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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

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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. In the second approach (Scheme 111, the 5-iodo-1-pentyne (21 was treated with catecholborane and the vinylboronic acid (8) obtained as a white crystal 1i ne sol id after hydrolysis. Treatment with 141 smoothly converted the boronic acid (8) to 1,5-diiodo-l-pentene (9). While the primary iodide of (9) was susceptible to nucl eophi 1 i c di spl acement, the vinyl iodi de moiety was stab1e under these reaction conditions. Our first successful synthesis of

HC C - (CH213 - CI (1)

Na - I I MeOOC - I - Te - Te - (CH2)Il - COOMc i 110) HC I C - !CH213 - I (2) 1 NaOH CATECHOLBORANE NaOOC - (CH211 - Te - Te - (CH211I - COONa

NaBH, \.- - i - H

I- ’. r

113) I

Scheme I1 3052325 6

18-iodo-13-tell ura-17-octadecenoi c acid (13) invol ved coup1 i ng of 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). The disodium salt (11) was prepared by NaOH hydrolysis of the bis-methyl ester (10). The crude reaction product was crystallized from pet eth to give (13) in 62% yield. While this route worked well on a large-scale (2-5 mol 1, an a1 ternate method was required for the mi cro-scal e synthesi s of the rad! ol abeled fatty acids. 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

MeOOC - (CH,), - Te - Te - (CH2),, - COOMe (10)

NaBH,

Na - Te - (CH2),, - COOMeI (14)

'\ 7 = CH - (CHZl3 Te - (CH,), - COOMe / C - H (15)

NaOH

I \ C = CH - (CH,), - Te - (CHpll, - COOH H / I (13)

Scheme 111 7 the sodium salt (14), generated by NaBH4 reduction of dimethyl-13,14- ditellurahexacosan-l,26-dioate (10) to give methyl 18-iodo-13tellura-17- octadecenoate (15). Subsequent basic hydrolysis then gave 18-iodo-13-tel lura- 17-octadecenoic acid (13). The trm-8 stereochemistry of the vinyl iodide moiety i n these compounds was readily establ i shed by proton nuclear magnetic resonance spectrometry (NMR). The chemical shift values and coupling constants (J) for the 01 ef i ni c protons exhibited the expected characteri sti c trans ABX2 coup1 i ng pattern. The expanded 1100-1500 Hz region of the NMR spectrum of 18-iodo-13-tel lura-17-octadecenoic acid (13) illustrates the characteristic ABX2 two proton vinyl iodide coupling pattern (Figure 2). The terminal vinyl proton HA is located as a doublet (J = 14.42 Hz) at 1210 Hz, with the components broadmed by 4JHH. The olefinic HB proton is located as a doublet of triplets centered at 1802 Hz, with JDoublet = 14.4 Hz and JTriplet = 7.2 Hz. The expected 1:2:2:2:1 intensity pattern is observed for this multiplet. Iodine-125-labeled (13) was prepared in the same manner using 1251+for substftution of the boronic acid. Tissue distribution studies in female Fischer

rats dmonstrated 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 is stable to in vivo deiodination. Introduction cf the vinyl iodide moiety is thus an effective method of stabilizing the

radioiodide in th2 tellurium fatty acid. The decreased heart uptake and low heart:bl ood ratios in comparison to 9-telluraheptadecanoic acid were unexpected.

To deternine the fate of the tellurium in comparison to the radioiodide, telluriuin-1239-1 abeled 18-iodo-13-te11ura-17-octadecanoic acid was a7 so synthesized. Evaluation of [123Tel-labeled (13) in rzts gave similar results to the [1251]-labeled analog (Table 11). The moderate myocardi a1 uptake and 1ow heart: bl ood ratios were unexpected since 18-iodo-13-tell ura-17-octadecenoi c acid (13) has a total chain length

1052321 8

J=7.2 Hz -1 I - J= (4.4 Hz

1 I I I I I I I I t 500 1450 1400 1350 4300 4250 4200 1450 tfoo FREOUENCY (Hz)

Fig. 2. Expanded llc)0-1500 Hz frequency region of the 200 MHz proton nuclear mgnetic resonance spectrum of 18-iodo-13-te11ura-17-octadecenoic acid, demonstrating the characteristic ABXz coup1 i ng pattern of the terminal vinyl iodide mjety: J(H,+g) = 14.4 Hz, trans coupling; J(HBHxz) = 7.2 Hz. The small peak at 1232 Hz is from an unknown impurity. (Cl,) w5ich is optimal for efficient extraction by the myocardium. These 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 tellura-

heptadecznoic acid analogs with the tellurium heteroatom in 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 of the

