New radionuclides for cardiac imaging

New Radionuclides D. Douglas

Miller,

John

B. Gill, Charles

Alan

for Cardiac Imaging

J. Fischman,

A. Boucher.

and

Massachusetts General Hospital, Boston. Supported in part by USPHS Cardiovascular Nuclear Medicine Training Grant HLO7416, and USPHS Fatty Acid Analogs for Myocardial Imaging HL29636. Dr Miller is a Fellow of the Canadian Heart Foundation. Address reprint requests to H. William Strauss, MD, Division of Nuclear Medicine, Massachusetts General Hospital. Boston, Massachusetts 02114. @ 1986 by Grune & Stratton, Inc. 0033-0620/86/2806-0002$05.00/0

The nuclide generator is a convenient method isotopes available at long Vol XXVIII,

No 6 (May/June),

R. Elmaleh,

From the Division of Nuclear Medicine, Department of Radiology and the Cardiac Unit, Department of Medicine,

of making short-lived

Diseases,

David

Strauss

Radionuclide generators provide a means of separating two genetically related radionuclides from one another.” The generator usually consists of a column of an inorganic powder, usually made of aluminum oxide, zirconium oxide, or charcoal, surrounded by a lead shield (Fig 1). The longer lived parent radionuclide is poured (absorbed) on the column, where it continually decays to produce its radioactive daughter. The separation of the daughter from the column is achieved by passing a solution (eluate) through the column. Differences in the adsorption characteristics of the two nuclides for the column at the pH, osmolality, etc, of the eluate causes the daughter to enter the solution while the parent remains on the column. This chromatographic procedure rarely provides a perfect separation of the daughter from the parent. Selection of the column material and elution solutions for the generator are predicated on their stability in high radiation fields. Radiation intensity in the generator typically reaches thousands of Gray, which results in the formation of superoxides in the column. This problem is compounded by aqueous eluates, since most generators are left wet (eluate in contact with the column between elutions). In addition to the potential formation of oxides, the eluate may contain undesirable radionuclide or chemical contaminants. These substances may arise when the parent is prepared in the reactor or cyclotron, or during the chemical separation of the nuclide

GENERATORS

in Cardiovascular

J. Callahan,

distances from the source of production. It serves as a continuous source of a short-lived isotope.-P. Richards, 1966l

WO RADIONUCLIDES, thallium-201 and technetium-99m, have assumed preeminence in cardiovascular nuclear medicine because their photon energies, kinetics, and dosimetry are well-suited to make three major physiologic measurements: perfusion, function, and viability. The photon energies of these nuclides are well matched to the characteristics of the Anger camera, which has optimum efficiency and resolution for energies between 100 and 200 keV. The spatial resolution of the “system” for the average cardiovascular nuclear medicine study (radiopharmaceutical, collimator, camera, and computer) at the depth of the heart is approximately 1 cm full width half maximum (FWHM). Against this background, new radiopharmaceuticals suggested for the evaluation of the heart (Table 1) must offer an improvement in dosimetry and resolution, or provide data on a previously unmeasurable parameter. This review will concentrate on the new radiopharmaceuticals that have met two criteria: (1) experience with the radiopharmaceutical in human subjects, and (2) some likelihood of commercial production of the agent for widespread clinical use. Although equilibrium studies provide high quality data for evaluation of regional and global cardiac function, a high photon flux first pass approach, which could evaluate ventricular function during breathholding (to eliminate respiratory motion), would improve resolution. The ideal first pass radionuclide should have a short physical halflife, have no particulate emissions, produce photons of 100 to 200 keV, and decay to a stable daughter. Such an agent would permit multiple measurements to be performed in each view and would allow repetitive determinations of ventricular function during the action of drugs, exercise, or physiologic maneuvers (Valsalva, etc). The following agents have some of these properties and may supplant Tc-99m as the radionuclide for first pass studies.

T

Progress

Ronald H. William

1986:

pp 419-434

419

420

MILLER

Table

1.

Uses

of Radionuelides Myocardial

Ventricular Radiiuclide

First-Pass

Ultrashort-Lived Krypton-8 Iridium-19 Gold-

Function

in Cardiac

Imaging

Perfusion WocVte

lntracoronary

Equilibrium

IV

Left Hewt

Viability

+4.6

1m 1m

+ 12.

+

26

+

25-Y +

126-131

+ Agents

N- 13 ammonia 0- 15 water

4s-a + ,143 +

C-l

fU

1 butanol

C-l 1 deoxyglucose F- 18 deoxyglucose

+ and

modified fatty acids Fatty Acids

Straight-chain

+

69-M)

(alkyl.

aryl) Branched (CH, substit) Technetium-99m Labeled (LDL)

+Ss,s7-7’ + M*s’32

+80 +sm

+ 72-78 + 6’~s’~82

Agents + (7)

Antimyosin Fab Hex-t-butyl-isonitrile

+ 106 +

+

112.113

Macroaggreg

atheroma

detection’w‘

8%902

+

Albumin Indium-1 11 Labeled Antimyosin

61-63.44

+“.s4.ss

1 palmitate

Lipoprotein

Miscellaneous

+=

13-W + + I*-2,

195m

Indium-113m Positron Emitting

lodinated

Metabolism

Agents

Rubidium-82 Xenon- 133

C-l

ET AL

Agents

Fab

Platelets Leukocytes Colloid

from the target material. To determine if a generator eluate is safe for use, it should be tested for the presence of these chemical contaminants. Since these tests may take hours to days, procedures have been devised to characterize specific generator/elution combinations. In these procedures, the quantity of parent and daughter radionuclide and chemical contaminants are carefully measured in several test generators as a function of elution volume. With repeated elutions, the location of the parent on the column gradually migrates from the top of the column toward the bottom. As a result, every generator will eventually reach a point where the parent can be eluted completely from the column. To avoid inadvertant administration of the parent material, every elution should be tested for the quantity of daughter and parent radionuclide in the eluate. This process can be readily accomplished with daughter radionuclides that have half-lives greater than

+ *s.s*.ss +114-118.11s-122 +

+ thromb”s”“l’s.l~s

,,S,lZ,

+ lymphoscintigraphy’w

several minutes by measuring the relative abundance of photons resulting from the decay of the daughter and the parent (as is commonly done with technetium-99m eluates). The ultrashortlived radionuclides, however, present special problems in this area, since the time required to perform the assay may require several half-lives of the daughter, making the eluate unusable for administration. Typically, quality control of ultrashort-lived generator systems has been accomplished by characterization of the eluate before administration, and knowledge of the generator system (eg plot of parent elution v eluate volume). To test for breakthrough, the eluate is immediately placed in a dose calibrator (ionization chamber calibrated to reflect the change in charge/unit time as a photon flux) to determine the total photon flux. The sample is measured a second time 20 to 30 half-lives later, when any remaining activity is the result of breakthrough. Most generators can be eluted to some total

NEW

CARDIAC

A /

--

421

RADIONUCLIDES

‘-\\

TUREE

YAV

POROUS LEID

sTOPCOcr

POL*ETtlYLLYE

DISK

StIlELD

BOUNDED

OSYIUY

RESIN

.D I x2

ANION EXC,‘ANEE RESIN POROUS l OLlElWYLENE

‘G I x4 DISK ANION EXCUANQE RESIN LG I x4 Op YEYIMNE FILTER POROUS

-

INFUSlON

POLYETWILENE

DISK

SET

Fig 1. (A) A photograph of the external appearance and internal components of the OS-191~lr-191m generator currently used in our laboratory. This generator system, orginally developed by Yeno and Anger in 1968 based on a method described by Campbell and Nelson, separates the short-lived daughter lr-191m (T1/2 = 4.9 seconds) from its parent radionuclide OS-191 fT112 = 15 days). (Courtesy of Dr F. F. Knapp, Oak Ridge National Laboratories.) IB) A diagram illustrating the basic generator components of the OS-~ 91 -b-l 91 m generator. The parent radionuclide. OS-1 91, is adsorbed as OsCl,in the strongly basic AGl anion exchange resin column. Saline eluate is passed through the column. with elution in less than 2 seconds of Ir-191 m for infusion. Osmium breakthrough and iridium extraction decrease with increasing cross-linking of OsCl,to the resin column. (Reprinted with permission of the American Heart Association.“‘)

volume before parent breakthrough increases to undesirable levels. As a result, it is usually possible to predict the breakthough in a given elution. Based on this information, ultrashort-lived generators have been employed for human studies based on characterization of the dose preceding the dose actually administered. The combination of low radiation burden to the subject and high photon flux make the ultra short-lived generators very attractive for use in cardiovascular nuclear medicine. The following discussion describes unique features of these generators. ULTRASHORT-LIVED

