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( A l l o w 3 - 5 Days For Clearance) c 34,c 1 1 2. TITLE: (Show in full unless classified) 3. AUTHOR: (List All Authors; i f not an ORNL employee, indicate address on a separate line) 4. PURPOSE: DO NOT ABBREVIATE Titles of Meetings, Journals, Universities (a) Oral Presentation (Give name, place, andexact dates of meeting) To b e published in program, booklet, brochure, etc. a Yes Copies of this document will be distributed a before, 0 after, c] during the meeting, or 0 no distribution will be made. 0 No a Not Known , , (b) Publication (Proceedings of a meeting, give place and dates; Journal, give publication date; Book, give editor and publisher) . T o beissued as a report 0 No 0 Yes (Number) To be condensed and published i n open literature 0 No 0 Yes (Where?) 5. INVENTIONS: ( L i s t Page No. of any item appearing to have significant novelty; indicate i f none.) 6. PREVlOUSLY CLEARED DOCUMENT: (Paper, abstract, progress report, etc., containing similar information; indicate if classified.) Yes 0 No - Determined by . Project Director Program Director Division 01 Progrom Director Date .' Classification Officer Date a Associato Laboratory Director Date Patent Distribution of Form 1. Clos si fico tion Office File 2. Pocont Offico File 4. Approved, Roturn to Division Offico 5. Loboratory Rocordr Dept. - Reprints Distribution of Documents 1. Classification Offico File 2. Potont Office File (if requcrtodl 3. DOE - TIC ( i f speech) 6, Public Informotion Office 8. Suspense Copy - Division File . 7. DOE - Technical Informotion Center
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MEW MYOCARDIAL IMAGING AGENTS: ST46ILIZATION OF RADIOIODINE A S A TERMINAL VINYL IOOIOE t4lIETY ON TELLURIUM FP.TTY ACIOS Nuclear Meaizine Grogp, Health and Safety Research Division, Oak R i 652 Nsti onal Laboratory, Oak R i dge, Tennessee 37530, Chgrni stry Department, University of Tennessee, Heal t h and Safety Research Di visi on, Bui1 di ng 3047, Oak R i dge National Labor at ary, Oak Ridge, TN 37830. Research sponsored by the Office of Health and Environmental Research, U.S. Depart mat of Energy under contract W-7405-eng-26 with the Union Carbide Corporation, and supported in part by USPHS grant HL-27012. By acceptance of this article. the publisher or recipient ac know1edges the US. Government’s right IO license i n and t o any copyright covering the article.
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To determine t h e myocardial uptake and retention properties of radio i odin a ted tellurium fatty acids, two new tellurium fatty acids i n which i odin i - 125 has been chemically stabilized by attachment asa trms vinyl iodide o f 13-iodo-13-te11ura-17-octadecenoic acid was accomplished by coup1 ing 1,5The a5solute heart uptake of this agent was moderate (1.47-2.52 % dose/g after 60 min)but the heart : blood ratios were low (-2.6:l). dei odi nation occurred since the thyroid uptake was low (15-182 dose/g after 60 min). To determine i f the lovr heart specificity and low heart : blood ratios were dependent upon the position of t be tellurium, an analog with the same chain length, 18-[L251]iodo7 - tell ~ r a - 1 7 - oct a dec ~ ~ o i ca cid, was prepared i n the same manner by reaction of 63 nin) and Fx longed retention (1.76-3.14% dose/g after4h)in rats. Furthermore, the heart : blood ratios remained high for several hours (13:l after acid is an attractive new compound for evaluation as a myocardial imaging agent. Only marginal in vivo The effect of tellurium i n position-13 was unexpected. This agent showed pronounced heart uptake (2.47-3.94 Idose/g after
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Radio i odin a ted long-chain fatty acids are important agents for the clinical evaluation of regional myocardial perfusion and fatty acid metabolism. Iodine-123-1 a be led 16-iodoheptadecanoic acid has been widely used as a 16-[ 1231]iodohexadecanoic acid8-' have also been used for clinical studies (Fig. 1). The significant in vivo dei odi nation of these agents results i n re1 at iv ely rapid 1oss of radioactivity from tlte myocardium with accumulation of radio iodide in the thyroid and blood. interferes with the neasurement of myocardial fatty acid uptake so a correction method is required to account for blood levels o f free radio iodide. 3-5 To overcome the problem of radio i odi de loss, iodine has been chemically stabil ized by attachment t o the para - position of the phenyl ring of 15-phenylpentaiodophenyl Ipentadecanoic acid have shown that this agent is stable to facile in vivo dei odin a tic n and shows moderate myocardial washout. 12y13 This agent has also be2n used i n hunans. Radioactivity in the blood pool 9 - TELLURAHEPTADECANOIC ACID 19 - THDA) Fig. 1. Structures of i odin a ted long-chain fatty aci ds.