1052328 10

Table 11. Distribution of Radioactivity in Tissues of Fischer 344 Rats Following Intravenous Administration of 18-10do-l3-[~~~~eltellura-17- octadecenoic Acid ([123Te]-13)

Mean percent injected dose/gram ( range) Time after injection Ti sstle 5 min 30 min 60 min Heart 2.09 (1.93-2.37) 1.98 (1.79-2.17) 1.92 (1.85-2.00) B1 God 0.32 (0.29-0.34) 0.84 (0.79-0.90) 0.95 (0.83-1.03) Lungs 0.91 (6.67-1.13) 1.03 (0.96-1.10) 1.00 (0.94-1.04) Kidneys 1.46 (1.42-1.56) 1.73 (1.61-1.84) 1.85 (1.71-2.03) Liver 7.78 (7.18-8.03) 5.53 (5.33-5.74) 4.49 (4.03-4.84)

Four rats were used for each time period. Each rat received -8.4 UCi of the 123";ie-labeled fatty acid (sp. act. -20 mCi/rnmol) administered by injection in a lateral tail vein in 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 1 i ties were rtudi ed by the syrrih2sis and evaluation of an analog of (13) having the same chain length with telllirilim in s. different position of the chain. The 7-tell ura isomer of 18-iodo-17-octadecenoic acid (24) was prepared as illustrated in Scaerne IV by the same method described earlier for the synthesis of (13). ih? ll-iodo-l-undecyne (17) was prepared from commercially available 10-undecynoic acid (16). Reduction of (16) with LiAlH,, gave l-undecyn-11-01 which was convertzd to the p-toluenesulfonyl (tosyl) ester by reaction with

tosyl chloride. Sodium iodide treatment of the tosyl ester then gavs (17). The boronic acid (18) was prepared by catechol borane addition across the acetylenic bond of (17) followed by hydrolysis. Treatment of (18) with NaI in the presence of chloranine-T gave 1,ll-diiodo-l-undecene (19) in 29% overall yield after

purification. 1052330 9 h h - n - cu e- a3 c3 4 9 9 2 4 0 0 0 0 0 I I I I I W m I- I- I- 0 0 9 O 0 0 0 0 0 0 Y Y Y v v

Q, m co QI 0 0 2 9 0 0 0 0 0 0

- - n 0 m W a3 m Q W I-. Q,. 0 a 0 0 0 cu I I I I I d W Ln In d I- v) W. co a3 0 0 0 0 8-l Y Y Y Y Y co Ln 8-l m LD b W I- cn m 0 0 8-l -aJ 0 0 U c a h n n n L b 0 8-l m 4 Y 8-l a3 QI 4 I- .-1 0 0 8-l w 5 I I I I I L 05 cu Ln b m U Q W N m \ co aJ 0 0 0 0 8-l v) v Y Y Y Y 0 Q cr) a3 8-l W v) 0 W m Q, Q * QJ 4 0 0 0 cu c, V aJ '7 - h h h n C cu * I- m I- .r In I- 8-4 cu. LD w cu 0 4 4 Ln C I I I I I W I- 8-l 0 W I- V d W Q, 0 I- L . W 4 0 0 4 m P Y Y Y Y Y c 4 Q, cu Ln QI a m CD 0 8-l cr) Q, 5: d 0 d 4 d

h h h h L3 co W v) m a W Q,. 8-l Ln d 0 0 4 Ln I I I I I m a0 m In N N. Ln I- Q, 0 4 0 O 0 u) v Y U Y Y

cu 8-l Q, d (u LD. W m 0 m 4 0 0 d Ln

h h - h d a3 W m N rl Ln 4 0 (u 0 8-l 0 4 4 4 I I I I I co d I- m 0 (u. d. b. co m 8-l 0 0 0 I- Y Y v Y Y