RADIONUCLIDES

Krypton-81 m In 1968 Yano and Anger3 proposed the use of the Rubidium-8 1/Krypton-8 1m generator sys-

tem to image the blood pool. The 4.7 hour half-life cyclotron produced Rb-81 (alpha particle bombardment of a Br-79 target [alpha, 2n]), is absorbed to a column, and the 13 second daughter inert gas Kr-81m produced. If the column is filled with dextrose, the resulting solution of dextrose/Kr-81m can be injected intravenously (IV) to determine right ventricular function4,’ and pulmonary perfusion, or intraarterially to determine myocardial perfusioP or regional cerebral perfusion.’ If the generator is opened to the air, the resulting gas can be inhaled to define regional ventilation. The 190 keV energy of the Kr-81m is well-suited for imaging with low or medium energy collimators available on most scintillation cameras. Kr-8 1m is particularly useful for the repetitive evaluation of right ventricular function due to its short effective half-life (ie, T1/2 effective = [(T1/2 biological x

422

T1/2 physical)/(T1/2 biological + T1/2 physi-Cal)]). The short effective half-life comes from the combination of short physical half-life and short biological half-life due to the evolution of the radionuclide from the blood into the alveolus during its passage through the lung. As a result, no significant activity enters the left heart. The short effective half-life results in a low radiation burden/MBq, which permits a large dose to be administered by injection. The resulting photon flux permits high count density data to be recorded during the initial passage of radionuelide through the right heart. Since right ventricular function varies with the respiratory cycle, it may be preferable to measure right ventricular ejection fraction (RVEF) during several respiratory cycles, rather than during a single inspiration or expiration, as is currently done during first pass studies. This can be accomplished by recording a gated collection during a continuous IV infusion over a 30 to 60 second interval instead of using the bolus injection technique. The calculated RVEF with this approach is typically higher than that calculated from equilibrium blood pool studies. Kr-8 1m right heart studies require high dose of Rb-81 on the infusion generator.4*5 The costs of producing the parent radionuclide, coupled with its short physical half-life make this an expensive nuclide. To market the generator, primarily intended for use with inhalation imaging, at a reasonable price, the manufacturer elected to make the generator with 5 mCi of rubidium on the column. As a result, the photon flux available from the typical commercial generators is low compared to that which is theoretically achievable. The detected photon flux of about 5,000 counts available from infusions of Kr-8 1m from this generator are less than 25% of that from Tc-99m during an equilibrium study. These low photon fluxes generate noisy images, which preclude the determination of regional wall motion of the right ventricle. If larger generators become available, Kr-8 1m will be useful for the determination of right heart function. The ultra short physical half-life of Kr-8 lm led to the development of a new approach to measure regional myocardial perfusion.3v@ Since the radionuclide decays in a shorter interval than the transit through the myocardial bed, images recorded during continuous infusion of KR-8 1m are dominated by its input function-myocardial

MILLER

ET AL

perfusion. The biologic half-life of the agent in the myocardium is approximately 30 seconds, while its physical half-life is 13 seconds, giving an effective half-life of 9 seconds. As a result, the usual inert gas clearance approach to measurement of regional myocardial perfusion with this nuclide is dominated by the physical decay of the nuclide, rather than the biologic clearance due to perfusion.” However, a static image recorded during continuous infusion of the agent at the root of the aorta depicts the regional distribution of myocardial perfusion,” as suggested by Kaplan et al.” The Kr-8 lm infusion approach can be used to evaluate the pattern of onset of ischemia with interventions such as pacing. As with the right ventricular (RV) function studies, however, these measurements require a minimum of a 2 mCi equilibrium infusion concentration in the aorta. Since the distribution of perfusion will be determined by the equilibrium activity concentration in the myocardium, the infusion catheter must be positioned to infuse Kr-81m into each coronary distribution in proportion to perfusion. This may be difficult to accomplish due to streaming at the aortic root. To avoid this problem, one coronary vessel may be perfused at a time. This requires a lower dose of activity and can be accomplished at lower infusion rates. An additional advantage of selective infusion of Kr81m is the delineation of the perfusion through collateral vessels. Iridium-I 91m Ir-191m is a generator-produced 4.7 second half-life radionuclide with gamma photons of 129 keV and x-rays of 65 keV.” The parent, reactor-produced OS-191, has a half-life of 15 days. The short half-life of the iridium product makes it difficult to characterize the chemical form of the Group VIII element. Although this generator was originally described in 1968 by Yano and Anger’ for the determination of pulmonary perfusion, it was not until the recent work of Trevesi3-I5 that a generator practical for human use was developed. The radionuclide is associated with a radiation burden of 3-5 mR/ mCi while providing a high photon flux (the majority of the radiation burden stems from the breakthrough of the parent OS-191 into the Ir19 1m eluate. Improvements in the column material recently suggested by Knapp et al indicate

NEW

CARDIAC

423

RADIONUCLIDES

that the radiation burden may be reduced by ten to 100 fold). The combination of high photon flux and exceptionally low radiation burden are well-suited to the pediatric population, to evaluate shunts and ventricular function. Although the agent can be used in adults, the intrathoracic transit time of 8 to 10 seconds is relatively long compared to the 4.7 second halflife. As a result, right heart data is recorded with a photon flux two to four fold greater than that of the left heart. To visualize the left heart well, the count rate from the right heart must be very high. This high photon flux may actually present a problem for Anger type scintillation cameras, since count rates in excess of 100,000 counts/s result in increased dead time of the camera, and a nonlinear relationship between activity in the field of view and counts recorded. The multicrystal gamma camera, or the multi-wire propordescribed by Lacy et al are tional chambe?’ able to take advantage of the very high count rates offered by Ir- 19 1m, since these instruments can process maximum count rates of 500 to 800,000 counts/s. Gold-l 95m Gold-195m is a 30.5 second half-life daughter of the 40.5 hour, cyclotron-produced Hg-195.‘*-” Au-195m has a 262 keV gamma photon which is 68% abundant. The chemical form of the gold eluted from the column is not well-characterized, but it is likely that this Group IB nuclide is ionic. The half-life of Au-195m is long with reference to the central circulation time and permits high quality studies of the left and right heart to be recorded. The combination of short half-life and high photon energy led Mena et al*l to suggest that Au-195m could be coinjected with Tl-201 at the time of bicycle exercise studies to permit an evaluation of global and regional function in conjunction with assessment of myocardial perfusion. The procedure described by Mena consisted of (1) recording a Au-195m first pass ventricular function study; (2) repeaking the camera for Tl-201; and (3) five minutes later recording myocardial perfusion data. As with other short half-life generator-produced radionuclides, the radiation burden to the patient is primarily the result of breakthrough of the parent Hg-195. Since mercury compounds localize in the kidneys, the radiation burden from breakthrough increases the renal dose. Although

improvements in the generator column and eluate have resulted in a marked decrease in the breakthrough problem, a limit of 300 mCi total dose is usually employed to minimize the radiation burden to the kidneys. An additional problem, unique to the Au195m generator system, is the decay of Au- 195m to a long-lived daughter, Au-195 (physical halflife, 190 days). This decay process is continuously underway on the generator, resulting in a high concentration of Au- 195 in the initial eluate from the generator. Biodistribution studies in animals suggest Au-195 localizes in the kidneys, adding to the potential radiation burden from breakthrough of the parent Hg- 195. To minimize the buildup of Au-195, the column should be preeluted within ten minutes of use. Other Single Photon Ultrashort-Lived Generator Systems Two other generator systems, the Cd-109 (half-life, 1.26 years)/Ag-109m (half-life, 39.6 seconds) and the Cs-137 (half-life, 30.3 years)/ Ba-137m (half-life, 2.55 minutes) have been described, but are unlikely to find widespread use in nuclear cardiology.** In the case of the Cd/Ag system, the primary 88 keV gamma of Ag-109m is only 5% abundant, while the energy of Ba137m is too high for use with conventional Anger cameras. An additional problem in both cases is the potential for a large radiation burden to be delivered to the patient by unexpected breakthrough of the parent. Rubidium-82 Rubidium-82 is a 75 second half-life positron emitting daughter of cyclotron produced Sr-82 (Rb-85 (p,4n) - T1/2 physical = 25 days). The production of the parent Sr-82 requires a high energy cyclotron and is accompanied by the production of small quantities of Sr-85 as a radiocontaminant. Since strontium radionuclides localize in bone and have a long biologic half-life, the generator system has been refined to minimize the breakthrough of the parent in the eluate. The generator is tested for breakthrough by the prior elution method described earlier (Fig 2). A maximum of 0.001 &!i Sr-82/mCi Rb-82 results in a radiation burden of 0.019 rads/mCi to the kidney and 0.001 rads/mCi to the total body.23 Rubidium-82, a member of Group IA, is

424

Fig 2. The general (A) and detailed (B) external presently used in our laboratory. Saline is delivered mL/minl. The top of the “pig” is removed to reveal through e system of two filters before reaching the allowed to decay for one hour. Generally, less than reelutad, at full potency. once every tan minutes.

