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NW/. Med. Viol. Vol. 18, No. 6, pp. 647-654, 1991

ht.

J. Radial. Appl. Instrum. Part B

Printed in Great Britain. All rights reserved

Recent Developments in ggmT~and 1231-Radiopharmaceuticals for SPECT Imaging P. V. KULKARNI Department of Radiology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235, U.S.A. Availability of ‘23Iof high radionuclidic purity has encouraged the development of ‘*‘I-based radiopharmaceuticals for the assessment of myocardial fatty acid metabolism, myocardial neuronal activity, and for receptor and antibody imaging. Advances in the chemistry of technetium have resulted in the development of novel agents for myocardial and cerebral perfusion and renal function studies. Monoclonal antibodies labeled with %Tc show promise for imaging neoplastic lesions, myocardial infarcts, and thrombus localization. Recent developments in ‘*rI and 94”T~agents for myocardial and brain imaging studies are discussed.

nuclide and is not always available for acute studies. The problems of attenuation of low energy photons Technetium-99m and lz31 are well suited radio(69-83 keV, Hg x-rays from 20’Tl) and limitations due nuclides for single photon emission computed to unfavorable radiation dosimetry limit the administomography (SPECT) studies. In recent years, several tered dose which results in a photon flux frequently new imaging agents have been labeled with these too low for tomographic imaging. In contrast, a high important radionuclides. These agents include 99mTcphoton flux available with larger administered doses labeled compounds for myocardial and brain perof 99mTcallows collection of first-pass data for calcufusion studies, for renal imaging, and for labeling of lating ventricular ejection fraction. Gated planar lipoproteins, monoclonal antibodies and cellular and tomographic studies also permit assessment of blood elements. Recently developed iz31 radioregional wall motion in addition to myocardial pharmaceuticals include agents for imaging myoperfusion. cardial fatty acid metabolism, adrenergic neuronal Development of 99mT~myocardial agents received activity, and for receptor imaging. Agents labeled a great impetus when Deutsch et al. in 1981 first with lz31 have also been used for imaging brain reported the synthesis and biological behavior of perfusion and receptors in the central nervous system, cationic complexes of 99mTc that accumulated in estrogen receptors in breast cancer patients and for normal myocardium of test animals (Deutsch et al., labeling monoclonal antibodies. This article will not 1981a,b). These were Tc(II1) compounds of the type discuss radiopharmaceuticals which are well estab(99mTc L2X2)+, where L is the bidentate ligand: lished in clinical practice, but will rather concentrate o-phenylene-bis(dimethyl arsine) (DIARS), or on some of the recent developments in new agents bis( 1,2-dimethyl phosphine) ethane (DMPE), and labeled with 99mTc and ‘23I for cardiovascular and X = F, Cl, Br or I. Similar complexes of technetium brain imaging applications. reported later in the + I oxidation state were tris[99mTc(DMPE),]+ and [99”Tc(TMP)h]+ where TMP represents trimethyl phosphite (Dean et al., Cardiovascular Imaging Agents 1984). Large interspecies variations in the myocardial Technetium-99m labeled myocardial perfusion agents uptake and blood clearance have been observed with 99mTc-DMPE agents. These variations have been Compared to currently used myocardial perfusion attributed to major differences in their plasma agent thallium-201 (“‘Tl), the ready availability, low protein-binding characteristics. Despite excellent cost, instant “kit” formulation at the clinical site, and ideal nuclear emissions for imaging are some of myocardial localization in various animal species, these agents were found unsuitable for human cardiac the advantages of WmTc-labeled agents. Thallium-201 imaging studies (Gerundini et al., 1986). (T,,,: 74 h) is a cylotron-produced, expensive radio-

Introduction

648

P. V. KULKARNI

Isonitrile compoundr. Jones et al. (1984) reported the synthesis of a new class of cationic technetium isonitrile compounds with a net charge of + 1. These are of the type Tc(CNR),+ where R can be i-propyl, n-butyl, i-butyl, or t-butyl. Of the various ggmT~ isonitriles studied, three derivatives that have been clinically investigated are: t-butyl isonitrile (TBI), carboxy-methyl isopropyl isonitrile (CPI), and hexakis-2 methoxy-2 isobutyl isonitrile (MIBI) (Holman et al., 1984a,b; Spom et af., 1986; Mousa et al., 1987). These 99mTc isonitrile derivatives are prepared by heating pertechnetate and Cu-isonitrile in aqueous media in the presence of stannous (Sn”) ions. TBI demonstrates higher initial lung and liver uptake. The lung activity clears within 1 h after injection. CPI clears rapidly from blood and lungs and accumulates in the liver and heart. Excellent images of the human heart can be obtained within 10min of injection of this agent. In normal human volunteers, the myocardial activity washes out with a T,,2 of 87min. Contrary to this, the 99mTc MIBI myocardial activity washes out very slowly (7’~ N 5 h) and, thus, permits delayed imaging. Various clinical protocols are currently being evaluated to optimize the clinical utility of this agent (RP-30, Cardiolites, DuPont, N. Billerica, Mass.). Radiation dosimetry is improved compared with 20’T1due to the shorter half-life of 99mTcand better pharmacokinetics of *mTc MIBI. Studies with electrocardiographic gating and tomographic imaging are feasible due to higher photon flux (Kahn et al., 1989) available with administered doses of ggmTc of IO-30mCi/70 kg. Measurements of both ventricular function using first-pass ventriculography as well as myocardial perfusion may be possible with the administration of a single dose of ““‘Tc MIBI (Perez-Balino et al., 1987). In practice, however, two doses of the radiopharmaceutical are needed-one for rest and another for exercise studies. Boronic acid adducts of technetium oxime complexes (BAT&). Boronic acid adducts of technetium

