The Development of Radioiodinated Fatty Acids for Applications in Nuclear Cardiology

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THE DEVELOPMENT OF RADIOIODINATED FATTY ACIDS FOR APPLICATIONS IN NUCLEAR CARDIOLOGY Nuclear Medicine Group Health and Safety Research Division Oak Ridge National Laboratory Nucl ear Medi ci ne Divi si on and Cardiac Unit Department of Yedi ci ne Massachusetts General Hospital Research sponsored by the Office of Health and Environmental Research, U.S. Department of Energy under contract W-7405-eng-26 with the Union Carbide Corporation and supported in part by USPI-(S grant HL-27209 from the National Institutes of Health. B y acceptance of this artlcle. the I publisher or recipient acknowledges I license in and to any copyright 1 0 5 2 3 5 5 coverinp the article.

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Interest in the use of radioiodinated long-chain fatty acids for the clinical evaluation of heart disease arose as a result of the properties of the i odi ne-123 radi oi sotope and the potenti a1 for measurement o f regional f a t t y acid metabol ism with these agents (Thrall e t a1 , 1978). Because of the attractive radionucl i dic properties of iodi ne-123 (159 keV gamma photon, 13.2 h physical ha1 f - life), measurement of regional myocardial metabolism with these agents coul d represent an a1 ter native to perfusion studies with th all ium-201. increase in detection and image quality using the abundant 159 keV gamma photon of iodine-123 i s an important consideration. The development o f radioiodinated agents with optimal biological properties, which are discussed in detail later, and tie availability and cost of iodine-123 are important factors which have limited the use of these agents as a replacement for thallium-201. Ir! this paper the methods of synthesis and the evaluation o f radioiodinated long-chain fatty acids i n laboratory animals and the evaluation o f several of these agents i n patients are reviewed. Several of these agents, such as 17-[: 12311iodoheptadecanoic acid have been evaluated extensively i n humans. addition, the development of several interesting new agents that may have important appl icati ons for the eval uati on of heart disease are a1 so di scussed.

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The first radioiodinated long-chain fatty acid evaluated in both laboratory animals and humans was the [1311]-labeled product obtained by reaction of ~13111iodide-rnonochloride(I-C1) with oleic acid (Evans etal, 1965). This product presumably consisted of a mixture of the olefin ic addition products, (Figure 1). Myocardial uptake of this agent was demonstrated in dogs (Poe e t a l , 1975) and myocardial images were obtained of normal dogs and animals w i t h partial coronary occlusion (Evans e t a1 , 1965; Bonte e t a1 , 1973). This agent Figure 1. Structures of the first generation radioiodinated fatty acids. was also evaluated i n humans (Gunton etal, 1965) but further use was not pursued because of low myocardi a1 extraction. The myocardial extraction efficiency with this agent was presumably reduced because o f the structural perturbation introduced by the attachment of the vicinal halogens t o the fatty of oleic acid with1311 (Robinson etal, 1975; Beierwaltes etal, 19751, this A1 though several studies investigated details of the radiolabeling agent was n o t further evaluated. These early studies, however, demonstrated that radioiodinated fatty acids could be used to mnitor myocardial perfusion defects and set the stage for additional research i n this area.

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Because the myocardi a1 u p t a k e of the ol ei c aci d-i odi ne-monochl ori de product was lower t h a n expected, other radioiodi nation techniques were investigated. Attachment of the radioiodine t o the terminal position ofa long-chain fatty acid was initially investigated by Robinson and co-workers who prepared 16-iodo-9-hexadecenoic acid (11) by nucleophilic displacement of the terminal bromi de o f commerci a1 l y avai 1ab1 e 16-bromo-9-hexadecenoi cacid with sodium iodide (Poe e t a1 , 1975; Robinson e t a1 , 1976) This agent showed rapid, pronounced myocardial extraction in dogs (2oe etal, 1976) and detailed studies of the factors affecting yield and purification of the [12311-labeled agent were reported (Robinson, 1977; Hoogland e t a l , 1979). This agent was evaluated i n humans and proved t o be effective for estimating regional myocardial perfusion and for distinguishing viable ischemic myocardial tissue from necrotic Investigators at the Institute for Medicine in Juli ch, West Germany, prepared 17-iodoheptadecanoic acid (111) by nucleophilic substitution which i nvol vzd iodide di spl acement of bromide from 16-brornoheptadecanoic acid almost identical to that observed with C1lCI-palmitic acid, and extensive clinical studies with this agent have been reported (See Clinical Studies Section, Freundl iebet a1 , 1980; Feinendegen e t a1 , 1981). Due t o the similarity in size of the iodine atom and a methyl group,it is felt that the 17-iodoheptadecanoic acid (C17) mimics the naturally occurring C18 fatty acids such as stearic acid. The [12311-labeled agent showed myocardial extraction Other investigators have studied a variety o f methods of synthesis of (1111, including iodide displacement of bromide i n acetone, a melt method, a phase transfer catalyst technique and displacement of a terminal p-toluenesul fonyl