MILLER

ET AL

appearance of the Strontium-%?-Rubidium-82 generator infusion system by a syringe pump at a constant infusion rata of 50 mL/min hnaximum 100 the entry and exit points of the saline aluata, which subsequently passes patient. To detect radionuclide impurities in the aluata, W-82 should be 0.001 mCi of Sr-82 is detected per mCi Rb-B2. The generator may be

NEW

CARDIAC

RADIONUCLIDES

eluted from the generator as a monovalent cation. The agent behaves as a Saperstein tracer (eg, the regional distribution of the radionuclide is proportional to perfusion in organs with high extraction.24) The radionuclide is concentrated in tissues by the Na-K ATPase pump and has a myocardial extraction between 65% and 75%. As with other generator-produced ultrashort-lived nuclides, quality control is by preelution calibration and direct infusion of the dose to the patient. Myocardial imaging with this radionuclide requires fast acquisition of data. Images recorded during the first one to two minutes after IV administration depict the blood pool distribution of the radionuclide (if images are recorded with gating, ejection fraction and regional wall motion can be determined), while images recorded after two minutes depict regional perfusion.25 Reasonable quality images can be recorded for four to six half-lives after infusion, one to two half-lives consumed with blood clearance, the remainder for myocardial perfusion. Although images of this positron emitting nuclide can be recorded with a single photon camera26*27 (see below), the highest quality images are recorded with a multi-slice positron tomograph.28-34 Recent studies by Gould and Mullaniz5”’ demonstrated the ability to measure absolute as well as relative myocardial perfusion from Rb-82 PET images with a time of flight positron camera. A limitation of this approach to calculating absolute flow is the problem of diffusion limitation at myocardial blood flows greater than two times baseline (flow rates commonly observed with dipyridamole infusions). At these perfusion levels, the deposition of Rb-82 in tissue will underestimate regional perfusion.3s However, since coronary disease is associated with a marked decrease in perfusion, the nonlinearity of the measurement in the higher ranges is not of great importance clinically. Selwyn and his colleagues have made several unique observations with the Rb-82 PET imaging technique: (1) In patients with coronary artery disease, marked changes in regional myocardial perfusion were observed during the performance of mental arithmetic. These changes were of similar severity to those induced by exercise.29 (2) Following restoration of perfusion to zones of ischemia,

prolonged abnormalities in cation uptake were observed, presumably due to disturbances in cation transport and trapping.28 If a PET camera is unavailable, images can be recorded with an Anger scintillation camera with a specially constructed high energy tungsten collimator.27 The sensitivity of this single photon approach, however, is about 0.1% that of the positron technique. Even with this low sensitivity, the quality of the images is similar to that of Tl-201. CYCLOTRON-PRODUCED POSITRON COMPOUNDS

EMITTING

Three types of cyclotron-produced positronlabeled radiopharmaceuticals have been described: blood pool agents, myocardial perfusion agents, and metabolic markers (see the article by Geltman et al for more details on the application of specific agents).3”39 The blood pool agents are similar in principle to those found with single photon emitting nuclides-eg, they label either the red cells (eg, carbon- 11 [half-life, 20 minutes] labeled carbon monoxide, which binds with high affinity to hemoglobin), or plasma proteins (eg, Ga-68 [half-life, 68 minutes], which binds to transferrin).40 The cyclotron-produced myocardial perfusion agents are N-l 3-labeled ammonia (half-life, 9.9 minutes), which may enter the cell by an active pump mechanism, O-l 5-labeled water (half-life, 2.2 minutes),4’A3 or C- 1 l-labeled alcohols.44 N- 13 ammonia does not provide a quantitative determination of perfusion in absolute terms,45 since the extraction of ammonia may be altered by tissue oxygenation, pH, and flow rate. Within the flow range of clinical interest, however, the regional distribution of ammonia reflects regional perfusion. To determine myocardial perfusion reserve, N- 13 ammonia has been used with dipyridamole.46p47 This technique has proven sufficiently sensitive to detect a 47% coronary stenosis!8 While the N-13 approach works well, it cannot be readily used to make rapid repetitive determinations of regional perfusion, as can Rb82 or 0-15labeled water, due to the relatively long effective half-life of N-13 in the myocardium.39 Following injection, oxygen-15-labeled water reflects regional perfusion because of its high

426

MILLER

diffusivity at the capillary level (extraction = 96%).4’42 Once out of the capillary, the water is diluted in a large intracellular pool. As a result, the regional concentration of oxygen- 15 immediately after administration of labeled water reflects regional perfusion. The water method has been correlated against microspheres with a correlation of r = 0.94. One difficulty with the water method is the relatively large water space of red cells. When water is used to determine perfusion, the blood volume (red cell space) of the organ provides an unwanted, confounding signal, which must be corrected to obtain the correct flow values. This is a particularly vexing problem in the myocardium, where both the red cell volume of the myocardium and that in the chambers contribute to the signal. (Myocardial blood volume is extremely small in comparison to flow). Butanol labeled with C-l 1 has been suggested for the determination of regional perfusion. The agent has an extraction approaching one, and a longer half-life than oxygen-l 5 thereby easing the constraints on recording the data. Although its manufacture is more complex than that of oxygen-15-labeled water, the precision of the flow measurements available with butanol may be greater than that from oxygen-15labeled water.44 Metabolic

Substrates

The synthesis of positron-labeled metabolic substrates permits the determination of regional myocardial metabolism. When natural substrates have one atom replaced with a radioactive form, the compound is intrinsically labeled, and behaves in an identical fashion to the unlabeled agent. However, the speed of catabolic processes in the myocardium places severe constraints on the time spent making measurements of the regional distribution of metabolism. Fatty acids labeled with carbon- 11, for example, are catabolized to produce CO2 within 30 seconds of entry into the myocardium.50 To permit measurements to be made over longer intervals of time, chemical analogs of the metabolic substrates have been developed, The analogs enter metabolic pathways and proceed through at least one committed step parallel with unmodified substrates. The chemically modified agents reach a specific step in the catabolic cycle where they are recognized

ET AL

as different from the native substance, and usually remain in the cell for a prolonged interval of time. Glucose analogs can be labeled either with C-11 (1X11-2 deoxyglucose)51-53 or with F-18 (2-Fluoro-deoxyglucose),54*s5 while the fatty acid analogs are labeled with either C-l 1 (1-C-l 1-3 methyl heptadecanoic acid) or with iodine.s6 The myocardial extraction of glucose is usually less than 20%, but can vary markedly depending on insulin levels in the blood. Fatty acids have extractions between 50% and 60% under basal fasting circumstances, which may vary depending on the free fatty acid and insulin levels of the recipient. If serial arterial blood samples are obtained at the time of positron imaging with these metabolic agents, the regional myocardial metabolic rates of these agents may be calculated.‘7-5g Although the absolute metabolic data may be important for research, the importance of these values for patient care remains to be defined. Preliminary data suggest that the regional distribution of the metabolic radiopharmaceuticals in the myocardium may be sufficient to identify conditions of clinical importance.6’M6 Whether the quantitative data will add significantly to the understanding of the disease is uncertain. Glucose and fatty acid analogs may play a major role in nuclear cardiology in the near future as a result of their ability to identify underperfused but viable myocardium. Both agents appear to have a relative increase in extraction in the zone of ischemia. IODINATED

FATI-Y ACIDS

Several analogs of fatty acids have been synthesized with iodine labels.67-7L These agents can be readily imaged with a conventional gamma camera, either as planar or single photon emission computer tomography (SPECT) images.‘6*72 To increase the residence time of the fatty acids in the myocardium, analogs were synthesized with a phenyl ring at the omega position of the molecule.73-80 The substitution served both to stabilize the iodine on the molecule and to prevent terminal beta oxidation. The residence halftime of the radiolabel was increased from approximately ten minutes with straight chain iodinated fatty acids, to approximately 20 minutes with the addition of the phenyl group. The