W Ln (u ,-I 03 d 4 0,. 0 b 4 0 0 8-l m

v) c, Q v) 3 L L 0 07 c aJ tu 0 c -0 > aJ I-- =I -r .r I m J Y -J 11

HC 5 C - (CHZI8 - COOH OANL WS.20386 I161

2. TsOCl Na2Te2 + Br - ICH21S - COOMe HC C C - lCH21g - I 1171

CATECHOLBORANE

HO MeOOC - ICH2)5 - Te - Te - ICH2)5 - COOMe (21) 'C 'C = CH - ICH2)9 - I NaBHJ H ' 118) Na - I YLORAMtNE - i

I 1 'C = id - ICH2)9 - I + Na - Te - (CH2j5 COOMe / H /19) I 1221

Scheme IV Couplicg of (19) with the telluride (221, generated by in situ NaBH4 reduction of dimethyl-7,8-ditelluratetradecane-l,l4-dioate (211, then gave (23) which was purified by silicic 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 radiolabel 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). This agent also showed the anticipated prolonged myocardial retention. After 33 mi n, the heart uptake (1.47-3.45% dose/g) had decreased only 20% from the peak levels detected 5 min after

I05233 I 12 - n - d Q rn 0 N v) 0 cu 1 0 0 m I I 1 0 4 m c, cu d d V 6 0 0 cu v v Y c1 cu b Ln In cu. s b Y 0 0 cu u* .c h V-J - c h aE d b m m a3 '9 0 0 Ln I I I d 4 W cu '9 0 0 0 m v Y Y

b b 0 c". b d 0 0 d

n CI n W d =? N ul 0 0 0 v) I I I 0 d b N ? m 0 0 * v Y Y m co a0 N a3 b 0 0 d

c.5 - CI W W (u. 41 W 0 4 rz) I I I Q b b 4 b 4 0 0 * Y Y Y

N v) m N 0, m 0 0 v)

n CI - b 0 Q cu d v) 0 d f- I I I v) 0 0 4 W ul 0 0 cu Y v Y cu ul c3 cu co W 0 0 L3

- h n 0 b 0 cr) 4 Y 0 4 b I I I d 4 b cu ul b 0 0 m Y Y Y

W v) N 0 2 0 4 W

V) 5 -0 OE -0 0 0 c i=I -I- 13

injection (2.82-4.15% dose/g). After 4 h, the heart uptake remained high (1.76-3.14% dose/g) and decreased to only 1.18% dose/g after 24 h. More importantly, the low blood levels resulted in high heart:blood ratios for all the time periods studied: 5 min, 13~1;30 rnin, 13:l; 60 min, 13:1, 4 h, 12:1, and 24 h, 5:l. The optimal properties of rapid and pronounced heart uptake, low in LJ;~dei odi nati on and hi gh heart: 57 ood rati os exhibited by 18-i odo-7- tell ura-17-octadeceooic acid suggest this agent should be further evaluated as a new myocardi a1 agent. These results also demonstrate that tellurium in position-13 must have some special effect in decreasing heart uptake, since both (13) and (24) have the same chain length. Earlier studies had suggested that the position of the tellurium heteroatom in a series of 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, 134123mTe]- telluraheptadecanoic acid (13-THDA) was prepared and evaluated in rats. To our surprise, this analog shows markedly decreased heart uptake and much lower heart: 51 aod ratios t3an 9-THDA (Tab1 e IV ) . The inhibitory effect of tellurium in 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 in rats and dogs, l6 In

addition, the reduced myocardial uptake in rats with th2 shorter chain 6- and 9-telluratridecanoic acid analogs, further suggested that the total chain length was the critical structural feature that dictated myocardial specificity. 16 More recently we have also observed that Te in position-13 has the same effect on the heart uptake of terminal ?henyl tellurium fatty acids, While 15-phenyl-

1052333 14

6-[ 123Te]pentadecanoic acid shows pronounced myocardial specificity and high heart: blood ratios,26 the 15-phenyl-13-[123~e]tellurapentadecanoic acid analog shows reduced heart uptake and markedly increased blood lev?ls, resulting in low heart:blood ratios. These results are siinilar to the data reported here for 13-1: 123*Teltelluraheptadecanoic acid and 18-c’ 251]-iodo-13-tel lura-17-octadecenoi c aci d.

