708 36 3 786 - R- 24,011 REVIEW OOCUMENT NO REMARKS to523 t 8 REQUEST FOR DECLASSIFICATION AND/OR RELEASE (Allow 3 - 5 Days For Clearance) c 34,c 11 2. TITLE: (Show in full unless classified) Mu Mvocardfil -ts: Stabl'i- of a rlp - Fatty Acids 3. AUTHOR: (List All Authors; if not an ORNL employee, indicate address on a separate line) FF ~napp,Jr., GbJ Kabilka, PM bdman, KAR Sastry, AP Callahan, LA Ferren 4. PURPOSE: DO NOT ABBREVIATE Titles of Meetings, Journals, Universities (a) Oral Presentation (Give name, place, andexact dates of meeting) ~~ To be published in program, booklet, brochure, etc. a Yes 0 No a Not Known ,, Copies of this document will be distributed a before, 0 after, c] during the meeting, or 0 no distribution will be made. (b) Publication (Proceedings of a meeting, give place and dates; Journal, give publication date; Book, give- editor and publisher) )' Thesis (Give University, place, degree) t IX)PytllGHT DLcCl.AlM'EB . 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Loboratory Rocordr Dept. - Reprints tBCN-87A MEW MYOCARDIAL IMAGING AGENTS: ST46ILIZATION OF RADIOIODINE AS A TERMINAL VINYL IOOIOE t4lIETY ON TELLURIUM FP.TTY ACIOS F. F. Knapp, Jr.*, M. M. Goodman, 4. P. Callahan and L. A. Ferren Nuclear Meaizine Grogp, Health and Safety Research Division, Oak Ri 652 Nsti onal Laboratory, Oak Ri dge, Tennessee 37530, and G. W. Kabalka and K. A. R. Sastry Chgrni stry Department, University of Tennessee, Knoxville, Tennessee 37916. *For reprints contact: F. F. Knapp, Jr., Nuclear Medicine Group, Heal th and Safety Research Di vi sion, Bui 1 di ng 3047, Oak Ri dge National Laboratary, Oak Ridge, TN 37830. Research sponsored by the Office of Health and Environmental Research, U.S. Departmat 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 re:ain a nonexclusive, royalty-free license in and to any copyright 1052320 covering the article. 1 AB STRACT To determine the myocardial uptake and retention properties of radioiodinated tellurium fatty acids, two new tellurium fatty acids in which iodini-125 has been chemically stabilized by attachment as a trms vinyl iodide ( I-CH=CH-R-Te-R'-CGOH) have been prepared and evaluated in rats. Fabrication of 13-iodo-13-te11ura-17-octadecenoic acid was accomplished by coup1 ing 1,5- di i odo-l-pentene with sodi urn 12-methoxycarbonyl -n-dodecan-l-yl tell uride. The 1,5-[ 12511di iodo-l-pmtene was prepared by an organoborane technique involving 1251+ treatment of 5-i odo-l-penten-l-yl boronic aci d [I- (CH2 ) 3 -CH=CH-B(OH 123. The 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). Only marginal in vivo deiodination occurred since the thyroid uptake was low (15-182 dose/g after 60 min). The effect of tellurium in position-13 was unexpected. To determine if the lovr heart specificity and low heart:blood ratios were dependent upon the position of tbe tellurium, an analog with the same chain length, 18-[L251]iodo- 7-tell~ra-17-octadec~~oicacid, was prepared in the same manner by reaction of 1,ll-[ 25Z]di i;do-l-undecene with sodium 6-methoxycarbonyl -n-hexan-l-yl telluride. This agent showed pronounced heart uptake (2.47-3.94 Idose/g after 63 nin) and Fxlonged retention (1.76-3.14% dose/g after 4 h) in rats. Furthermore, the heart:blood ratios remained high for several hours (13:l after 60 min; 9:l after 4 h). Iodine-123 labeled 18-iodo-7-tellura-17-octadecenoic acid is an attractive new compound for evaluation as a myocardial imaging agent. I05232 I 2 INTRODUCTION Radioiodinated long-chain fatty acids are important agents for the clinical evaluation of regional myocardial perfusion and fatty acid metabolism. 1 Iodine-123-1 abeled 16-iodoheptadecanoic acid has been widely used as a myocardial imaging and 16-[12311iodo-9-hexadecenoic aci d6'7 and 16-[ 1231]iodohexadecanoic acid8-' have also been used for clinical studies (Fig. 1). The significant in vivo deiodination of these agents results in re1 atively rapid 1 oss of radioactivity from tlte myocardium with accumulation of radioiodide in the thyroid and blood. Radioactivity in the blood pool interferes with the neasurement of myocardial fatty acid uptake so a correction method is required to account for blood levels of free radioiodide. 