NEW

CARDIAC

427

RADIONUCLIDES

addition of a methyl group at the 3 position (the same branched chain concept employed for the C-l l-labeled analog) in conjunction with a phenyl group at the omega position (to permit a stable attachment of the iodide) provided an increase in the residence half-time to over five hoUrs.WW From a metabolic perspective, the only way the branched chain, phenyl substituted fatty acid can clear from the myocardium is via simple back diffusion, or alpha oxidation. When labeled with the cyclotron-produced 13 hour half-life I-l 23 (159 keV), this radiopharmaceutical provides high quality images with a conventional gamma camera.83 In both animals1*82 and human studies,64 regional differences in the myocardial concentration of branched chain fatty acid analogs have been observed in the pressure overloaded and ischemically stunned myocardium. DETECTION OF ACUTE MYOCARDIAL NECROSIS

Radiopharmaceuticals suggested for the detection of acute myocardial necrosis include radioiodine, chlormerodrin, fluorescien, tetracycline,84 glucoheptonate,85 and pyrophosphate.8”92 An alternative aproach to the detection of acute necrosis is the use of a radiolabeled antibody directed against the heavy chain of human cardiac myosin, antimyosin.93-‘0’ This antibody localizes only in those cells whose membranes have been sufficiently damaged to permit the development of large holes clearly visible on electron micrographs. When cells reach this phase of damage, cell death is inevitable. Since exposure of the antigen can only occur when the membrane is disrupted, localization of antimyosin in the cell is associated only with that tissue that has undergone irreversible necrosis. To maximize the rate of blood clearance, a fragment of the antibody, Antimyosin-Fab, has been used for studies in human subjects.95-97 Antimyosin-Fab has been labeled with TC-99m and In-l 11. Coupling of the radionuclide to the antibody was achieved via a “bifunctional” chelate. The chelate is bifunctional in the sense that one of its functional groups is coupled to a lysine on the protein, while the remaining sites are available to couple to the radiolabel. Preliminary experience with this imaging approach in 24 patients with acute infarction has defined a strong relationship

between the extent of uptake observed on planar or SPECT images and prognosis.“’ Tc-99m

LOW DENSITY

LIPOPROTEINS

Atheromatous lesions are metabolically active, undergoing a repetitive cycle of endothelial injury and repair. During the repair phase, the endothelium recovering the area of damage has an increased permeability to low density proteins and the cholesterol carried by these proteins, resulting in the buildup of the atheromatous lesion. To determine if this could be detected by radionuclide imaging, Roberts et allo3 performed autoradiographic studies in rabbits with catheter-induced injury of the aorta. The autoradiographs demonstrated a marked increase in permeability to radioiodinated low-density lipoproteins (LDL) at the sites of reendothelialization. Subsequent studies by Lees et a1’04*‘05demonstrated that these lesions can be detected by radionuclide imaging in both the intact animal and man. Studies in eight human subjects with Tc-99m-labeled LDL have demonstrated localization in carotid, femoral, or coronary atheromatous lesions in 7/8.1°5 The radiopharmaceutical is prepared by dithionite reduction of TcO, in the presence of autologous LDL. This labeling approach has two disadvantages: (1) the six-hour half-life precludes imaging beyond 24 hours, at times when blood clearance would permit detection of zones of minimal concentration; and (2) the dithionite reduction results in the unavoidable production of some colloid-like material, which increases the liver concentration of the radiopharmaceutical. Despite these shortcomings, examination of surgical specimens obtained at carotid endarterectomy in two patients confirmed the concentration Tc-99m LDL in the most severely narrowed areas. Further studies are underway to couple In-l 11 or Ga-67 to the lipoprotein, to permit imaging at 48 to 72 hours after administration. Tc-99m-LABELED

AGENTS FOR MYOCARDIAL PERFUSION

While Tl-201 is currently the agent of choice for myocardial imaging, it has a number of limitations as a radiopharmaceutical. Thallium has a low energy photopeak (70 to 80 keV mercury x-rays), which results in significant soft tissue attenuation. Its long half-life of 72 hours

42%

and high concentration in the kidney limits the administered dose to about 3 mCi/S rads to the kidneys. Thus, prolonged imaging times are required. Finally, thallium is cyclotron-produced and is expensive. In recent years, there has been much interest in developing a Tc-99m-labeled agent for myocardial perfusion imaging to overcome the limitations of thallium. Deutsch et al have shown that some Tc-99m-labeled cationic complexes accumulate in the myocardium.‘06~‘07 These included Tc-99m DiArs, a diarsenical compound and DMPE-dimethlyphosphinoethane, an organophophosphate ligand.‘08*112 Tc99m DMPE showed promising results in rats and dogs and had the advantage of being soluble in aqueous solution. 108-11’Compared with Tl-201, Tc-99m DMPE showed similar blood clearance, equally good correlation over a wide range of regional blood flows, a higher heart to lung ratio, but higher liver uptake which could potentially interfere with interpretation of the inferior wall of the heart. Unfortunately, patient studies revealed poor uptake by the heart.“’ Liver uptake is prominent. The decrease in heart activity is slower than that of the liver but any improvement in contrast is lost by gradually increasing lung activity. This decreased uptake of Tc-99m DMPE by the human heart points out the importance of different species’ behavior. Another cationic Tc-99m complex, hexakis (t-butylisonitrile)technetium(I) (TBI) has marked cardiac uptake in a number of animal species. After IV injection, there is prompt myocardial uptake with a relatively constant concentration maintained for several hours. There is significant initial lung activity, which clears substantially after one hour. This initial pulmonary activity precludes early visualization of the myocardium. After intracoronary injection there is no myocardial washout for one hour. Initial experience in humans reported by Holman is encouraging. ‘I3 Planar and tomographic images of excellent quality were obtained. By one hour, the heart to lung ratio is 1.5 to 1, permitting satisfactory images. If, as in the animal studies, there is minimal washout of Tc-99m TBI for several hours, ischemia should be readily detected with this agent. In one patient who had both a fixed and transient defect on Tl-201 study, both perfusion defects were demonstrated by To99m TBI one and four hours following

MILLER

ET AL

exercise. Thus, two injections may be necessary to distinguish ischemia from scar. The possibility of some redistribution from clearing lung activity into the myocardium must also be considered. Whole body images of Tc-99m TBI five hours after injection showed primarily heart, liver, spleen, and skeletal muscle uptake. Liver uptake rises steadily after injection. Primary clearance appears to be through the hepatobiliary system into the small bowel. Imaging in the LAO 70“ view is complicated by the superimposition of this liver activity onto the inferior segment of the myocardium. With exercise, the amount of activity in the myocardium remains the same; however, there is less liver uptake and intense uptake by the leg muscles. Although TBI looks promising, more patient experience as well as further research into the cellular mechanisms of uptake and retention by the myocardial cell are needed. Further understanding of these mechanisms may allow modification of the molecule to produce other complexes with more desirable biologic properties such as more rapid lung and liver clearance. INDIUM-111

LABELED

RADIONUCLIDES

Indium-1 11, a 2.7 day half-life cyclotronproduced Group IIIA radionuclide, has been used to label leukocytes, platelets, and antibodies. The nuclide decays via electron capture and gamma emission to Co-l 11 with major photons at 247 and 173 keV. The electron capture mode of decay results in the production of Auger electrons, which are associated with a high radiation burden to the intracellular structures in the immediate vicinity of the nuclide. Concerns about this microdosimetry limit the administered dose of this nuclide to c2 mCi for most human applications (200 to 500 &i are typically employed for studies with labeled cells). Platelets “4-‘18~‘19-‘22and white blood cells’23~‘2’ are the major blood components labeled with this nuclide. Platelet imaging has been advocated for the detection of thrombi in left ventricular aneurysms, “4*1’8~1’9 while labeled leukocytes have been advocated for evaluation of the clearance of zones of myocardial necrosis following infarction.‘23*‘21 In-l 11-labeled leukocytes provide an indication of the inflammatory response to infarction. The biologic half-life of autologous In- 11 l-labeled platelets is approximately 45

NEW

CARDIAC

429

RADIONUCLIDES

hours. The slow clearance of blood pool activity, however, requires images to be recorded at 24 to 72 hours for the detection of thrombi. The potential role of both of these imaging techniques remains to be defined. Xenon-l 33