The present studies have thus demonstrated that the terminal vinyl iodide moiety of sslected tsilurium long-chain fatty acids is an effective method of stabilizing radioiodide to overcome facile -in vivo deiodination. The presence

Table IV. Distribution of Radioactivity in Tissues of Fischer 344 Rats Fol1owing Intravenous Admi ni stration of 13-1: 23iTe]tel1 uraheptadecanoic Acid (13-[ 23”FTe]-THDA)

Mean percent injected dose/gram (range) Time after injection

Ti SSUP 5 min 30 min 60 rnin Heart 1.06 (0.8901.23) 0.98 (0.93-1.05) 0.83 (0.73-0.97)

81 024 0.25 (0.21-0.30) 0.89 (0.78-1.05) 1.12 (0.97-1.26)

Lungs 1.27 (0.98-1.44) 1.40 (1.20-1.56) 1.49 (1.27-1.87) Kidneys 1.54 (1.41-1.66) 1.62 (1.48-1.93) 1.59 (1.49-1.75) Liver 8.26 (8.10-8.58) 5.71 (4.66-6.25) 6.01 (5.43-6.43)

Four rats were ilsed for each time period. Each rat received -6.8 uCi of the 123?z-laSeled fatty acid (sp. act. -20 mCi/mol) administered by injection in a lateral tail voin in 65 bovine serum albumin solution (0.5 mL). Other tissues analyzed included tie brain, intestines, pancreas and spleen.

of the vinyl iodide moiety is compatible with the pronounced myocardial uptake that has been reported previously with alkyl-substituted tellurium fatty

acid~.’~-l’ We have also stabilized radioiodide to in vim deiodination by I052334 15

attachment to the para-posi tion of a phenyl ringZ7 and radioiodinated 15-( p-iodophenyl)-6-tel lurapentadecanoic acid shows pronounced heart uptake in rats with little deiodination.28 Radioiodinated 18-iod0-7-tellura-17-octadecenoic acid is presently being evaluated in a canine model to determine the myocardi a1 uptake (extraction) under conditions of normal and reduced (ischemia) blood flow (myocardial perfusion). In addition, the distribution of this agent in relation to regional myocardial fatty acid metabolism is being evaluated.

Because of the attractive radionucl idic properties of the iodi ne-123 isotope for nuclear medicine inagi ng procedures, the iodi ne-123-1 abel ed vinyl iodide telltiriuin fatty acid is an attractive agent for evaluation. The rost desirable route for introducing the radioiodide woilld be at a final stage of the synthesis and attempts to prepare (24) by such methods are now being pursued.

EXPERIMENTAL SECTION

All salvents and chemicals were analytical grade and were used without further purificatim. The 123qemetal was produced by neutron bombardment of

enricned 122Te in th2 Oak Ridge High Flux Isotope Reactor (HFIR) and the

id a- [ 12 5 i j , Na-Ci2iII and C1251110dine Monochloride (I-Cl) were obtained from New England !luc:eat Corporation (North Billerica, MI). The silicic acid (acidic grade, 60-20C mesh) used for column chromatography was obtained from Sigma Chemical Co. (St. Louis, MO). The thin-layer chromatographic analysis (TLC) were performed ilsing 250-um thick layers of silica gel G PF-254 coated on glass plates (Analtech, Inc. 1 using the solvent systems indicated. The melting points were determined in capillary tubes using a Buchi SP apparatus and are

uncorrected. The infrared spectra (IR) were recorded on a Beckman 18-A spectro- photometer with NaCl plates or KBr pellets. The low resolution mass spectra

I052335 16

(MS) were recorded using a Kratos tils-25 low-resolution instrument under the f ol 1owing condi tions: ionizing energy, 70 eV; accel erati ng potenti a1 , 8000 V; trap current, 100 PA; probe temperature, 20r3-3OO0C. The proton nuclear magnetic resonance spectra (NMR) were obtained at 60 FNz with a Varian 360-L instrument or at 200 MHz with a Nicolet high resolution instrument. Samples (30-40 mg) were Ci ssolved in deuteriochloroform and the resonances are reported in parts per million (pprn) d9wnfield (6 1 from the internal tetrarnethylsilane standard.

Animal Tissue Distribution ExPeriments. The tissue distribution studies were performed using 18-12 week old female Fischer 344 rats (170-200 9). The animals were allowed food and water ad libitum prior to and during the course of the experiment. The radioiodinated fatty acid was dissolved in 0.5 mL absoluts ethanol md added dropwise to a stirred solution of 6% bovine serum albumin at 4OOC. The final ethanol concentration was 10%. The solution was filtered through a 22 urn Millipore filter and injected via a lateral tail vein into ether anethestized animals. After the times indicated in Tables 1-4, the animals were killed by cervical fracture and blood samples obtained by cardiac puncture. The orgms were then removed, rinsed with saline solution and blotted dry to reqove residual blood. The organs were weighed and counted in a NaI autogamma comter {Packard Instruments). Samples of the injected radioactive

solutions were also assayed as a standard to calculate the '3 injected dose/g of tissue values. The thyroid glands wsre not weighed directly. The weight or' the thyroid glands was calculated in the usual manner by multiplying the animal weight by (7.5 mg/lOO 9). 29