dioxime complexes (BATOs) are a novel class of compounds with an affinity for the myocardium (Trechen et al., 1986). These are neutral, lipophilic, heptacoordinate complexes in which technetium is bound to the six nitrogens of the three vicinal dioximes and an axial chloride ligand. They are easily prepared by template synthesis from vicinal dioximes and a boronic acid (Trechen et al., 1989). The BAT0 agents are supplied as lyophilized powder in sterile vials. The radiolabeling is accomplished by first reconstituting the contents of the vial with 1 mL of sterile, pyrogen free 99mTcgenerator eluate containing no more than 50mCi of pertechnetate, and then heating the vial in a water bath for 15 min at 100°C. The resulting product is cooled to room temperature and is used within 3 h of preparation. One of these BAT0 complexes, AQ302 17 (Cardiotee%, Squibb Diagnostics, New Brunswick, N.J.) is under clinical evaluation. The agent has shown high myocardial extraction, low lung uptake, rapid blood clearance, and no interspecies differences in the myocardial uptake (Coleman et al., 1986). Phase I studies showed rapid myocardial uptake with excellent visualization at 2 min after administration. Myocardial clearance of this agent was rapid, with a biexponential clearance. The half times were 5 min (68%) for the fast component and 78 min (32%) for the slow component. Seldin et al. (1989) performed myocardial perfusion imaging with ‘%Tc SQ30217 and compared this with “‘Tl imaging in 10 normal volunteers and 20 patients with coronary artery disease. Planar *O’Tlimaging followed treadmill exercise and planar SQ30217 imaging was followed by upright bicycle exercise. This study indicated that imaging with ggmT~SQ30217 was equally sensitive to that with ‘O’Tl in detecting coronary artery disease. Myocardial clearance of the agent was rapid so that a second study could be performed within 2 h. Table 1 compares the characteristics of the various above ggmT~myocardial agents. It is expected that the

Table 1. Comparison of the in vim performance of *Tc

myocardial agents

Isonitriles’ TBI

BATOt

CPI

MIBI

(SQ30217)

Myocardial extraction

15% of ““TI

Same as TBI

70% of ‘O’Tl

126% of 2”‘Tl

Myocardial distribution

Proportional to regional blood flow; no redistribution

Same as TBI

Same as TBI

Proportional

Myocardial clearance

Slow washout (4 h)

Fast clearance (90 min)

Slow (5 h)

Fast clearance; 5 min fast component (68%); 78 min slow component (32%)

Lung activity & clearance

High retention; clears slowly, I h post injection

Little lung retention

Rapid clearance

Low lung activity

Liver activity & clearance

Activity increases with time

Hepatic uptake rapid; clears similar to heart

Rapid clearance

Hepatic activity increases with time

Image contrast

Poor

Fair

Excellent

Fair

lTBI, t-bntyl isonitrile;CPI, carboxy-methyl isopropyl isonitrile; MIBI, hexakis-2-methoxy-2 isobutyl isonitrile. tBAT0,

boronic acid adduct of technetium oxime.

to blood

BOW

*Tc

and ‘Z31-radiophannaceuticals

649

In order to reduce the rapid in vivo deiodination of continued clinical evaluation of these 99”Tc-labeled alkyl fatty acids, Machulla et al. agents will soon lead to optimized patient imaging radioiodinated (1980) proposed the use of a phenyl fatty acid (phenyl protocols. pentadecanoic acid) with radioiodine substituted on the phenyl ring. Metabolic end products of such a Radioiodinated tracers for myocardial studies fatty acid are iodobenzoic acid and iodohippuric acid Many biologically important molecules such as both of which are cleared rapidly compared to free iodine from circulation. Phenyl fatty acids are conmetabolic substrates and receptor binding agents ventiently radioiodinated by radioisotopic exchange can be readily radioiodinated. However, the relative reaction in the presence or absence of ammonium high cost and the lack of ready availability of pure sulfate, or a catalyst (Cu) at elevated temperatures lz31 have hampered the growth in clinical appli(Eisenhut, 1982; Dougan et al., 1986). Organometalcations of lz31 based radiopharmaceuticals. Iodinelit intermediates (Hg or Tl salts) also have been used 123, high in radionuclidic purity (>99.5%) and successfully for efficient radioiodination (Flanagan suitable for radiolabeling is produced in commercial et al., 1986; Kulkarni and Parkey, 1982). It has been cyclotrons by utilizing one of the following nuclear reactions. In one approach (Mausner et al., 1986; observed that efficiency of myocardial extraction and Lagunas-Solar, 1985), protons with energies of turnover of phenyl fatty acids are related to alkyl carbon chain length and stereoisomerism. Phenyl58-65 MeV are used to irradiate targets of elemental pentadecanoic acid is extracted more efficiently than iodine or potassium iodide to produce the following phenylhexadecanoic acid. Phenylpentadecanoic acid nuclear reaction: radioiodinated in the ortho position is turned over ‘271(p,5n) 4 ‘23Xe from myocardium much more slowly than paraiodophenylpentadecanoic acid (Machulla et al., Xenon- 123 (T,,,: 2.1 h) then decays to Iz31.In another 1986; Antar et al., 1986). In order to block the approach (Grabmayer and Nowotny, 1978), protons /?-oxidation and increase the residence time of the of less than 42 MeV energy are used to irradiate radiolabel in the myocardium, various derivatives enriched ‘24Xe gas target: (/I-methyl, 9-methyl, 3,3-dimethyl, etc.) of phyenylpentadecanoic acid have been proposed (Goodman 124Xe(p,2n) -_, ‘*‘Cs -b 123Xe -b 1231; et al., 1982; Knapp et al., 1986). A number of clinical studies using radioiodinated ‘24Xe(p,pn) - ‘23Xe---) ‘231. phenylpentadecanoic acid (IPPA) have been reported (Dudczak et al., 1983; Kennedy et al., 1986; Hansen Labeled fatty acids. Fatty acids are the major et al., 1987; Pippin et al., 1987; Ugolini et al., 1988). substrates for cardiac energy metabolism and thus radiolabeled fatty acids have attracted considerable These studies, both at rest and exercise, included planar and tomographic imaging. Myocardial attention as probes for myocardial metabolic studies. Alkyl fatty acids (16-18 carbon chain) labeled with IPPA-SPECT imaging has been used to measure myocardial mass and monitor efficacy of therapy with radioiodine at the terminal position have been shown the alpha adrenergic inhibitor, prazosin, in patients to have myocardial extraction kinetics and imaging with hypertension and left ventricular hypertrophy properties similar to native “C palmitic acid (Poe (Ram et al., 1989). et al., 1976). A number of studies in Europe have Metaiodobenzyl guanidine. Metaiodobenzyl guanishown that ‘23I heptadecanoic acid is a useful myocardial imaging agent (Freundlieb et al., 1980). Howdine (MIBG), a structural analog of guanathidine and norepinephrine, was originally developed for ever, the rapid metabolism of the agent by the heart detection of pheochromocytoma and used successand the liver, and the in vivo deiodination (due to fully for locating neuroblastoma (Wieland et al., j-oxidation) lead to image degradation thus limiting 1980; Fischer et al., 1985). However, it also localizes its use to single projection planar imaging. Table 2. Recent *Tc Perfusion agents ‘*“I IMP

