LS, M&Donald NS. Experimental basis for myocardial imaging with “jI-labeled hexadecanoic acid. J Nucl Med 1976;17:1077. Machulla H-J, Stocklin G, Kupfernagel C, Hock FA, Vyska K, Feinendegen LE. Comparative evaluation of fatty acids labeled with C-11, Cl-34m, Br-77, and I-123 for metabolic studies of the myocardium: concise commimication. J Nucl Med 1978;19:298. Jansen DE, Pippin J, Hansen C, Henderson E, Kulkarni P, Ugolini V, Corbett JR. Use of radioactive iodine-labeled fatty acids for myocardial imaging. Am .I Cardiac Imaging 1987;1:132. Kennedy PL, Corbett JR, Kulkarni PV, Wolfe CL, Jansen DE, Hansen CL, Buja LM, Parkey RW, Willerson dT. Iodine-123 phenypentadecanoic acid myocardial scintigraphy: usefulness in the identification of my>cardial ischemia. Circulation 1986;74:1007. Hansen CL, Corbett JR, Ugolini V, Kulkarni l?, Kennedy PL, Jansen DE, Buja LM, Parkey RW, Willerson JT. Comparison of exercise iodine-123 phenylpentadecanoic acid with thallium scintigraphy in patients with chronic ischemic heart disease [Abstract]. Circulation 1986;74:21!