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A different strategy that has been studied involves the introduction of the tellurium heteroatom i n the fatty acid to inhibit B-oxidation and " trap " the acid (9-THDA) shows rapid and pronounced myocardial uptake in rats are the prolonged myocardial retention and high heart : blood ratios. To take advantage of the more attractive radio nucl i dic properties o f the dhalf - life), the dwelopment of radio i odin a ted fatty acids containing stable The unique properties of 9-THDA and similar tellurium fatty acids tellurium to inhibit inetabol ism has been explored. Evaluation in rats indicated that the WrJcardial uptake of 17-[13111iodo-9-tel lu ra hepta decano ic acid (17-[13111iodo-9-THDA) is accompanied by significant in vivu deiodination." A cornparison of the heart uptake and dei odi nation of 17-[1311]- iodo-3-THDA and 16-[13111iodopalmitic acid has demonstrated a close similarity i n blood levels of radioactivity and thyroid uptake of radio iodide after administration of these agents to rats. To overcone th2 problem of facile dei odi nation of the radio i odin a ted tellurium fatty acids, methods have now been evaluated to chemically stabilize the iodide on mdel compounds. The conversion of terminal trms-vinyl boronic acids to the corresponding vinyl iodides using I2 has been known for some More recently, formation of vinyl iodides from vinyl boron ic acids t o develop a synthesis of vinyl iodide - substituted tellurium fatty acids and t o evaluate the bio distribution properties of the iodine-125-labeled agents in The goal s of the present investigation were
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RESULTS AND DISCUSSION The initial synthetic approach involved fabrication of the intact acetyl eni c 1,ll - diyne (3) was prepared by treatment of (2) with sodium ditelluride (NazTee) The 6,7-di tell ura do dec a - 2. IODINE MONOCHLORIDE (I-CI)1. CATECHOLBORANE generated by Nay reduction of tellurium metal i n DMF. ~n s ?U NaBH4 reduction ofthe orange-col ored di tell uri de gave a col or1 ess sol ution of the tell uri de (41, which readily reacted with methyl 12-bromododecanoate (5) t o give methyl 13-tellura-17-octadecynoate (6)in 35% yield after purification by sil ici c acid column chromatography. Reaction of(6)with catecholborane followed by
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treatment with I-C1 gave an intractable product which appeared to contain a major component in which the I-C1 had added t o the tellurium t o form a tel luronium product(7). Although the halogens could probably be subsequently was pursued in which the iodovinyl moiety was introduced prior to fabrication of the tellurium fatty acid chain. In the second approach (Scheme 111, the 5-iodo-1-pentyne (21 was treated with cat echo lb or a ne and the vinyl boron ic acid (8) obtained as a white crystal 1i ne sol id after hydrolysis. was susceptible t o nucl eophi 1 i c di spl acement, the vinyl i o d i de moiety was stab1 e under these reaction conditions. Our first successful synthesis of Treatment w i t h 1 4 1 smoothly converted the While the primary iodide of (9)
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18-iodo-13-tell ura-17-octadecenoi cacid (13) invol ved coup1 ingof excess (9) with the sodium salt (121, generated by the in situ NaBH4 reduction of the disodium salt of 13,14-ditellurahexacosane-1,26-dioate (11). (11) was prepared by NaOH hydrolysis of the bis-methyl ester (10). reaction product was crystallized from pete th to give (13) i n 62% yield. this route worked well on a large - scale (2-5 mol 1, an a1 ternate method was required for the mi cro-scal e synthesis of the rad! ol a be led fatty acids. The disodium salt In this route (Scheme III), methyl 18-iodo-13-te11ura-17-octadecenoate (15) was prepared first, and purified by column chromatography prior to basic hydrolysis to the free acid (13). The 1,5-diiodo-l-pentene (9) was coupled with
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the sodium salt (14), generated by NaBH4 reduction o f dimethyl-13,14Subsequent basic hydrolysis then gave 18-iodo-13-tel luraThe trm-8 stereochemistry of the vinyl iodide moiety i n these compounds was readily establ i shed by proton nuclear magnetic resonance the 01 ef i ni c protons exhibited the expected characteri stic trans ABX2 coup1 i ng 18-iodo-13-tel lura-17-octadecenoic acid (13) illustrates the characteristic p r o t o n HA is located as a doublet (J = 14.42 Hz) a t 1210 Hz, with the components broad med by 4JHH. The olefinic HB proton is located as a doublet of triplets expected 1:2:2:2:1 intensity pattern i s observed for this multiplet. The chemical shift values and coupling constants (J)for The expanded 1100-1500 Hz region o f the NMR spectrum of Iodine-125-labeled (13) was prepared in the same manner using 1251+f o r substftution of the boronic acid. Tissue distribution studies i n female Fischer rats dm on st rated modest myocardial uptake (Table 1) but the heart:blood ratios were low. The low blood levels and marginal thyroid uptake, however, demonstrated that this agent i s stable t o in vivo deiodination. the vinyl iodide moiety is thus an effective method o f stabilizing the radioiodide in th2 tellurium fatty acid. T h e decreased heart uptake and low heart:bl ood ratios i n comparison to 9-telluraheptadecanoic acid were unexpected. To deternine the fate of the tellurium i n comparison t o the radioiodide, Evaluation of [123Tel-labeled (13) i n rzts gave similar results The moderate myocardi a1 uptake and 1ow heart: b l ood ratios were unexpected since 18-iodo-13-tell ura-17-octadecenoi c acid (13) has a total chain length