Syntheses - General Coments. All reactions were performed in an argon atmosphere under red lights in dry, three-necked flasks. The reaction vessel 17 was fitted with a rubber septum and an argon purged addition funnel for the introduction of reactants and was equipped with a magnetic stirrer. Condensers were protected with a CaC12 drying tube and a slight positive argon atmosphere was maintained by an oil pressure-release valve.

Ditelluride Intermediates (10) and (21). The dimethyl-13,14-ditellurahexacosane-l,26-di oate (10) was prepared (Scheme I1 ) as described earl i erZo and exhi bi t2d the expected physical properties. The dimethyl -7,8-di tell ura- tetradxane-14-dioate (21) was prepared in the same manner (Scheme IV) by methyl -6-bromohexanoate (20) a1 kyl ation of Na2Te generated in aqueous solution by reduction of metallic Te with NaBHl, under an inert atmosphere.

5-Iodo-1-Pentyne (2). Commercial (K&K Laboratories, Inc. 1 5-chloro-1- pentyw (1; 10.25 g, 100 mol) was refluxed on a steam bath in 2-butanone (SO0 mL) with Na-I (45 g, 300 mnol). The majority (-550 mL) of the solvent was distilled, the mixture was cooled and diluted with pentane (100 mL). After

filtration, H20 (253 mL) was added and the mixture extracted with Et20 (250 mL).

The crganic layer iras dashed with H20 and dried over anhyd. HgSOb. The solvent to give 17 g (87%) of 5-iodo-1-pentyne; low resolution Ms, 100%) and .67 (M+-I, 88%); NMR (CDC13) -2.0 (m, 3H, 2H, -CH2-CH2CrCH)- and 3.30 (t, J=6 Hz, 2H, -CH2-I).-

E-1,5-Diiodo-l-pentene (9). The 5-iodo-1-pentyne (2; 14.6 g, 75 mnol ) was

treated under nitrogen with catecholborane (10.9 mi, 100 mole) at OOC. The mixture was heat2d at 60°C for 6 hrs, cooled and diluted with 500 mL of H20. After sti rri ng overni ght at room temperature, the flocculent white boronic aci d

(8) precipitate was filtered and washed thoroughly with H20 and then with

C6H6 (50 mL) to remove any catechol. After drying in 'LICZCIAO,13.5 g (75%) of 18

5-iodo-l-penten-l-yl boronic acid (8) was obtained as a tan solid, rnp 100-?02"C; low resolution MS, ions at m/z 240 (M', 39%), 113 (H+-I, 127,) and 69 (100%);

NMR (Acetone-D6) 2.05 (m, 4H, -CH2CH2CH=C 1, 3.10 (t, ZH, -CH2- I), 4.4 (s, -(OH)2 and H20), 5.30 (d, J = 16 Hz, 1 H, =CH-B(OH)2)- and -6.3 (doublet of triplets, 1 H, -CHzCH=CH-B(OH)z).- The boronic acid (8) was sensitive to both light and heat, but could be stored indefinitely in the freezer with minimal decomposition. Anal. (CSH1~021B)C, H, I.

The boronic ac'd (8; 2.4 g, 10 mol ) was dissolved in 10 nL of dry THF under a nitrogen atmosphere. The solution was cooled to -78°C and after the addition of 20 mL of 1 -M so:(i%ion of NaOAc (20 mol) in NeOH, 10 mL of a freshly prepared 1 -M methanol solution of I-C1 (10 mol) was added and tine solution stirred 5 nin at -73°C. After warvling to --1O"C, a saturated solution of Na2S2O3 was added to destroy the excess 141. The mixture was diluted with H20 and extracted with pentane. The organic layer was washed thoroughly with H20, dried over anhyd. MgSO,, sad the solvent removed in vacuo. The crude product was purified by chrcnatography on SiS2 by elution with pentane to give 1.28 g of E-1,S-diiodo- l-pentene (43%) as a clear oil; TLC Rf 0.36 (pet eth); 12 (NaC1) 660(m), 685(s), 945(vs), 1170Is), 1290(vs), 1230(vs), 1435(m), 1615(m), 2840(w), 2930(vs),

3050(~)cm-~;low rzsolution pils, ion at m/z 322 (id+, 49%); NMR (CDC13) 2.10 (m, 4H, -CH2CH2-CH=CHI), 3.10 (d, J = 6 Hz, 2H, -CHzI)- and complex coupling pattern at -5.8-6.8 (ABX2, ZH, I-CH=CH-CH2-;-- See Figure 2 and Discussion for coupling analysis). Anal. (CsHaI) C, H, I.