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group (Argentini etal, 1981). A series of terminally iodinated alkanoic acids labeled with iodine-125 varying i n chain length from 11 t o 27 carbon atoms have been prepared and evaluated i n rats (Otto et al, 1981). Researchers have found that the agents are primarily metabolized by 6-oxidation for chain lengths less than 15 carbon atoms, whi 1e the longer-chai n agents were mta boli zed by i ncorporation into triglycerides. Another method sui tab1 efor the synthesis of io do al kyl - substituted fatty rapid chemistry and high specific activity. Terminal alkenyl fatty acids are treated with dicyciohexyl borane t o provide the termi nal boronic acid intermediates which are relatively stable and can be stored indefinitely. substrates to the terminal io do fatty acids. This technique offers the advantages of high yields, I n order t o ovzrcome the significant ?:n v?:vo deiodination observed with radioiodinated long-chain f a t t y acids such as 16-iodo-9-hexadecenoic acid (11) and 17-iodoheptadecanoic aci d ( I 1 I 1, Machull a and co-workers prepared and agent, the iodine i s chemically stabilized by attachment t o the para position of the terminal phenyl ring. The rel at iv s isomer distribution obtained ina typical synthesis consisted of 29% of the meta isomer and 71% of the para isomer of 15-(iodophenyl Ipentadecanoic acid. This method t h u s requires This new agent was prepared by electrophilic iodination o f the phenyl

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subsequent high pressure liquid chromatographic purification of the pma-isomer. pronounced heart uptake in rats and very little dei odi nation demonstrating that the pea-iodophenyl moiety is an effective method of overcoming dei odi nation o f radi oi odi na ted fatty aci ds. A variety o f methods are available for introduction of radioiodine into the pctra-i odophenyl substituted long-chai n fatty aci d s (Tab1e I).The choice of an appropriate method for the synthesis of these radioiodinated fatty acids is generally based upon a number of important factors such as the regio specificity and the radiochemical and chemical yields. compatible with other functional groups that may be present i n the molecule (-COOH, -COOMe, etc.), and the substrate used for the radioiodination step radioiodide displacement o f bromide from a para-bromophenyl substrate is regio specific but has not been reported in detail (Eisenhut etal, 1981). Radi oi odi de di spl acenent of the bis - trif 1uoroacetyl thal 1i urn mi ety is a1 so applicable {Kulkarni etal, 1982) with the following limitations. th all ation of the phenyl ring does not give the para-isomers exclusively. Secondly, th2 b:s-trifluoroacetyl thallium intermediate will probably require fresh formation from the highly corrosive reagents and this may be beyond the scope of many clinical facilities. Thirdly, a minimum ofa 2:l iodide-substrate ratio is generally required, indicating that only a fraction of the radioiodide would be incorporated into the desired products. T h e iodination step must be The ha1 i de-exchange method invol ving The tri azene decomposition route is therefore the most attractive approach

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Table 1. Iodination methods that have been used t o prepare radioiodinated para - io do phenyl - substituted fatty acids. REGI OSPECI F IC FRESH SUBSTRATE REQUIRED; STRATE RATIO; SEPARATION RAPID, HIGH YIELD, EISENHUT. et al, 1981 MACHULLA, et al, 1980 for the synthesis of the para-iodophenyl fatty acids. This mt hod is regio specific and excess substrate can be used t o consume all of the radioiodide. The excess t riaz ene can then be readily removed by chromatography. The decomposition is rapid and can be performed a t the carrier - free level, although this i s generally not a major prerequisite for the radioiodinated fatty acids. One potential drawback of the method i s the sensitivity of yields of the decomposition product t o the structure of the t riaz ene intermediate. This sensitivity has been recently studied for a number of substrates (Goodman etal, 1982a and b ) and was found not t o be a major problem. regiospeci fi city of this method, the t riaz ene intermediates are generally very stable substances and can be prepared in large amounts and stored indefinitely. There are also two other attractive methods that may be useful for the introduction of radioiodine into the para position (Table 2). Iodide substitution (destannyl ati on) of the tri butyl tin mi e ty for the synthesi s of radio i odi nated iodotamoxi fen has been reported Tonnesen e t a1 , 1981). In addition t o the