Xenon-133, an 80 keV, 5.3 day half-life fission product, is an inert noble gas that has been used for the determination of right heart function’ and regional myocardial perfusion.‘2”30 Since the agent is produced as a byproduct of uranium fission, it is available in curie quantities at modest cost. When administered IV in doses of 50 to 80 mCi, the 35% incidence of gamma photons provides a suitable photon flux for the determination of RV function.*31 In patients with normal lung parenchyma, >85% of the dose will be cleared in the first pass.” While the 0.5 rad/ injection radiation burden from these studies is higher than that with Kr-Slm, multiple injections can be administered without exceeding the accepted guidelines of t5 rad/examination. The determination of regional myocardial perfusion, either with direct intracoronary12”‘26 injection or administration via the left ventricular catheter12’ can be recorded with either the single’25,‘26 or multi-crystal’24 camera. The mathematics necessary to convert the observed clearance of the gas into perfusion/g of tissue were described by Kety,13’ and have been well validated by a number of other investigators.” This technique has been found to be particularly useful in conjunction with the coronary arteriogram to define the dynamic significance of a specific antomic abnormality.‘28*‘29 We have used a left heart bolus of Xe-133, administered via the left heart catheter, to determine left ventricular ejection fraction and regional wall motion (from data recorded in the first 10 seconds after injection) and regional myocardial perfusion (from the late myocardial clearance phase).12’ The data recorded with this technique have a good correlation (r = 0.9) with Tc-99m gated blood pool data for the determination of ventricular function. Zones of diminished myocardial perfusion were well-defined, but areas of hyperemia were underestimated due to the loss of the early portion of the clearance curve. Higher energy noble gases, such as cyclotron-

produced Xe- 127 (physical half-life, 36 days) with gamma photons of 172, 203, and 375 keV, may improve spatial resolution over that with Xe-133.13’ The radiation burden from this nuclide is less than that from Xe-133, despite its threefold increase in imageable photons, due to the lack of particulate emissions in the course of its decay. Unfortunately, the high cost of this nuclide has limited its clinical use. Should the cost of this nuclide come down, the combination of a long shelf life and its reasonable gamma energy would make this agent attractive for the performance of myocardial perfusion studies. FUTURE APPLICATIONS

Specific antibodies can be raised to bind to receptor sites. These antiidiotypic antibodies can be used both as tracers of the agonist-receptor distribution and as pharmaceuticals by competing with agonists to occupy receptor sites.‘33-‘40 In addition to antiidiotypic antibodies, receptors can be imaged with labeled antagonists such as hydroxybenzylpindolol. One can envisage imaging the up- and down-reguiation of cardiac alpha and beta receptors in diseases such as congestive heart failure,141 cardiac transplantation,‘42 coronary spasm, 143and sudden death,‘44 or after the chronic administration of adrenergic drugs.‘45 With the use of highly purified cardiac membrane preparations to raise monoclonal antibodies, the degree of nonspecific binding to low affinity sites should diminish. Binding sites for the biologically active peptide atria1 natriuretic factor (ANF) and opiate receptors modulating systemic and coronary vascular tone146,‘47 may soon be imaged in the cardiovascular and central nervous systems of patients with hypertension and coronary vasospasm. Aside from their potential for characterizing hormone- and drug-receptor interactions at the molecular level in vivo, these radioligands may provide valuable insights into the complex neurohumoral relationship between the heart and brain. Meta- [ 12311 iodobenzylguanidine (M- 1231IBG), an analog of the adrenergic neuron blocking agent guanethidine, is taken up by adrenergic neurons via a mechanism similar to norepinephrine. This agent has been employed to image the heart, presumably binding to cardiac adrenergic receptors, in normal human volunteers’48 and patients with suspected pheochromocytoma.‘49

430

Although the myocardium was well-visualized in normal subjects,14* M- 13 1I-IBG uptake was significantly reduced in pheochromocytoma patients, presumeably due to down-regulation of cardiac adrenergic receptors from high circulating levels of norepinephrine.‘49

MILLER

ET AL

The diagnostic promise of metabolic imaging and tomography can only be realized if these and other radiopharmaceuticals are developed to keep pace with rapidly expanding imaging technology.

REFERENCES 1. Richards P: Nuclide generators, in Andrews GA, Kniquantitation of left-to-right shunts in infants. J Pediatr seley RM, Wagner HN (eds): Radioactive Pharmaceuticals. 101:210-213,1982 United States Atomic Energy Commission, 1966, pp 15516. Lacy JL, Verani MS, Packard A, et al: Minute to 164 minute assessment of left ventricular function with a new 2. Yano Y: Radionuclide generators: Current and future multiwire gamma camera and an ultra-short lived isotope applications in Nuclear Medicine, in Subramanian G, Ir-191m. J Am Co11Cardiol5:388, 1985 (abstr) Rhodes BA, Cooper JF, Sodds (eds): New York, Society of 17. Lacy JL, Verani MS, Ball ME, et al: New multiwire Nuclear Medicine, Inc, pp 236-245 gamma camera with a unique short-lived isotope tantalum3. Yano Y, Anger HO: Ultrashort-lived radioisotopes for 178. J Am Co11Cardiol5:389, 1985 (abstr) visualizing blood vessels and organs. J Nucl Med 9:2-6. 18. Dymond DS, Elliott AT, Flatmane W, et al: The 1968 clinical validation of gold-195m: A new short half-life radio4. Sugrue B, Kamal S, Deanfield JE, et al: Assessment of pharmaceutical for rapid, sequential, first pass angiocardiright ventricular function and anatomy using peripheral vein ography in patients. J Am Co11Cardiol2:85-92, 1983 infusion of krypton-llm. Br. J Radio1 56:657-663, 1983 19. O’Keefe JC, Dymond DS, Caplin JL, et al: The effect 5. Neinaber CA, Spielmann RP, Wasmus G, et al: Cliniof nisoldipine on exercise left ventricular performance in cal use of ultrashort-lived radionuclide krypton-81m for coronary artery disease assessed by first-pass radionuclide noninvasive analysis of right ventricular performance in angiography and gold-195m. J Am COB Cardiol 3:552, 1984 normal subjects and patients with right ventricular dysfunc(abstr) tion. J Am Co11Cardiol5:687-698, 1985 20. Findlay IN, Gillen G, Wilson J, et al: Gold-195m 6. Selwyn AP, Steiner R, Kivisaari H, et al: Krypton-8lm radionuclide ventriculography in the assessment of the cold in the physiologic assessment of coronary arterial stenosis in pressor test. J Am COB Cardiol3:524, 1984 (abstr) man. Am J Cardiol43:547-53, 1979 21. Mena I, Narahara KA, deJong R, et al: Gold-195m, 7. Selwyn AP, Forese G, Fox K, et al: Patterns of an ultrashort-lived generator-produced radionuclide: Clinical disturbed myocardial perfusion in patients with coronary applications in sequential first-pass ventriculography. J Nucl artery disease: Regional myocardial perfusion in angina Med 24:139-144,1983 pectoris. Circulation 64:83-90, 1981 22. Blau M, Zielinski R, Bender M: 137mB,Cow-a new 8. Kleynhans PHT, Lotter MG, van Aswegen A, et al: The short lived isotope generator, Nucleonics 24:60-62,1966 imaging of myocardial perfusion with 81m Krypton during 23. Kearfott KJ: Radiation absorbed dose estimates for coronary arteriography. Eur J Nucl Med 7:405-409, 1982 positron tomography (PET): K-38, Rb-81, Rb-82 and Cs9. DeValois JC, Smith J, Pepperkamp TPR, et al: A 130. J Nucl Med 23:1128-1132,1982 computer programme for the determination of cerebral blood 24. Saperstein LA, Moses LE: Cerebral and cephalic flow using the KR-85 or Xe-133 intraarterial injection methblood flow in man: Basic considerations of the indicator od, Biomed Comput 1:49-53,197O fractionation technique in Knisely RW (ed): Dynamic Clini10. Cannon PJ, Weiss MB, Sciacca RR: Myocardial cal Studies With Radioisotopes. United States Atomic blood flow in coronary artery disease: Studies at rest and Energy Commission Division of Technical Information No. during stress with inert gas washout techniques. Prog Cardio3,1964, pp 135-152 vast Dis 20:95-120,1977 25. Mullani NA, Gould KL, Goldstein RA, et al: Gated 11. Kaplan E, Mayron LW, Friedman AM, et al: Defmiblood pool and myocardial perfusion imaging by PET after a tion of myocardial perfusion by continuous infusion of krypsingle IV injection of rubidium-82. Circulation 7O:II-24 ton-8lm. Am J Cardiol37:878-884, 1976 (abstr) (suppl2) 12. Cheng C, Treves S, Samuel A, et al: A new osmium26. Williams KA, Ryan JW, Resnehov L, et al: Feasibility 191 iridium-19lm generator. J Nucl Med 21:1169-1176, of single-photon rubidium-82 myocardial perfusion imaging 1980 in acute myocardial infarction. J Am COB Cardiol 5:476, 13. Treves S, Cheng C, Samuel A, et al: Iridium-191 1985 (abstr) angiocardiography for the detection and quantitation of 27. Grover M, Schwaiger M, Ramirez B, et al: Rubidiumleft-to-right shunting. J Nucl Med 21:1151-l 157, 1980 82 for evaluating regional myocardial blood flow with 14. Treves S, Fogle R, Lang P: Radionuclide angiography gamma camera imaging. Circulation 7O:II-124, 1984 in congenital heart disease. Am J Cardiol 46:1247-1255, (abstr) 1980 28. Wilson RA, Shea MJ, deLandsheere CM, et al: 15. Treves S, Fyler D, Fujii A, et al: Low radiation Persistent metabolic abnormalities of rubidium-82 extraction iridium-19 lm radionuclide angiography: Detection and