121,

%Tc *“Tc @“‘Tc *Tc

HIPDM NEP-DADT Methyl-NEP-DADT d,l HM-PA0 1,1, ECD

Agents for imaging receptors Receptor system CNS dopamine Dl and D2

Serotonergic receptors Benzodiazepine receptors Muscarinic acetyl choline receotors

and “‘I-labeled brain imaging agents

N-Isopropyl-p-(1231)-iodoamphetamine N,N,‘-Trimethyl-N’-(2-hydroxy-3-methyl-S-iodobenzyl)-1,3-propanediamine Ph”Tc-N-piperidinyl-ethyl-diaminodithiol @“‘Tc-N-piperidinyl-methyl-diaminodithiol 9R”Tc-d,l-hexamethylpropyleneamine oxime *Tc- 1.1 -ethylcyst&nate dimer References

Kung et al. (1986a), Thonoor and Berridge (1988), Kung et (11.(1988a,b), Janowski er a!. (1988) Kung et al. (1986b). Chumpadit et al. (1989). Mertens et al. (1989) Hoe1 et al. (1988) Eckelman et al. (1984), Holman et al. (1985). Gibson et al. (1989). Wilson et al. (1989).

650

P. V. KULKARNI

in human heart. Both planar and SPECT imaging of human heart has been reported in the assessment of adrenergic function of the heart (Sisson et al., 1987). Radioiodination of MIBG was performed by solid phase exchange reaction in the presence of ammonium sulphate (Mangner et al., 1984). MIBG-SPECT imaging has been compared to ‘O’Tl imaging in subjects with cardiomyopathy (Henderson et al., 1988; Schafer et al., 1988) and myocardial infarction or ischemia (McGhie et al., 1991). Accelerated myocardial clearance of the tracer has been reported in patients with adrenergic dysfunction or neuropathy. In a patient with cardiac autonomic neuropathy, MIBG-SPECT imaging showed regional losses of the tracer despite the normal ‘O’Tl perfusion images (Kahn et al., 1988).

Brain Imaging Agents

Radioiodinated amines and diamines are taken up by the brain, proportional to cerebral blood flow, and are retained for a sufficient time to permit cerebral imaging with a SPECT camera. Among the various agents investigated, two compounds, the monoamine, N-isopropyl-p-[‘231]iodoamphetamine (IMP), and the diamine N,N,N’-trimethyl-N’-(2-hydroxy-3-methyl5iodobenzyl)- 1,3-propane diamine [‘231]HIPDM, have been successful in clinical studies of various brain disorders (Winchell et al., 1980; Kuhl et a/., 1982; Baldwin and Wu, 1988; Royal et al., 1985; Kung et al., 1983; Holman et al., 1984a,b; Lee et al., 1984; Lucignani et al., 1985; Cohen et al., 1986; Blau, 1985). The diamine, HIPDM, is radiolabeled by a simple isotopic exchange reaction: a reaction mixture Tracers of cardiac receptors of (cold) HIPDM and radioiodine is heated in a boiling water bath for 30min (Kung et al., 1983). Regional changes in /3-adrenoreceptor density in IMP([‘231] iofetamine-HCl; Spectamine%, Medinormal and ischemic myocardium could be measured Physics, Paramus, N.J.) is available commercially. in vivo by imaging with radioiodinated B-adrenoNormally, 3-6 mCi of IMP is administered i.v., with receptor binding ligands: iodopindolol and iodothe patient’s eyes closed. Scanning commences after cyanopindolol (Hughes et al., 1986; Sisson et al., 20 min. A medium or high energy collimator is used 1988). These agents were radioiodinated using chlorif ‘23I is produced by the ‘24Te(p,2n)‘231 reaction. amine-T and purified on a reverse phase HPLC Iodine-123 so produced contains lz41and ‘26I which column. The use of p-2 antagonists to selectively emit high energy photons that degrade the images. inhibit the binding to lungs has been suggested. Up to 7% of the administered activity accumulates in Clinical application of these imaging agents is the brain and first-pass extraction by normal brain awaited. is about 85%. The bioIogica1 half-life of the agent is about 3 days. Administration (i.v.) of a potent cerebral vasodilator, acetazolamide (Diamor) has Thrombus and LDL Receptor Imaging been used to increase the sensitivity for detecting A variety of substances labeled with 13’1or ‘23I minor degrees of ischemia. Although the clinical use of ‘23Iamine compounds have been proposed to localize venous thrombi and has been well accepted, 99mTc-labeled cerebral pulmonary emboli; however, none of them are perfusion (rCBF) agents would find more widespread accepted clinically. These include streptokinase, use for reasons stated previously. Several neutral, urokinase, fibrinogen, heavily iodinated fibrinogen, lipophilic 99mTcchelates have been known to cross soluble fibrin, fibronectin, fragment El, plasmin, the blood-brain barrier (BBB) but only a few are plasminogen, tissue plasminogen activator (TPA), and inactivated TPA. Iodine-123 or “‘In labeled efficiently extracted by the brain and retained there antifibrin and antiplatelet antibodies are under clinifor long enough to be useful as brain perfusion agents with SPECT. The most useful rCBF agents cal investigation. A kit for tagging with 99mTcwas developed to label fragments of a monoclonal antiare the derivatives of 99mTc propyleneamineoxime body (MoAb 50H.19) crossreacting with normal (99mTc-PnAO) (Troutner et al., 1984; Volkert et al., platelets (Som et al., 1986). Fresh canine thrombi in 1984) 99mTc-diaminodithiols (99mTc-DADT) (Burns peripheral veins could be imaged in l-2 h. Other et al., 1979; Kung et al., 1984; Lever et al., 1985), and monoclonal antibodies labeled with “‘In have been 99”Tc-boron adduct capped Tc-oximes c9mT~-BATO) (Linder et al., 1987). Many derivatives of these successful in detection of old and fresh clots in experimental animals (Hui et al., 1983; Knight et al., chelates have been evaluated. Among these, 99mTcd, 1-hexamethylpropyleneamine oxime (99mTc-d,l1988; Lavender et al., 1988; Oster et al., 1985; Rosebrough et al., 1988). HMPAO) (Neirinckx et al., 1987) and Radioiodinated (‘*‘I, 1231)low density lipoproteins 99mTc-1,1-ethylcysteinate dimer ctiTc-ECD) (Chess(LDL) have been used for noninvasive detection of man et al., 1988) have been shown to be quite suitable atheromatous lesions and LDL receptors (Lees et al., for human SPECT brain imaging studies. Both these 1983). LDL has been labeled with 99mT~ using agents are rapidly taken up by the brain in relation dithionite as a reducing agent (Lees et al., 1985). to cerebral perfusion and are retained there for a Technetium-99m-labeled LDL has been used to long enough period (few hours without undergoing redistribution) thus enabling brain imaging with a study LDL receptor uptake and metabolism SPECT gamma camera. One of the *“Tc-BAT0 (Vallabhajosula and Goldsmith, 1990).