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This method may also be applicable for regio specific introduction of radioiodide into the para position of the phenyl ring. phenyl boronic acid has been used t o prepare iodobenzene and this route may also be applicable for the synthesis of the iodophenyl fatty acids (Kabal ka e t a1 , Substitution with radioiodide o f A second method that has been investigated to chemically stabilize radio iodine on fatty acids to overcome the problem of i~ V ~ V Odeiodination involves direct attachment o f iodine t o an sp2 hybridized carbon atom as ina terminal vinyl io did z (I-CH=CH-) . Methods have been developed similar to the formation of alkyl iodides described above for the synthesis of vinyl iodides. These methods invol v e conversion o f terminal acetyl enes t o a1 kenyl -boronic acids boronic aci d s t o the correspondi ng vi nyl iodi des. The terminal substituted Treatment with I-C1 was shown t o smoothly convert the vinyl iodide fatty acid prepared by this route was o f medium chain length(Cll). I n this study the f3tty acid was not radioiodinated o r evaluated i n animals. Table 2. New i odi nation mt hods that may be useful for the synthesis o f radioiodi nated para-iodophenyl-substi tu ted fatty acids. BORONIC ACID SUBSTITUTION: BOTH METHODS ARE REGlOSPEClFlC AND HAVE EXPECTED HIGH YIELDS. PARA SUBSTITUTED SUBSTRATES, HOWEVER, ARE REQUIRED FOR SYNTHESIS OF THESE INTERMEDIATES TONNESEN, et al, KABALKA, et at,

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RADIOIODINATED FATTY ACIDS CONTAINING STRUCTURAL FX)DIFICATIONS TO INHIBIT METABOLISM One approach which has been extensively investigated as a means to retain radiolabeled fatty acids i n the myocardium involves the introduction ofthe divalent tellurium (Te) and selenium (Se) heteroatoms i n the fatty acid chain ( K n a p p , 1981). Tell uri um and sel eni urn can be readily incorporated whi 1e maintaining the linearity of the fatty acid molecule, and were envisioned as unique structural features that could possibly inhibit catabolism of the molecule and result in prolonged retention or "trapping" of the modified fatty acids i n the myocardium. several 75Se and 123zTe-labeled fatty acids have demonstrated that significant levels of radioactivity are retained i n the heart after intravenous administrauptake in rats (Knapp e t a1 , 1979). High quality myocardial images of normal The results of tissue distribution studies with dogs and dogs with partial coronary artery liga tion have been obtained with this agent (Elmaleh etal, 1981). The kinetics of tracer uptake in the normal and i schemi c dog myocardi um have a1 so been measured w i t h cadmium-tel 1uri de The effects of chain length and Te position on the heart uptake o f these agents i n rats has been investigated (Knapp etal, 1981). Several of the Te fatty acids such as 9-THDA exhibit a unique property of rapid, pronounced myocardial uptake followed by prolonged retention. In dogs, 70% of the peak activity extracted within a few minutes after intravenous injection is retained (Elmaleh etal, 1981). These results suggested that w-radiohalogenated fatty aci ds containing stab1 etell uri um may demonstrate si mi 1a r rapid uptake and After 5 d, 30% of the activity is retained prolonged retention in the myocardium and may represent attractive new agents

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9 - TELLURAHEPTADECANOIC ACID (9 - THDA) Figure 2. Structures of structurally modified fatty acids. for the measurement o f regional myocardial metabolism. More recently, tissue distribution and autoradiographic analyses have indicated that the alkyl (R) the myocardium 60 min after administration (Knapp etal, 1981). The alkyl region of 9-THDA would therefore aprJear t o be an attractive region t o introduce radi oi odi de.

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Iodoalkyl-substituted tellurium fatty acids such as 17-iodo-9-telluraheptadecanoic acid (VI) have been prepared by amute involving iodide Fischer r a t s were administered 17-[13111iodo-9-tel 1uraheptadecanoic acid (17- [ 1311]iodo-9-THDA) intravenously. A study of the distribution of radioactivity i n tissues indicated that the level of accumulation i n the myocardium i s not as high as observed with 9-[123Te]-THDA, but similar to that observed with reached a maximum at2min and remained constant t o 60 min. After 60 min, the HOURS AFTER INJECTION Figure 3. Comparison of the tissue distribution of radioactivity i n rat hearts after injection of 17-~13111iodo-9-telluraheptadecanoic acid and 16-[ Ili odopal mi tic aci d. heart t o liver ratio was 1.6:l and the heart t o lung ratio was 2.2:l. The heart t o blood ratio reached a maximum of 3 : lat 60 min. The accumulation of activity in the thyroi d gl ands conf irmed that si gni fi cant Cn vivo dei odi nation occurs with 17-iodo-9-tel luraheptadecanoic acid and 16-iodohexadecanoic acid.

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The tissue distribution of 17-iodo-9-[123~e]telluraheptadecanoic acid was also examined in rats (Goodman e t a1 , 1982b). The similarity of the magnitude o f myocardial uptake of radioactivity from 17-[l 311]iodo-9-THDA and 17-iodo9-[ 23Te]THDA suggested that si gni fi cant deiodi nation did not precede myocardial uptake. These results also indicated that the presence ofthe terminal iodide may be responsible for the decreased myocardial uptake i n very similar to that observed in rats with 16-[13111iodohexadecanoic acid T h e extensive iodide loss from 17-[1311]iodo-9-THDA was The myocardial uptake of 17-[13111iodo-9-THDA could therefore not HOURS AFTER INJECTION Figure 4. Comparison of the thyroid uptake of radioiodide i n female Fischer rats …