NEW

CARDIAC

431

RADIONUCLIDES

in myocardium recovery from transient &hernia. J Am Co11 Cardiol 3:547, 1984 (abstr) 29. Shea MJ, Deanfield JE, deLandsheere CM, et al: Marked responses of the normal coronary circulation to mental excitement and cold. Circulation 70:11-141, 1984 (abstr) 30. Camici P, Araujo L, Spinks T, et al: Persistent chronic metabolic abnormalities in patients with unstable angina. Circulation 7O:II-249, 1984 (abstr) 31. Shea MJ, Wilson RA, deLansheere CM, et al: A new and independent measure of the volume of viable myocardium: The effects of transient ischemia. J Am Co11 Cardiol 5:475, 1985 (abstr) 32. Goldstein RA: Time course of rubidium-82 uptake after experimental coronary occlusion. Circulation 70:341, 1984 (abstr) (suppl2) 33. Goldstein RA, MacLean JC: A non-invasive marker of myocardial viability after reperfusion based on leakage of rubidium-82. J Am Co11Cardiol 5:475, 1985 (abstr) 34. Goldstein RA, Hicks CH, Kuhn JL, et al: Myocardial infarct imaging with rubidium-82 and PET in man. Circulation 70:11-9, 1984 (suppl2) 35. Mullani NA, Gould KL: First-pass measurements of regional blood flow with external detectors. J Nucl Med 24577-581, 1984 36. Bergmann SR, Fox K, Rand A, et al: Non-invasive measurement of regional myocardial perfusion by positron tomography. Circulation 66:11-48, 1982 (suppl 2) 37. Budinger TF, Yano Y, Huesman RH, et al: Positron emission tomography of the heart. Physiologist 26:31-34, 1983 38. Sobel BE: Diagnostic promise of positron tomography. Am Heart J 103:673-679, 1982 39. Schelbert HR, Henze E, Phelphs ME, et al: Assessment of regional myocardial ischemia by positron-emission computed tomography. Am Heart J 103588-597, 1982 40. Erhardt GJ, Welch MJ: A new germanium-68 gallium-68 generator. J Nucl Med 19925-929, 1978 41. Bergmann SR, Fox KAA, Rand AL, et al: Quantification of regional myocardial blood flow in vivo with H*“O. Circulation 70:724-733, 1984 42. Knabb RM, Fox KAA, Bergmann SR: Detection of coronary stenoses by positron emission tomography with H2”0. Circulation 70:11-340, 1984 (suppl2) 43. Bergmann SR, Fox KAA, Ter-Pogossian NM, et al: Clot-selective coronary thrombolysis with tissue type plasminogen activator. Science 220:1181-l 183, 1983 44. Phelps ME, Schelbert HR, Maziotta JC: Positron computed tomography for studies of myocardial and cerebral function. Ann Intern Med 98:339-359, 1983 45. Bergmann SR, Hack S, Tewson T, et al: The dependence of accumulation of ‘rNH3 by myocardium on metabolic factors and its implications for quantitative assessment of perfusion. Circulation 61:34-43, 1980 46. Sorenson S, Groves B, Chauduri T: Regional myocardial blood flow and hemodynonics in man after intravenous dipyridamole. Circulation 62:III-9, 1980 (suppl 3) 47. Schelbert HR, Wisenbert G, Phelps ME, et al: Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologic vasodilation: VI. Detection of coronary artery disease in man with intravenous N-13 ammo-

nia and positron computed tomography. Am J Cardiol 49:1197-1207,1982 48. Gould L, Schelbert HR, Phelps ME, et al: Noninvasive assessmentof coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilation: V. Detection of 47 percent diameter coronary stenosis with intravenous nitrogen- 13 ammonia and emission computed tomography in infarct dogs. Am J Cardiol43:20&207,1979 49. Schelbert HR, Phelps ME, Huang SC, et al: N-13 ammonia as an indicator of myocardial blood flow. Circulation63:1259-1272,198l 50. Liedtke JA: Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart. Prog Cardiovasc Dis 23:321-336,198l 51. Marshall RC, Tillisch JH, Phelps ME, et al: Identification and differentiation of resting myocardial ischemia and infarction with positron computed tomography. F-18 labeled fluorodexyglucose and N-13 ammonia. Circulation 67:766 778,1983 52.

Henze E, Perloff JK, Schelbert HR: Alterations of regional myocardial perfusion and metabolism in Duchenne’s muscular dystrophy (DMD) detected by positron computed tomography (PCT) Circulation 4:279, 1981 (suppl4) 53. Weiss ES, Hoffman EJ, Phelps ME, et al: External detection and visualization of myocardial ischemia with “C-substrates in vitro and in vivo. Cir Res 39:24-32, 1976 54. Schelbert HR, Phelps ME, Selin C, et al: Regional myocardial ischemia assessed by ‘8F-fluro-2-deoxyglucose and positron emmission computed tomography, in Heiss HW (ed): Advances in Clinical Radiology, vol 1, Quantification of Myocardial Ischemia. New York, Gerhard Witzstrock, 1980, pp 437-449 55. Phelps ME, Hoffman EJ, Selin C, et al: Investigation of ‘8F-2-deoxyglucose for the measurement of myocardial glucose metabolism. J Nucl Med 19:1311-1319, 1978 56. Feinendegen LE, Shreeve WW: On behalf of I-123 fatty acids for myocardial metabolic imaging. J Nucl Med 24:545-546,1983

57. Sokoloff L, Reivich M, Kennedy C, et al: The (“C)deoxyglucose method for the measurement of local cerebral glucose utilization: Theory, procedures and normal values in the conscious and anesthetized albino rats. J Neurochem 28:897-916,1977 58. Schelbert HR, Phelps ME: Positron computed tomography for the in vivo assessment of regional myocardial function. J Mol Cell Cardiol 16:683-693, 1984 59. Sochor H, Schelbert HR, Henze E, et al: Quantitication of regional C-l 1 palmitate kinetics by positron tomography (PET). Circulation 70:11-340, 1984 (suppl 2) 60. Goldstein RA, Klein MS, Sobel BE: Detection of myocardial ischemia before infarction, based on accumulation of labeled pyruvate. J Nucl Med 21:1101-l 104, 1980 61. Ter-Pogossian NM, Klein MS, Markham J, et al: Regional assessment of myocardial metabolic integrity in vivo by positron emission tomography with “C-labeled palmitate. Circulation 61:242-255, 1980 62. Geltman EM, Biello D, Welch MJ, et al: Characterization of non-transmural myocardial infarction by positronemission tomography. Circulation 65:747-755, 1982 63. Lerch RA, Bergmann SR, Ambos HD, et al: Effort of flow-independent reduction of metabolism on regional myo-