*Tc

651

and ‘231-radiopharmaceuticals

(AQ 32,097, Squibb Diagnostics, New Brunswick, N-J.), as well as *Tc-ECD, are under clinical investigation. *Tc-d, I-HMPAO (Ceretec@, Amersham International) is now commercially available for clinical studies. Technetium-99m-labeled propyleneamineoxime (%Tc-PnAO) was initially developed at the University of Missouri (Troutner ef al., 1980; Volkert et af., 1984). *Tc-PnAO, a neutral lipophilic chelate with an octanol/water partition ratio of approx. 50: 1, was found to be a single species (as determined by HPLC), and is stable for 24 h. x-Ray crystallographic data indicated that Tc-PnAO is a S-coordinate chelate with pyramidal geometry containing a Tc(V)mono-oxo core. 99”Tc-PnA0 freely diffuses across the BBB with a high first-pass extraction efficiency that is similar to ‘Z I IMP. However, it was not retained in the brain long enough for brain SPECT studies. It was recognized that simple N4 ligand chemistry could be utilized to prepare a number of small neutral, lipophilic compounds that could potentially be more useful as rCBF agents. A series of this type of agents was synthesized and screened at Amersham International, U.K. (Chaplin et al., 1986). One of these agents, HMPA0(4,8-diaza-3,6,6,9tetramethylundecane-2,lO,dione-bisoxime) has been found to have high cerebral extraction and long retention in the brain. These properties make it quite suitable for brain SPECT studies (Neirinckx et al., 1987). HMPAO has two stereoisomers due to two asymmetric carbon atoms (at the 3 and 9 positions), and these two isomers have dramatic differences in their cerebral retention characteristics (Sharp et al., 1986). The meso form is cleared rapidly from the brain; however, d, I-HMPAO demonstrated excellent cortical retention. 9gmTc-d,l-HMA0 is somewhat unstable in aqueous solution (Hung et al., 1988). Thus, it is recommended that the product be used within 30min of preparation. Causes of this instability and ways to correct it are being explored. Diamine dithiol (N2S2) ligands are known to form single, stable, neutral lipophilic complexes with *Tc. Several derivatives have been synthesized and evaluated. Among them, g9”Tc-N-piperidinylethyl-diaminodithiol (NEP-DADT) and methylNEP-DADT have given promising results in experimental studies (Bok et al., 1987). In humans, the most promising results hve been obtained with *Tc-ethyl cysteinate dimer (ECD; DuPont, Billerica, Mass.). Only the I,I-ECD distereoisomer is retained in the brain whereas %Tc-d, d-ECD is not. %Tc 1,l-ECD crosses the BBB and a rapid conversion of the lipophlic chelate to a hydrophilic form takes place inside the cells. It cannot diffuse back and is retained in the brain for a long period of time (T,,2 > 24 h) (Leveille et al., 1989). Initial clinical brain imaging studies with these neutral lipophilic chelates have been reported (Podreka, 1987).

CNS Receptor Imaging Agents

complexes

During the past 10 years, a number of agents labeled with radioiodine have been proposed for imaging various receptors in the central nervous system (CNS). These include agents for imaging: CNS D-l and D-2 dopamine receptors (Kung et al., 1986a, 1988a,b; Thonoor and Bemidge 1988; Janowski et al., 1988); muscarinic acetylcholine receptors (Eckelman et a[., 1984; Wilson ef al., 1989); serotonin receptors (Kung et al., 1986b; Chumpadit et al., 1989; Mertens et al., 1989); and benzodiazepine receptors (Hoe11 ef al., 1988). Due to the lipophilic nature of these agents, the initial distribution may be related to blood flow and the delayed distribution may reflect the receptor levels (Blau, 1985). Application of these agents is still in the experimental stage. QNB(R)-3-quinuclidinyl-4-iodo-benzilate has been labeled with lz31with high specific activity (Gibson et al., 1989). Radioiodinated QNB has been used to image the receptor distribution in normal subjects and in patients with Alzheimer’s disease (Holman et al., 1985). Further evaluation of the clinical utility of these agents is awaited.