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nuclear mg ne tic resonance spectrum o f 18-iodo-13-te11ura-17-octadecenoic acid, demonstrating the characteristic ABXz coup1 i ng pattern of the terminal vinyl iodide mjety: The small peak a t 1232 Hz i s from an unknown impurity. (Cl,) w5ich i s optimal for efficient extraction by the myocardium. These Expanded llc)0-1500 Hz frequency region of the 200 MHz proton results could indicate that tellurium ‘in position-13 exhibits some special effect that decreases the myocardial specificity of (13). Earlier studies, however, have demonstrated that heart uptake in rats was similar with telluraheptadecznoic acid analogs with the tellurium heteroatom i n the 6-, 9-, and 11-positions. A second explanation for the low heart uptake observed with (13) could be the perturbation on heart uptake resulting from the introduction o f the
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Table 11. Distribution o f Radioactivity i n Tissues o f Fischer 344 Rats Time after injection Ti sstle 5 min 30 min 60 min Four r a t s were used for each time period. Each rat received -8.4 U C i of the lateral tail vein i n 6% bovine serum albumin solution (0.5 mL). Other tissues analyzed included the brain, intestines, pancreas and spleen. termi ;la1 trans-vi nyl iodide mi ety .Both these possi bi 1i t i es were rtudi ed by the syrrih2sis and evaluation o f an analog o f (13) having the same chain length with telllirilim i n s. different position of the chain. The 7-tell ura isomer o f 18-iodo-17-octadecenoic acid (24) was prepared as illustrated in Scaerne I V by the same method described earlier for the synthesis which was convertzd to the p-toluenesulfonyl (tosyl)ester by reaction with tosyl chloride. Sodium iodide treatment o f the tosyl ester then gavs (17). The boronic acid (18) was prepared by catechol borane addition across the acetylenic bond o f ( 1 7 ) followed by hydrolysis. of chloranine-T gave 1,ll-diiodo-l-undecene (19) i n 29% overall yield after Treatment of (18) with NaI i n the presence
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Couplicg o f (19) with the telluride (221, generated by in situ NaBH4 reduction of dimethyl-7,8-ditelluratetradecane-l,l4-dioate (211, t h e n gave (23) which was purified by sil ici c acid column chromatography. Basic hydrolysis and crystallization from pet eth gave 18-iodo-7-tellura-17-octadecenoic acid (24). The 18-~1251~iodo-7-tellura-17-octadecenoicacid was prepared by the same method using I'ia-[12511 to radio label the 1,ll-diiodo-1-undecene intermediate. Iodi ne-125-1 abel ed (24) was evaluated in female Fi scher rats and showed pronounced heart uptake (Table 111). prolonged myocardial retention. After 33 min, the heart uptake (1.47-3.45% dose / g ) had decreased only 20% from the peak levels detected 5min after This agent also showed the anticipated
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(1.76-3.14% dose/g) and decreased t o only 1.18% dose/g after 24 h. importantly, the low blood levels resulted in high heart:blood ratios for all the time periods studied: and 24 h , 5:l. The optimal properties of rapid and pronounced heart uptake, low tell ura-17-octadeceooic acid suggest this agent should be further evaluated as a new myocardi a1 agent. After 4 h, the heart uptake remained h i g h These results also demonstrate that tellurium i n position-13 must have some special effect in decreasing heart uptake, since both (13) and (24) have the same heteroatom in a series o f telluraheptadecanoic acid analogs did not effect heart uptake since the 6 ,9-, and 11-telluraheptadecanoic acid analogs all showed high heart uptake in rats.16 To determine further the effect of tellurium position on the myocardi a1 speci f i ci ty of this type of compound, 1 3 4 123mTe]- telluraheptadecanoic acid (13-THDA) was prepared and evaluated i n rats. To our surprise, this analog shows markedly decreased heart uptake and much lower Earlier studies had suggested that the position of the tellurium The inhibitory effect of tellurium i n position-13 was unexpected since studies described earlier had indicated that the position of the Te heteroatom did not a?p?ar to effect heart uptake of these agents i n rats and dogs, l6 In addition, the reduced myocardial uptake i n rats with th2 shorter chain 6- and 9-telluratridecanoic acid analogs, further suggested t h a t the total chain length was the critical structural feature that dictated myocardial specificity. More recently we have also observed that Te i n position-13 has the same effect on the heart uptake of terminal ?henyl tellurium f a t t y acids, While 15-phenyl-
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6-[ 123Te ] penta decano ic acid shows pronounced myocardial specificity and high shows reduced heart uptake and markedly increased blood lev ? ls,resulting in low heart : blood ratios. These results are si in i lar to the data reported here for The present studies have thus demonstrated that the terminal vinyl iodide moiety of s s lect ed tsilurium long-chain fatty acids is an …
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