432 cardial clearance of “C-palmitate. Circulation 65:73 l-739, 1982 64. Livni E, Elmaleh DR. Levy S, et al: Beta-methyl (l-“C) heptadecanoic acid: A new myocardial metabolic tracer for positron emission tomography. J Nucl Med 23:169-175.1982 65. Grover M, Schwaiger M, Sochor H, et al: C-11 palmitic acid kinetics and positron emission tomography detect pacing-induced ischemia in patients with coronary artery disease. Circulation 7O:II-340, 1984 (suppl2) 66. Schwaiger M, Schelbert H, Sochor H, et al: Metabolic abnormalities adjacent to ischemic myocardium in dogs demonstrated by positron tomography (PET). Circulation 70:11-84, 1984 (suppl2) 67. Machulla HJ, Stocklin G, Kupfernagel CH, et al: Comparative evaluation of fatty acids labelled with C-11, Cl-34m, Br-77, and I-123 for metabolic studies of the myocardium: Concise communication. J Nucl Med 19:298302,197s 68. Hock A, Freundlieb C, Vyska K, et al: Myocardial imaging and metabolic studies with 17-41z31 iodoheptadecanoic acid in patients with idiopathic congestive cardiomyopathy. J Nucl Med 24:22-28.1983 69. Freundlieb C, Hock A, Vyska K, et al: Myocardial imaging and metabolic studies with 17-l? iodoheptad,ecanoic acid. J Nucl Med 21:1043-1050, 1980 70. Roesler H, Hess T, Weiss M, et al: Tomoscintigraphic assessment of myocardial metabolic heterogeneity. J Nucl Med 24:285-296,1983 71. Van der Waal EE, den Hollander W, Heindendal GAK, et al: Metabolic myocardial imaging with iz31-labeled heptadecanoic acid in patients with angina pectoris. Em J Nucl Med 8:391-396,198l 72. Goldstein RA: Reply: On behalf of I:123 fatty acids for myocardial metabolic imaging. J Nucl Med 24545-546, 1982 73. Rellas JS, Morgan CG, Corbett JR, et al: Quantitative tomographic imaging evaluation of myocardial clearance of I-123 phenyl pentadecanoic acid in acute myocardial infarction. J Nucl Med 2413, 1983 (abstr) 74. Rellas JS, Corbett JR, Kulkarni P, et al: I-123 phenylpentadecanoic acid: Detection of acute myocardial infarction and injury in dogs using an iodinated fatty acid and SPECT. Am J Cardiol52:1326-1332, 1983 75. Reske SN, Knopp R, Machulla HJ, et al: Clearance patterns of 15 (p-I-123) phenyl-pentadecanoic acid in patients with CAD after bicycle exercise. J Nucl Med 2413, 1983 (abstr) 76. Reske SN, Knust EJ, Machulla H-J, et al: Comparison of cardiac C-14 palmitic acid and I-123 phenyl-pentadecanoic acid oxidation. J Nucl Med 24: 118, 1983 (abstr) 77. Reske SN, Simon H, Machulla HJ, et al: Myocardial turnover of p-( 1- 123)) phenyl-pentadecanoc acid inpatients with CAD. J Nucl Med 23:24-82,1982 78. Dudcazale R, Homan R, Zangeneh A, et al: Myocardial metabolic studies in patients with cardiomyopathy. J Nucl Med 24:20, 1983 79. Dudczale R, Sochmoliner R, Angelberger P, et al: Myocardial studies with I-123 p-phenylpentadecanoic acid in patients with coronary artery and idiopathic cardiomyopathy. J Nucl Med 23:35, 1982

MILLER

ET AL

80. Jansen D, Gabliani G, Wolfe C, et al: Determination of viable myocardial mass with iodinated phenylpentadecanoic acid and single photon emission computed tomography. Circulation 70:11-449, 1984 (suppl2) 81. Miller DD, Gill JB, Barlai-Kovach M, et al: Identification of the ischemic border zone in reperfused canine myocardium using iodinated fatty acid analogs. Clin Res 33:21 IA, 1985 82. Miller DD, Gill JB, Barlai-Kovach M, et al: Modified fatty acid analog imaging: Correlation of SPECT and clearance kinetics in ischemic reperfused myocardium. J Nucl Med 26:84,1985 83. Harbert J, Goncalves da Rocha AF: Textbook of Nuclear Medicine, vol 1 (ed 2). Philadelphia, Lea & Febiger, 1984 84. Holman BL, Lesch M, Zweiman FG, et al: Detection and sizing of acute myocardial infarcts with %Tc (Sn) tetracycline. N Engl J Med 291:159-163, 1974 85. Rossman DJ, Strauss HW, Siegel ME, et al: Accumulation of 9A”Tc-glucoheptonate in acutely infarcted myocardium. J Nucl Med 16:875,1975 86. Strauss HW, Pitt B: Evaluation of cardiac function and structure with radioactive tracer techniques. Circulation 57:645-654,1978 87. Bonte FJ, Parkey RW, Graham KD, et al: A new method of radionuclide imaging of myocardial infarcts. Radiology 110:473-474, 1974 88. Holman BL, Goldhaber SZ, Kirsch CM, et al: Measurement of infarct size using single photon emission computed tomography and technetium-99m pyrophosphate: A description of the method and comparison with patient prognosis. Am J Cardiol50:503-5 11, 1982 89. Buja LM, Tofe AJ, Kulklarni PV, et al: Sites and mechanisms of localization of technetium-99m phosphorus radiopharmaceuticals in acute myocardial infarcts and other tissues. J Clin Invest 60:724740, 1977 90. Dewanjee MK, Kahn PC: Mechanism of localization of 99mTc-labeled pyrophosphate and tetracycline in infarcted myocardium. J Nucl Med 17:639646, 1976 9 1. Lewis SE, Devous MD, Corbett JR, et al: Measurement of infarct size in acute canine myocardial infarction on single-photon emission computed tomography with technetium-99m pyrophosphate. Am J Cardio154: 193-l 99,1984 92. Tamaki S, Kadota K, Kambara H, et al: Emission computed tomography with *“Tc pyrophosphate for delineating location and size of acute myocardial infarction in man. Br Heart J 52:30-37,1984 93. Haber E: Antibodies in vivo. Pharmacol Rev 34:7784,1982 94. Khaw BA, Strauss HW, Pohost GM, et al: Relationship of immediate and delayed thallium-201 distribution to localization of I-125 antimyosin antibody in acute experimental myocardial infarction. Am J Cardiol 51:1428-1432, 1983 95. Khaw BA, Beller GA, Haber E: Experimental myocardial infarct imaging following intravenous administration of iodine- 133 labeled antibody (Fab’) 2 fragments specific for cardiac myosin. Circulation 57:743-750, 1978 96. Khaw BA, Goid HK, Yasuda T, et al: Identification and quantification of myocardial infarction in patients by myosin-specific antibody imaging. Circulation (in press)

NEW

CARDIAC

RADIONUCLIDES

97. Khaw BA, Strauss HW, Carvalho A, et al: Technetium-99m labeling of antibodies to cardiac myosin Fab and to human fibrinogen. J Nucl Med 23:lOl l-1019,1982 98. Khaw BA, Strauss HW, Carvalho A, et al: Letters to the editor (reply). J Nucl Med 24545, 1982 99. Khaw BA, Yasuda T, Moore R, et al: In-l 11 monoclonal antimyosin and 99mTc pyrophosphate imaging in reflowed hearts. Circulation 7O:Ii-274, 1984 (suppl2) 100. Yazaki Y, Isobe M, Tsuchimochi H, et al: A new method of myocardial infarct sizing by single photon emission tomography using labeled monoclonal antibody specific for ventricular myosin heavy chain. Circulation 70:11-985, 1985 (suppl2) 101. Khaw BA, Mattis JA, Melincoff G, et al: Monoclonal antibody to cardiac myosin: Imaging of experimental myocardial infarction. Hybridoma 3:l l-23, 1984 102. Liu P, Yasuda T, Newell J, et al: Infarct sizing by Tc-99m labeled antimyosin antibody: A powerful predictor of complications of myocardial infarction (MI). Circulation 70:11-123, 1984 (suppl2) 103. Roberts AB, Lees AM, Lees RS, et al: Selective accumulation of low density lipoproteins in damaged arterial wall. J Lipid Res 24:1160-l 167, 1983 104. Lees RS, Parkey RW, Graham KD, et al: A new method for radionuclide imaging of myocardial infarcts. Radiology 110:473474, 1974 105. Lees RS, Lees AM, Strauss HW, et al: The distribution and metabolism of %Tc labeled low density lipoprotein in human subjects. J Nucl Med 26:1056-1062,1985 106. Deutsch EW, Glavan KA, Nishiyama H, et al: Tc-99m complexes as potential myocardial imaging agents. J Nucl Med 22:897-907, 198 I 107. Deutsch E, Bushong W, Galavan KA, et al: Heart imaging with cationic complexes of technetium. Science 214:85-86,198l 108. Nishiyama H, Deutsch E, Adolph RJ, et al: Basal kinetic studies of Tc-99m DMPE as a myocardial imaging agent in the dog. J Nucl Med 23:1093-l 101,1982 109. Sullivan PJ, Werre J, Elmaleh DR, et al: A comparison of the technetium-labeled myocardial agents DIARS and DMPE to 201 Tl in experimental animals. Int J Nucl Med Biol 11:3-10, 1984 110. Dudczak R, Andelberger P, Homan R, et al: Evaluation of 99mTc-dichloro dis (1,2-dimethlyphophino) ethane (((m Tc-DMPE) for myocardial scintigraphy in man. Eur J Nucl Med 8:513-515,1983 111. Pendleton DB, Sands H, Gallagher BM, et al: Characterizing potential heart agents with an isolated perfused heart system. J Nucl Med 25:24, 1984 (abstr) 112. Pendleton DB, Delano ML, Sands H, et al: Pharmacological characterization of Tc-99, (CN-t-butyl)6+: A potential heart agent. J Nucl Med 25:15, 1984 (abstr) 113. Holman BL, Johnes AG, Lister-James J, et al: A new Tc-99m-labeled myocardial imaging agent, hexakis (t:-butylisontrile)-technetium(l)[Tc-99mTBl]: Initial experience in the human. J Nucl Med 25:1350-1355, 1984 114. Ezekowitz MD, Leonard JC, Smith EO, et al: Identification of left ventricular thrombi in man using indium11 l-labeled autologous platelets. Circulation 63:803, 198 1 115. Fuster V, Dewanjee MK, Kaye MP, et al: Noninvasive radioistopic technique for detection of platelet deposition