Conclusions Monovalent cationic and neutral complexes of *Tc for myocardial perfusion studies have been developed. One of the isonitrile derivatives, WmT~ methoxyisobutyl isonitrile (%Tc MIBI), has been shown to be an excellent myocardial imaging agent. Gated tomographic imaging and first-pass studies are possible with this agent. Technetium-99m-labeled BAT0 compounds display fast clearance from the myocardium and thus appear promising for repeat studies within a couple of hours. Imaging protocols, which are quite different from those of *‘IT1 imaging, are utilized for these new agents. Radioiodinated (lz31IMP) as well as 99”Tc-labeled (%“‘TcHMPAO, %Tc-ECD) agents that are excellent for brain perfusion studies are now available. Steady availability of lz31 at a reasonable cost would be able to promote further clinical evaluation and applications of ‘231-labeled radiopharmaceuticals for myocardial metabolic studies and for receptor imaging. Acknowledgements-The

author thanks MS Anca Constantinescu and MS Gayle Blust for their assistance in the preparation of this manuscript.

References Antar M. A., Spohr G., Herzog H. H. et al. (1965) IS-(ortho ‘*‘I-phenyl)-penta-decanoic acid, a new myocardial imaging agent for clinical use. Nucl. Med. Commun. 7, 683-696.

Baldwin R. M. and Wu J-L. (1988) In uivo chemistry of iofetamine HCI iodine-123 (IMP). J. Nucl. Med. 29, 122-124. Blau M. (1985) Radiotracers for functional brain imaging. Semin. Nucl. Med. 15, 329-334.

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P. V. KULKARNI

Bok B. D., Scheffel U., Goldfarb H. W., Bums H. D., Lever S. Z., Wong D. F. and Wagner H. N: Jr (1987) Comparison of *Tc comdexes (NEP-DADT. ME-NEP-DADT. and HMPAO) wi-ti ‘231-IMPfor brain SPECT imaging in dogs. Nucl. Med. Commun. 8, 631-641. Burns H. D., Manspeaker H., Miller R., Risch V., Emrich J. and Heindel N. D. (1979) Preparation and biodistribution of neutral, lipid soluble Tc-QQmcomplexes of bis(2-mercaptoethyl)amine ligands. J. Nucl. Med. 20, 654 (Abstr.). Chaplin S. B., Oberle P. A., McKenzie E. H., Hoffman T. J., Volkert W. A., Holmes R. A., Canning L. R., Pickett R. D., Nowotnik D. P. and Neirinckx R. D. (1986) Regional cerebral uptake and retention of 99mTc-tetramethyl- and pentamethyl-propyleneamine oxime chelates. Nucl. Med. Biol. 13, 261-267. Chessman E. H., Blanchette M. A., Ganey M. V., Maheu L. J.. Miller S. J. and Watson A. D. (1988) TechnetiumQQmECD: ester-derivatized diamine-dithiolTc complexes for imaging brain perfusion. J. Nucl. Med. 29, 788 (Abstr.).- _ Chumpadit D., Jung H. F., Billings J., Guo Y-Z., Wu Y. and Shih J. (1989) Preoaration and biodistribution of l-[2-(3-(12sI]i~do-~-amihophenyl)ethyl]-4-(3-(trifluoromethyl)phenyl]piperazine and l-[2-(3-[‘2SI]iodo-4-azidophenyl)-ethyl]-4-[3-(trifloromethyl) phenyllpiperazine. J. Med. Chem. 32, 543-547.

Cohen M. B., Graham S., Lake R., Metter E. J., Fitten J., Kulkami M. K., Sevrin R., Yamada L., Change C. C., Woodruff N. and Kling A. S. (1986) Diagnosis of Alzheimer’s disease and multiple infarct dementia by tomographic imaging of iodine-123 IMP. J. Nucl. Med. 27, 769-774. Coleman R. E., Maturi M., Nunn A. D. et al. (1986) Imaging of myocardial perfusion with SQ 30217: dog and human studies. J. Nucl. Med. 27, 893 (Abstr.). Dean R. T., Adams M. D., Miller F. W. et al. (1984) Synthesis, characterization and identification of the hexakis(trimethylphosphite)[Tc-QQm] technetium(I) cation as a myocardial imaging agent. J. Nucl. Med. 25, PlS (Abstr.). Deutsch E., Bushong W., Glavan K. A. er al. (1981a) Heart imaging with cationic complexes of technetium. Science 214, 85-86. Deutsch E., Glavan K. A., Sodd V. J. ef al. (1981b) Cationic Tc-QQm complexes as potential myocardial imaging agents. J. Nucl. Med. 22, 897-907. Dougan H., Lyster D. M. and Vincent J. S. (1986) Efficient production of lS-(para[‘231]iodophenyl) pentadecanoic acid. Appl. Radiat. Isot. 37,Q19--921. Dudczak C.. Schmoliner R.. Kletter K. et al. 11983)Clinical evaluation of ‘“)I-labeled p-phenylpentadecanoic acid (P-IPPA) for myocardial scintigraphy. J. Nucl. Med. Allied Sci. 27, 267-278.

Eckehnan W. C., Reba R. C. and Rzeszotarski W. (1984) External imaging of cerebral muscarinic acetylcholine receptors. Science 223, 291-293. Eisenhut M. (1982) Simple labeling of w-phenyl fatty acids by iodine isotope exchange. Appl. Radiat. Isot. 33, 499-W.

Fischer M., Galanski M., Winterberg B. and Vetter H. (1985) Localization procedures in pheochromocytoma and neuroblastoma. Cardiology 72, 143-146. Flanagan R. J., Charleson F. P., Synnes E. L. et al. (1986) Radiolabeling with organomercury compounds: part 2. High specific activity synthesis of I-125 and I- 13I-6-iodocholest-S-en-3-01 and its tissue distribution in rats. J. Nucl. Med. 27, 1165-1171.

Freundlieb C., Hock A., Vyska K. et al. (1980) Myocardial imaging and metabolic studies with [ 17-I-123]iodoheptadecanoic acid. J. Nucl. Med. 21, 1043-1050. Gerundini P., Savi A., Gilardi M. C. et al. (1986) Evaluation in dogs and humans of three potential technetiumQQm mvocardial nerfusion agents. J. Nucl. Med. 27. 409-416.