Methyl-18-Iodo-13-Tellura-17-0ctadecenoate (15). Dimethyl-13,14- ditellurahexacosane-l,Z6-dioate (10; 343 mg, 0.5 mol ) was reduced under argon (Scheme 111) in 20 mL of MeOH at room temperature by the addition of excess

NaBH4. After the addition of 1,5-diiodo-l-pentene (9; 354 mg, 1.1 mol) the

1052338 19

colorless mixture was stirred under argon for 30 min. Following dilution with H20, the product was extracted twice with Et20, the coinbined extracts washed twice with H20, dried over anhyd. Na2S04 and evaporated under argon to give a yellow-calored gum. Analysis by TLC (CsHs) indicated the presence of three products: Rf 0.74, excess 1,5-diodo-l-pen-tene (9); Rf 0.45, methyl-18-iodo- 13-tellura-17-octad~c~noate(15); and Rf 0.15, the ditelluride (10). The crude product was disso1v.d in -2 mL C6H6 and applied to a silicic acid column (1x20 cm) slurried in pet eth. Fractions (20 mL in volume) were collected as follows: 1+10, p2t eth; and ll+30, C6H6. Aliquots of each fraction were analyzed by TLC (Si02-G, C6F(,). Fractions 16-19 (Rf 0.45) were combined to give 130 mg (22%) of (15) as a lisht yellow oil; I2 (neat, NaC1) 945 (w), 1170(m), 1200(m), 1440(m), 1745(s), 28SO(s) and 2930(s) cm-l; low resolution MS, M+ at m/z 538 absent, ions present at m/z 410 (M+[130Tel, P-HI, 63%); NMR (CDC13) 2.34 (t, J

= 6 Hz, 2H, -CH2-C30CH3),- 2.64 (t, J = 6 Hz, 4H, -CH2-Te-CH2-),- - 3.67 (5, 3H, -COOCS3), and a comp?ex mltiptet at -5.85-6.85 (ZH, ABX2, I-CH=CH-CHz-, See -- -- Figure 2).

18-Igdo-13-Tel: ura-17-Octadecenoic Acid (13).

Method A. Froin Direct Synthesis of the Free Acid (Scheme 11). Dirnethyl-13,14-ditellurahexacosane-1,26-dioate (10; 340 mg, 0.5 mol 1 was refluxed under argon in 15 mL of EtOH containing 3 mL of 1N- NaOH for 1 h. After cooling to room temperature, a solution of 1,5-diiodo-l-pentene (9; 356 mg, 1.1 mmol 1 in 15 mL of THF was added to the orange-colored solution of the ditelluride (11). An aqueous solution of NaBH4 was added dropdse to the reaction mixture until a colorless solution was obtained. The mixture was stirred for 2 h under argon at raom temperature, diluted with H20 and washed three times with pet eth to remove the excess diiodopentene. After careful

1052339 20

acidification of the aqueous layer to pH 2-3 with 10% HESOL, at O'C, the cloudy mixture was extracted three times with Et2O. The combined organic extracts were washed thoroughly with H20, dried over anhyd. Na2S04 and the solvent removed under argon. The resulting light yellow-colored solid was boiled in pet eth. The solution was dxanted from a small amount of insoluble naterial. Crystallization at 0°C gave 300 rng (62%) of (131, mp 57-59°C. The product was hcnogeneous (Xf 0.26) upon TLC analysis (CHCI3-MeOH, 4:9) and exhibited the

292O(vs) crn-l; lei* resolution MS, Mi at m/z 524 not observed, ions detected at m/z 395 (M+[13*Te]-HI, 29%); high resolution :4S, Calcd. for C17H3102TeI: 397.1397; Found, 397.1403; NMR (CDCl 3, 200 MHz) 2.16 (m, 4H, -CH2-CH2-Te-CH2-CH2-),- - 2.36 (t, J = 6 Hz, 2H, -CHz-COOH),- 2.62 (m, 4H, -CHZ-Te-CHz)- - and -6.02-6.54 (ZH, ABX2, I-CH=CH-CHz-,-- See Figure 2). Anal. (C17H3102TeI) C, H, I.