433

in coronary artery bypass grafts in dogs and its reduction with platelet inhibitors. Circulation 60:1508, 1979 116. Riba AL, Thakur ML, Gottschalk A, et al: Imaging experimental coronary artery thrombosis with indium-1 11 platelets. Circulation 60:767, 1979 117. Bergmann SR, Lerch RA, Mathias CJ, et al: Noninvasive detection of coronary thrombi with indium-1 11 platelets: Concise Communication. J Nucl Med 24:13&135, 1983 118. Seabold J, Bruch P, Ponto J, et al: Sensitivity and specificity of In-l 11 platelet scintigraphy and two-dimensional echocardiography for detection of left ventricular thrombi: Clot size threshold. J Am Co11Cardiol 5:389, 1985 119. Ezekowitz MD, Burrow RD, Heath PW, et al: Diagnostic accuracy of indium-1 11 platelet scintigraphy in identifying left ventricular thrombi. Am J Cardiol51:1712-1716, 1983 120. Laws KH, Clanton JA, Starnes VA, et al: Kinetics and imaging of indium-I 1 l-labeled autologous platelets in experimental myocardial infarction. Circulation 67:l l&l 17, 1983 12 1. Romson JL, Hook BG, Rigot VH, et al: The effect of ibuprofen on accumulation of indium-1 1 l-labeled platelets and leukocytes in experimental myocardial infarction. Circulation 66:1002-1011, 1982 122. Davies RA, Thakur ML, Berger HJ, et al: Imaging inflammatory response to acute myocardial infarction in man using indium-11 l-labeled autologous platelets. Circulation 63:826-832, 198 1 123. Thakur ML, Gottschalk A, Zaret BL: Imaging experimental myocardial infarction with indium-1 1 l-labeled autologous leukocytes: Effects of infarct age and residual regional myocardial blood flow. Circulation 60:297-305, 1979 124. Cannon PJ, Dell RB, Dwyer EM: Measurement of regional myocardial perfusion in man with ‘13Xe and a scintillation camera. J Clin Invest 51:964-977, 1972 125. Holman BL, Adams DF, Jewitt D, et al: Measuring regional myocardial blood flow with “‘Xe and the Anger camera. Radiology 112:99-l 07, 1974 126. L’Abbate A, Maseri A: Xenon studies of myocardial blood flow: Theoretical, technical and practical aspects. Semin Nucl Med 10:2-16, 1980 127. Ruddy TD, Yasuda T, Barlai-Kovach M, et al: Near simultaneous measurement of LV function and myocardial perfusion with xenon-133. Circulation 70:11-123, 1984 (suppl2) (abstr) 128. Nichols AB, Brown C, Esser PD, et al: Effect of coronary stenotic lesions on regional myocardial blood flow at rest. Circulation 70:11-22, 1984 (abstr) 129. Port SC, Lassar TA, Schmidt DH: Coronary flow reserve after dipyridamole predicts adequacy of ventricular function during exercise. Circulation 70:11-22, 1984 (suppl) 130. Khuri SF, Karaffa S, Kloner RA, et al: Determination of intramyocardial blood flow with xenon-127. J Thorac Cardiovasc Surg 80:262-270, 1980 131. Tweddel AC, Martin W, Simpson IA, et al: Right ventricular function from gated xenon scans. J Am Co11 Cardiol 3:476, 1984 (abstr) 132. Kety S: The theory and applications of the exchange

434 of inert gas at the lungs and tissue. Pharmacol Rev 3:1-41, 1951 133. Heinsimer JA, Lefkowitz RJ: Adrenergic receptors: Biochemistry, regulation, molecular mechanism and clinical implications. J Lab Clin Med 100:641-658, 1982 134. Homey CJ: The ligand binding assay and its role in understanding adrenergic receptor function. J Thorac Cardiovas Surg 86:193-194, 1983 135. Homey CJ, Rockson SG, Haber E: An antiidiotypic antibody that recognized the beta receptor. J Clin Invest 69:1147-1154,1982 136. Alexander RW, Williams LT, Lefkowitz RJ: Identification of cardiac beta adrenergic receptors by ‘Halprenolol binding. Proc Nat Acad Sci USA 72:1564-l 568, 1975 137, Haber E, Wrenn S: Problems in identification of the beta adrenergic receptor. Physiol Rev 56:317,1976 138. Heald SL, Jeffs PW, Lavin TN, et al: Synthesis of Iodine-125 labeled 15 (Cazidobenzyl) carazolol: A potent beta adrenergic photoaffinity probe. J Med Chem 26:832, 1983 139. van Koppen CJ, Siero HLM, Rodriques de Miranda JF, et al: Simultaneous assayof muscarinic and beta adrenergic receptors using a double-isotope technique. Biochem Biophys Res Commun 120~665.1984 140. Williams RS, Lefkowitz RJ: Alpha-adrenergic receptors in rat myocardium. Circ Res 43:721, 1978 141. Fowler MB, Laser JA, Bristow MR, et al: Betaadrenergic receptor density in right ventricular biopsy samples: Correlation with hemodynamic indices. J Am Co11 Cardiol5:535,1985 142. Lurie KG, Bristow MR, Reitz BA: Increased beta adrenergic receptor density in an experimental model of

MILLER

ET AL

cardiac transplantation. J Thorac Cardiovasc Surg 86:195, 1983 143. Mehta J, Mehta P, Ostrowski N, et al: Enhanced platelet aggregation and post-synoptic adrenergic activity in unstable angina: Potential mechanisms of decrease in coronary blood flow. J Am Co11Cardiol5:445, 1985 144. Corr PB, Gillis RA: Autonomic neural influences on the dysrhythmias resulting from myocardial infarction. Circ Res 43:1-9, 1978 145. Glaubiger G, Tsai BS, Lefkowitz RJ, et al: Chronic guanethedine treatment increases beta adrenergic cardiac receptors. Nature 273:240, 1978 146. Jacobowitz DM, Skofitsch G, Keiser HR, et al: Evidence for the existence of atria1 natriuretic factorcontaining neurons in the rat brain. Neuroendocrinology 40:92-94, 1985 147. Pitt B, Pasyk S, Walton J, et al: Endogenous vasopressin release in patients with coronary artery spasm. Circulation 66:11-88, 1982 148. Kline RC, Swanson DP, Wieland DM, et al: Myocardial imaging in man with I- 123 meta-iodobenzylguanidine. J Nucl Med 22:129-132, 1982 149. Nakajo M, Shapiro B, Glowiak J, et at: Inverse relationship between cardiac accumulation of meta [r3’I] iodobenzzylguanidine (I-l 3 1 MIBG) and circulating catecholamines in suspected pleochromocytoma. J Nucl Med 24:1127-l 134,1983 150. Osbakken MD, Kopiwoda SY, Swan A, et al: Cardiac lymphoscintigraphy following closed-chest catheter injection of radiolabeled colloid into the myocardium of dogs. J Nucl Med 23:883-889,1982 151. Treves S, Kulprathipanja S, Hnatowich DJ: Angiocardiography with iridium-19lM: An ultrashort-lived radionuclide [T’/z 4.9 set]. Circulation 54: 275-279, 1976