Gibson R. E., Schneidau T. A., Cohen V. I., Sodd V., Ruth J., Melograna J., Eckelman W. C. and Reba R. C. (1989) In vitro and in vivo characteristics of [iodine-1251 3-(R)quinuclidinyl(S)-4-iodobenzilate. J. Nucl. Med. 30, 1079-1087. Goodman M. M., Knapp F. F., Callahan A. P. and Farren L. A. (1982) Radioiodinated IS-(p-iodophenyl)-6-tellurapentadecanoic acid: a new myocardial imaging agent exhibiting prolonged myocardial retention. J. Nucl. Med. 23, 904-908. Grabmayer P. and Nowotny R. (1978) Statistical-model based evaluations of reactions producing 123Iand i2’Xe. Int. J. Appl. Radiat. Isot. 29, 261-267.

Hansen C. L., Jansen D. E., Corbett J. R. et al. (1987) Increased sensitivity of I-123 phenylpentadecanoic acid in the identification of exercise-induced myocardial ischemia. J. Am. Coil. Cardiol. 9, 2SA (Abstr.). Henderson E. B., Kahn J. K., Corbett J. R. et cd. (1988) Abnormal I-123 metaiodobenzylguanidine myocardial washout and distribution may reflect myocardial adrenergic derrangement in patient with congestive cariomyopathy. Circulation 78, 1192-l 199. Hoe11K., Deisenhamer E., Dauth J., Loeffler W., Carmann H. and Schubiger A. (1988) SPECTR mapping of human brain benzodiazepine receptors. J. Nucl. Med. 29, 759 (Abstr.). Holman B. L., Jones A. G., Lister-James J. et al. (1984a) A new Tc-QQm-labeled myocardial imaging agent, hexakis(t-butvlisonitrile)~technetium(I) lTc-99m TBIl: initial experience in the human. J. Nucl. ked. 25, 1350-1355. Holman B. L., Lee R. G. L., Hill T. C., Lovett R. D. and Lister-James J. (1984b) A comparison of two cerebral perfusion tracers N-isopropyl I-123 p-iodoamphetamine and I-123 HIPDM, in the human. J. Nucl. Med. 25, 25-30.

Holman B. L., Gibson R. E., Hill T. C. et al. (1985) Muscarinic acetylcholine receptors in Alzheimers’ disease: in vivo imaging with iodine 123-labeled 3-quinuclidinyl-4iodobenzilate and emission tomography. J. Am. Med. Ass. 254, 3063-3066.

Hughes B., Marshall D. R., Sobel B. E. et al. (1986) Characterization of beta-adrenoreceptors in vivo with iodine-131 pindolol and gamma scintigraphy. J. Nucl. Med. 27, 660-667.

Hui K. Y., Haber E. and Mats&a G. R. (1983) Monoclonal antibodies to a synthetic fibrin-like peptide bind to human fibrin but not fibrinogen. Science 22, 1129-l 132. Hung J. C., Corlija M., Volkert W. A. and Holmes R. A. (1988) Kinetic analvsis of technetium-QQm d. 1-HM-PA0 decomposition in aqueous media J. Nucl. Med. 29, 1568-l 576.

Janowski A., dePaulis T., Clinton J. A., Smith H. E., Ebert M. H. and Kessler R. M. (iz31)Iodopride: a specific high affinity radioligand for labeling striatal dopamine D-2 receptors. Eur. J. Phnrmac. 150, 203-205. Jones A. G., Abrams M. J., Davison A. et al. (1984) Biological studies of a new class of technetium complexes: the hexakis (alkylisonitrile) technetium(I) cations. Nucl. Med. Biol. 11, 225-234. Kahn J. K., Sisson J. C. and Vinik A. I. (1988) Prediction of sudden cardiac death in diabetic autonomic neuropathy. J. Nucl. Med. 29, 1605-1606. Kahn J. K., McGhie I., Akers M. S. et al. (1989) Quantitative rotational tomography with 20’T1 and %Tc 2methoxyisobutyl isonitrile: a direct comparison in normal individuals and patients with coronary artery disease. Circulation 79, 1282-1293.

Kennedy P. L., Corbett J. R., Kulkarni P. V. et al. (1986) I-123-phenyl penta-decanoic acid myocardial scintigraphy: usefulness in the identification of myocardial ischemia. Circulation 74, 1007-1015. Knapp F. F., Goodman M. M., Callahan A. P. et al. (1986) Radioiodinated 15-(p-iodophenyl)-3,3-dimethyl

99mTcand ‘231-radiopharmaceuticals pentadecanoic acid: a useful new agent to evaluate myocardial fatty acid uptake. J. Nucl. Med. 27, 521-531. Knight L. C., Maurer A. H., Ammar I. A., Slealy D. J. and Mattis J. A. (1988) Evaluation of indium-I1 l-labeled anti-fibrin antibody for imaging vascular thrombi. J. Nucl. Med. 29, 494-502. Kuhl D. E., Barrio J. R., Huang S-C., Selin C., Ackermann R. F., Lear J. L., Wu J. L., Lin T. H. and Phelps M. E. (1982) Quantifying local cerebral blood flow by Nisopropyl-p-[1231]iodoamphetamine (IMP) tomography. J. Nucl. Med. 23, 196-203. Kulkarni P. V. and Parkey R. W. (1982) A new radioiodination method utilizing organo-thallium intermediate: radioiodination of phenyl pentadecanoic acid (PPA) for potential applications in myocardial imaging. J. Nucl. Med. 23, PlO5 (Abstr.). Kung H. F., Tramposch K. M. and Blau M. (1983) A new brain perfusion imaging agent: [I-123lHIPDM: N,N,N’trimethyl-,‘-[2-hydroxy-3-methyl-5-iodobenzyl]-1,3-propanediamine. J. Nucl. Med. 24, 66-72. Kung H. F., Billings J. B. and Guo Y-Z. (1986a) In vivo biodistribution of SKF-103 108A: a potential D-l receptor site specific imaging agent. J. NucL Med. 27, 906. Kune H. F.. Guo Y-Z. and Billings J. (1986b) New serotoiin receptor-site specific brain imaging agent: radioactive iodinated 8-OH-DPAT. J. Nucl. Med. 27, 972 (Abstr.). Kung H. F., Molnar M., Billings J., Wicks R. and Blau M. (1984) Synthesis and biodistribution of neutral lipidsoluble Tc-99m complexes that cross the blood-brain barrier. J. Nucl. Med. U, 326-332. Kung H. F., Alavi A., Billing J., Kung M. P., Pan S. and Reilley J. (1988a) (‘*‘I)IBZP: A potential CNS D-l dopamine receptor imaging agent: in vivo biodistribution in the monkey. J. Nucl. Med. 29, 758 (Abstr.). Kung H. F., Alavi A., Kung M. P. ef al. (1988b) In vivo and in vitro biodistribution of (‘*)I)IBZM: a potential CNS D-2 dopamine receptor agent. J. Nucl. Med. 29, 759 (Abstr.). Lagunas-Solar M. C. (1985) Cyclotron production of highpurity jz31 for medical applications via the ‘*‘I @,5n)‘23Xe-+ I211nuclear reaction. In The Developing Role of Short-lived Radionuclides in Nuclear Medicine Practice (Edited by Raras P. and Thiesen J. W.).