Method 3. From "osic Hydrolysis of (15) (Scheme 111) The ester (15) was refluxed for 30 min under argon in 20 mL of EtOH containing 1 mL of !!i- !laOH. After cooling the reaction mixture was poured into H20, acidified to p'i! 2-3 with 1N- HC1 and the cloudy mixture extracted twice with Et20. The combined extracts were washed thoroughly with H20, dried over anhyd. Na2S04 and evaporated under argon to give a light-yellow solid.

crystallization frorn pet eth gave 62 mg of (13), mp 55-59°C; IR, NMR and TLC identical to properties of (13) prepared as described in :4et'nod A abovg.

1,ll-Diiodo-1-undecene (19) (Scheme IV) . Commercial 10-undxyn-1-oic acid (16; 18.2 g, 100 mol) was dissolved in it20 (100 mL) and rgduced to 10-undecyn-1-31 with LiAIHI, (3.8 g, 100 mol) by stirring at 0°C for 4 h (Scheme

1052340 21

IV). After the cautious addition of H20 (3.8 mL), 15% NaOH (3.8 mL) was added followed by H20 (7.6 mL) and the solution filtered through Celite. The organic layer was washed with H20 and the solvent evaporated to give crude l-undecyn-11-01. The product was purified by distillation to give 10.5 g (63%) of l-undecyn-11-01, NMR (CDC13) -1.3 (broad s, 14H, alkane), 1.93 (t, J = 2.5

Hz, lH, -HC = C-1, 2.13 (m, 2H, HC z C-CHz-1,- 2.50 (5, lH, OH)- and 3.56 (t, ZH, -CH2-0-- ) . The l-undecyn-11-01 (8.4 g, 50 mol) was dissolved in pyridine (50 mL) and the solution cooled t3 0°C and added slowly (30 min) to a pyridine solution (200 mL) containing tosyl chloride (19 g, 100 mol). The solution was left to stand at 10°C for 24 h, diiuted with H20 (200 mL) and extracted with Et20 (200 mL). The organic layer was washed with 10% HCl, then H20, dried over an'nyd. K2C03-Na2S04 and the solvent removed in uacuo to give the crude l-tosyloxy-10- undecyne; NMR (CDZ3) -1.3 (broad s, 14H, alkane), 1.90 (t, J = 2.5 HP, lH, -CH =- C-), 2.13 (m, ZH, HC I- C-CH2),- 2.43 (5, 3H, -CH3),- 3.93 (t, 2H, -CHz-O-)- and 7.46 (A2X2, 4H, aromatic). The tosylate (3.22 g, 10 mol) was refluxed in 100 mL of 2-butanone with Na-I (7.5 g, 50 mol) for 12 h. The 2-butanone was distilled off, the mixture cooled and diluted with pentane. The product was then filtered and washed with H20. Evaporation of the solvent gavg the product which was chromatographed on silicic acid (pet eth) to give 2.1 g (75%) of ll-iodo-l-undecyne (17); NHR (CDC13) 1.3 (s, broad, 14 H, alkane), 1.90 (t, J = 2.5 Hz, 1 H, -HC z C-), 2.13

(in, 2H, HC 3 -3-1, and 3.30 (t, 2H, -&-I). Anal. (C11H191), C, H. The ll-iodo-l-undecyne (2.78 9, 10 mol ) was treated with catecholborane (1.64 mL, 15 mol) at 0°C and then heated at 60°C for 6 h under nitrogen. After

the addition of H20 (100 mL), the mixture was stirred 18 h and the solid boronic

IO5234 E 22 acid (18) was filtered and washed thoroughly with cold H20 to give the product (2.61 g, 80%); low resolution E, m/z 324 (M+, 00%); NNR (acetone-D6) 1.3 (broad

S, 14H, alkane), 2.03 (m, 2H, HC=CHCHz),- 3.23 (t, 2H, -CH2-1),- 5.33 (d, J = 18 Hz, lH, -HC = -CH-B), 6.5 (m, lH, -HC=CHB)- and -6.5 (s, 2H, -(OH);?).- The boronic acid (18; 0.659. 2 mnol) was dissolved in THF-H2O (8 mL, l:l), cooled to O°C and treated with 2 mL of a 1 M Na-I solution (2 mnol ) and chloramine-T (0.91 g, 4 mmol) in 8 mL of the THF-H20 mixture. After 15 min the mixture was extracted with pet eth, the organic extract washed with H20, dried over anhyd. MgS04 and the solvent evaporated in vacuo. The product was chromatographed on Si02 by elution with pet eth to give 1,ll-diiodo-1-undecene (19; 620 mg, 76%); NMR