3-5 To overcome the problem of radioiodi de loss, iodine has been chemically stabil ized by attachment to the para-position of the phenyl ring of 15-phenylpenta- decanoic aci d.lo-l2 Ti ssue distribution studies in mice with 154p-[ 231]- iodophenyl Ipentadecanoic acid have shown that this agent is stable to facile in vivo deiodinaticn and shows moderate myocardial washout. 12y13 This agent has 14 also be2n used in hunans. 1 - 16CH2 - iCH2)5 - CH = CH - ICH2)7 - COOH 16 - IODO - 9 - HEXADECENOIC ACID I - 17CH2 - ICH,),, - COOH 17 - IODOHEPTADECANOICACID Io '5CW2 - iCH,) I - COOH 15 - ip1ODOPHENYL) PENTADECANOIC ACID H3C - (CH217 - Te - ICH,), - COOH 9 - TELLURAHEPTADECANOIC ACID 19 - THDA) I - CH2 - ICHz)I - Te - ICH2)7 - COOH 17 - IODO - 9 - TELLURAHEPTADECANOIC ACID Fig. 1. Structures of iodinated long-chain fatty aci ds. 1052322 3 A different strategy that has been studied involves the introduction of the tellurium heteroatom in the fatty acid to inhibit B-oxidation and "trap" the fatty acid in the r;iyocardium.15 Tellurium-123m labeled 9-telluraheptadecanoic 15-17 and acid (9-THDA) shows rapid and pronounced myocardial uptake in rats dogs. '*-19 The unique properties of 9-THDA and similar tellurium fatty acids are the prolonged myocardial retention and high heart:blood ratios. To take advantage of the more attractive radionuclidic properties of the iodine-123 radioisotope (13.3 h half-life) in comparison to tellurium-123m (119 d half-life), the dwelopment of radioiodinated fatty acids containing stable tell urium to inhibit inetabol ism has been explored. Evaluation in rats indicated that the WrJcardial uptake of 17-[13111iodo-9-tel luraheptadecanoic acid (17-[13111iodo-9-THDA) is accompanied by significant in vivu deiodination." A cornparison of the heart uptake and deiodination of 17-[1311]- iodo-3-THDA and 16-[13111iodopalmitic acid has demonstrated a close similarity in blood levels of radioactivity and thyroid uptake of radioiodide after administration of these agents to rats. To overcone th2 problem of facile deiodination of the radioiodinated 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 boronic acids using iodine mnochl~ride~~'~~or via the in situ oxidation of I- with chl orami ne-TZ5 has been reported. The goal s of the present investigation were to develop a synthesis of vinyl iodide-substituted tellurium fatty acids and to evaluate the biodistribution properties of the iodine-125-labeled agents in rats. 1052323 4 RESULTS AND DISCUSSION The initial synthetic approach involved fabrication of the intact acetylenic tellurium fatty acid substrate, mthyl 13-tellura-17-octadecynoate (6; Scheme I). Commercially avail ab1 e 5-chl oro-1-pentyne (1) was converted to 5-iodo-1-pentyne (2) by treatment with NaI in ref1 uxi ng 2-butanone. The 6,7-di telluradodeca- 1,ll-diyne (3) was prepared by treatment of (2) with sodium ditelluride (NazTee) CI - (CH2)3 - C CH (1) 1 Nal DMF Te + NaH -NaZTe2 + I - (CH2l3 - C 3 CH _C (2) HC C - (CH2)3 - Te - Te - (CH2)3 - C E CH HC H C - (CHZ)3 - Te - Na + Br - (CHI), - COOMe (4) 1 (5) HC C - (CH2)3 -le - iCH2), , - COOMe (6) 1. CATECHOLBORANE 1 2. IODINE MONOCHLORIDE (I-CI) I I I ‘C = CH - (CH2)3 - Te - (CH2)1, - COOMe H‘ I CI Scheme I generated by Nay reduction of tellurium metal in DMF. ~n s ?U NaBH4 reduction of the 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) to give methyl 13-tellura-17-octadecynoate (6) in 35% yield after purification by silicic acid column chromatography. Reaction of (6) with catecholborane followed by 5 treatment with I-C1 gave an intractable product which appeared to contain a major component in which the I-C1 had added to the tellurium to form a tel luronium product (7). Although the halogens could probably be subsequently removed using a mild reducing agent [Te(IV) -f Te(II)], a more convenient route was pursued in which the iodovinyl moiety was introduced prior to fabrication of the tellurium fatty acid chain.