pp. 203-221. DOE Symp. Series 56, US. DOE. Lavender J. P., Stuttle A. W. J., Peters A. M. ef al. (1988) In vivo studies with an antiplatelet monoclonal antibody, P256. J. Nucl. Med. Commun. 9, 811-822. Lee R. G. L., Hill T. C., Holman B. L., Royal H. D., O’Leary D. H. and Clouse M. E. (1984) Predictive value of perfusion defect size using N-isopropyl+1 23)-p iodoamphetamine emission tomography in acute stroke. J. Neurosurg. 61, 449-452. Lees R. S., Lees A. M. and Strauss H. W. (1983) External imaging of human atherosclerosis. J. Nucl. Med. 24, 154-156. Lees R. S., Garabedian H. D., Lees A. M., Schumacher D. J., Miller A., Isaacsohn J. L., Derksen A. and Strauss H. W. (19851) Technetium-99m low density lipoproteins: preparation and biodistribution. J. Nucl. Med. 26, 1056-1062.

Leveille J., Demonceau G., DeRoo M., Rigo P., Taillefer R., Morgan R. A., Kupranick D. and Walovitch R. C. (1989) Characterization of technetium-99m-L,L-ECD for brain perfusion imaging, Part 2: biodistribution and brain imaging in humans. J. Nucl. Med. 30, 1902-1910. Lever S. Z., Burns H. D., Kervitsky T. M., Goldfarb H. W., Woo D. V., Wong D. F., Epps L. A., Kramer A. V. and Wagner H. N. (1985) Design, preparation, and biodistribution of a technetium-99m triaminedithiol complex to assess regional cerebral blood flow. J. Nucl. Med. 26, 1287-1294.

653

Linder K., Feld T., Juri P. N., Nunn A. D. and Treher E. (1987) The synthesis of a new technetium agent, SQ32,097, which can be used to assess regional cerebral blood flow. J. Nucl. Med. 28, 592 (Abstr.). Lucignani G., Nehlig A., Blasberg R., Patlak C. S., Anderson L., Fieschi C., Fazio F. and Sokoloff L. (1985) Metabolic and kinetic considerations in the use of [1251]HIPDM for a quantitative measurement of regional cerebral blood flow. J. Cereb. Bid Flow Metab. 5, 86-96.

Machulla H. J., Knust E. J. and Vyska K. (1986) Radioiodinated fatty acids for cardiological diagnosis. Appl. Radia:. Isot. 31, 777-188.

Machulla H. J., Marsmann M. and Dutschka K. (1980) Biochemical synthesis of a radioiodinated phenyl fatty acid for in vivo metabolic studies of the myocardium. Eur. J. Nucl. Med. 5, 171-173. Mangner T. J., Wu J. L. and Wieland D. M. (1984) Solid-phase exchange radioiodination of aryl iodides. Facilitation by ammonium sulfate. J. Org. Chem. 47, 1484-1488. Mausner L. F., Srivastava S. C., Mirzadeh S. et al. (1986) lz31 research and production at Brookhaven National Laboratory. Appl. Radia?. Isot. 37, 843-851. McGhie A. I., Corbett J. R., Akers M. S. et al. (1991) The effects of acute myocardial infarction on regional cardiac adrenergic function. Am. J. Cardiol. In press. Mertens J., Bossuyt-Piron C., Guns M. et al. (1989) High selective serotonin S, receptor mapping with SPECT in baboon brain. J. Nucl. Med. 30, 741 (Abstr.). Mousa S. A., Cooney J. M. and Williams S. A. (1987) Regional myocardial distribution of RP-30 in animal models of myocardial ischemia and reperfusion. J. Nucl. Med. 38, 620 (Abstr.). Neirinckx R. D., Canning L. R., Piper I. M., Nowotnik D. P., Pickett R. D., Holmes R. A., Volkert W. A., Forster A. M., Weisner P. S., Marriott J. A. and Chaplin S. B. (1987) Technetium-99m d,l-HM-PAO: a new radiopharmaceutical for SPECT imaging of regional cerebral blood perfusion. J. Nucl. Med. 28, 191-202. Oster Z. H., Srivastava S. C., Som P. et al. (1985) Thrombus radioimmunoscintigraphy: an approach using monoclonal antiplatelet antibody Proc. Null. Acad. Sci. U.S.A. 82, 3465-3468.

Perez-Baslino N., Sporn V., Kuschnir E. er al. (1987) Simultaneous test of ventricular function and myocardial perfusion with Tc-99m RP-30. J. Nucl. Med 28, 662 (Abstr.). Pippin J. J., Jansen D. E., Henderson E. B. et al. (1987) Single-photon emission computed tomography utilizing I-123 phenyl pentadecanoic acid to assess myocardial fatty acid metabolism before and after percutaneous transluminal coronary angioplasty. J. Nucl. Med. 28,1084 (Abstr.). Podreka I., Suess E., Goldenberg G. et al. (1987) Initial exoerience with technetium-99m HM-PA0 brain SPECT. J.;l’ucl.

Med. 28, 1657-1666.

Poe N. D., Robinson G. D., Graham S. L. ef al. (1976) Experimental basis for myocardial imaging with “?labeled hexadecanoic acid. J. Nucl. Med. 17. 1077-1082. Ram C. V., Gonzales D., Kulkarni P. V. et al. (1989) Regression of left ventricular hypertrophy in hypertension: Effects of prazosin therapy. Am. J. Med. 86, 66-69.

Rosebrough S. F., Grossman Z. D., McAfee J. G. et al. (1988) Thrombus imaging with indium-11 1 and iodine131 labeled fibrin-specific monoclonal antibody and its F(ab’), and Fab fragments. J. Nucl. Med. 29, 1212-1222. Royal H. D., Hill T. H. and Holmes B. L. (1985) Clinical brain imaging with isopropyl-iodoamphetamine and SPECT. Semin. Nucl. Med. 15, 357-316. Schafer J., Spielmann R., Schubert A. et al. (1988) Iodine123 metaiodobenzylguanidine scintigraphy: a noninvasive

654

P. V. K.ULKARNI

method to demonstrate myocardial adrenergic nervous system disintegrity in patients with idiopathic dilated cardiomyopathy. J. Am. Coil. Cardiol. 12, 1252-1258. Seldin D. W., Johnson L. L., Blood D. K., Muschel M. J., Smith K. F., Wall R. M. and Cannon P. J. (1989) Myocardial perfusion imaging with Tc-99m SQ30217: comparison with thallium-201 and coronary anatomy. J. Nucl. Med. 30, 312-319. Sharp P. F., Smith F. W., Gemell H. G., Lyall D., Evans N. T. S.. Gvozdanovic E. D.. Davidson J.. Tvrell D. A.. Pickett R. D. and Neirinckx’ R. D. (1986) Technetium: 99m HM-PA0 stereoisomers as potential agents for imaging regional cerebral blood Row: human volunteer studies. J. Nucl. Med. 27, 171-177. Sisson J. C., Wieland D. M. and Johnson J. W. (1988) Scintigraphy of beta receptors in the heart. Circulation 78, 349. Sisson J. C., Shapiro B., Beyers L. ef al. (1987) Metaiodobenzyl guanidine to map scintigraphically the adrenergic nervous system in man. J. Nucl. Med. 28, 1625-1636. Som P., Oster Z. H., Zamora P. 0. et al. (1986) Radioimmunoimaging of experimental thrombi in dogs using technetium-99m labeled monoclonal antibody fragments reactive with human platelets. J. Nucl. Med. 27, 1315-1320. Sporn V., Perez-Balino N., Holman B. L. et al. (1986) Myocardial imaging with Tc-99m CPI: initial experience in the human. J. Nucl. Med. 27, 878 (Abstr.). Thonoor C. M. and Berridge M. S. (1988) In uivo biodistribution and competitive binding of I-125 iodocyanopindolol. J. Nucl. Med. 27, 971 (Abstr.). Trechen E. N., Francesconi L. C., Gougoutas J. Z., Malley M. F. and Nunn A. D. (1989) Monocapped trisdioxime complexes of technetium(II1): synthesis and structural characterization of TcX(dioxime), B-R (X = Cl, Br; Dioxime = dimethyl glyoxime cyclohexane dionedioxime; R = CH,, C,H,). Inorg. Chem. 28, 3411-3416.

Trechen E. N., Gougoutas J., Malley M., Nunn A. D. and Unger S. E. (1986) New technetium radiopharmaceutitalc boronic adducts of vicinal dioxime complexes. J. Lubelled Compd. Radiopharm. 23, 118-120. Troutner D. E.. Volkert W. A.. Hoffmann T. J. and Holmes R. A. (1984) A neutral lipolipophilic complex of %Tc with a multidentate amine oxime. Znr. J. Appl. Radial. Isot. 35, 467-470. Troutner D. E., Simon J., Ketring A. R., Volkert W. and Holmes R. A. (1980) Complexing of Tc-99m with cyclam: concise communication. J. Nucl. Med. 21, 443-448. Ugolini V., Hansen C. L., Kulkarni P. V. et al. (1988) Abnormal fatty acid metabolism in dilated cardiomyopathy detected by iodine-123 phenylpentadecanoic acid and tomographic imaging. Am. J. Cardiol. 62, 923-928. Vallabhajosula S. and Goldsmith S. J. (1990) 99mTc-low density lipoproteins: intracellularly trapped radiotracers for noninvasive imaging of low density lipoprotein metabolism “in viva”. Semin. Nucl. Med. 20, 68-79. Volkert W. A., Hoffmann T. J., Seger R. M., Troutner D. E. and Holmes R. A. (1984) 99mTc-propylene amine oxime p”Tc-PnAO); a potential brain radiopharmaceutical. Eur. J. Nucl. Med. 9, 511-516. Wieland D. M., Wu J. I., Brown L. E. et al. (1980) Radiolabeled adrenergic neuron-blocking agents. Adrenomedullary imaging with [I-131]iodobenxylguanidine. J. Nucl. Med. 21, 349-355. Wilson A. A., Dannals R. F., Ravert H. T., Frost J. J. and Wagner H. N. Jr (1989) Synthesis and biological evaluation of [1Z31]-4-iododexetimide, a potential muscarinic cholinergic receptor antagonist. J. Med. Chem. 32, 1057-1062. Winchell H. S., Horst W. D., Braun L., Oldendorf W. H., Hattner R. and Parker H. (1980) N-Isopropyl-(1Z31)-piodoamphetamine: single pass uptake and washout, binding to brain synaptosomes, and localization in dog and monkey brain. J. Nucl. Med. 21, 947-952.