(CDC13) 1.26 (broad s, 14 H, -CH2's), 2.00 (m, 2H, HC=CH&), 3.16 (t, 2H,

-%I), 5.93 (d, J = 15 Hz, lH, -CH=CHI),- and 6.40 (m, lH, -CH=CHI);- Anal.

(CllH20I2) C, H-

Methyl -18-Iodo-7-Tel lura-17-Octadecenoate (23). This fatty acid methyl ester was prepared (Scheme IV) in the same manner as that described in detail for methyl-18-iodo-13-tellura-17-octadecenoate (13). An ethanolic solution (10 mL) of dimethyl-7,8-di telluratetradecane-l,14-dioaie (21; 150 mg, 0.3 mnol ) was reduced under argon at room temperature with excess NaBH, to a colorless solution of the sodium tellurol (22). Following the addition of 1,ll-diiodo- 1-undecene (19; 100 mg, 0.25 mol), the mixture was stirred at room temperature for 1 h and the product obtained in the usual manner. Purification by Si02 column chromatography gave methyl -18-iodo-7-tell ura-17-oc$adecenoate (23;

130 mg, 98%); TLC Rf 0.50 (C6Hs); IR (neat, NaC1) 950(w), 1170(m), 1203(m), 1430(m), 1745(s), 2850(s), and 2925(s) cm-'; low resolution MS, ions at m/z 528 ([M+[ 30Te], -lo%), 507 (Pc130Te]-Me0, 15%), 490 (M+[l 30Tel-48, 18%),and 411 (M+[130Tel-I, 30%); high resolution 6,Calcd. for ClaH3302Te (M+-I), 411.1547;

1052342 23

Found: 441.1541; NMR :D 13) 2.33 (t, J = 6 Hz, 2H, -CHZ-COOCH~),- 2.64 (t, J = 6

Hz, 4H, -CH3-Te-CH2-),- 2.68 (5, 3H, -COOCH3J and a complex pattern from

-5.85-6.80 (ZH, ABX2, I-CH=CH-CHz-).--

18-Iodo-7-Tellura-17-Octadecenoic Acid (24). The methyl ester (23; 75 mg,

0.14 mol ) was hydrolyzed in ethanol ic-KOH as described for (15) and the product crystal 1 ired from pet eth to give 18-iodo-7-tel lura-17-octadecenoic acid (24) as white micro-crystals (50 mg, 68%), mp 49-50°C, TLC, Rf 0.27 (4% MeOH-CHC13); IR (KBr) essentially identical to that described above for (13); low resolution Tils ions at m/z 524 (P.*['3'GTe], 12%) and 397 (M+C130TeI-I, 38%); high resolution

MS; Calcd. for C1+-i3:fI2Te(Mf-I), 397.1391; Found: 397.1387; NMR (C0Cl3, 60 HHz) 2.22 (t, J = 6 Hz, ZH, -CH2-COOH),- 2.60 (t, J = 6 Hz, 4H, -CH2-Te-CH2-),- - and a complex multiplet frm -5.84-6.75 (ZH, ABX2, I-CH=CH-CH2).-- Anal. (C17H3102TeI) C, H, I.

-18-?0do-l3-[~~~~Te]Tel Iura-17-Octadecenoic Acid ([123"Te]-13). Tellurium-123m (4.5 &i; 64 ng, '3.5 mol) was stirred in 3 mL of H20 at 80'C under argon. An argon-purged aqueous solution of NaBH4 was added until a clear, colorless solution was obtained. After cooling to room temperature a solution of 1,Sdiiodo- 1-pentene (9; 177 mg, 0.6 mol) and methyl-12-iodododecanoate (162 mg; 0.4 mol) in THF (35 nL) was added and the rnixtgre stirred at room temperature for 60 min. After dilcrtion with H20, the mixture was extracted with Et20, the organic layer washed well with water, dried over anhyd. Na2S04 and evaporated to dryness under argon. The crude product was chromatographed on a silicic acid column by elution with pet eth (1-10) and C6H6 (11-30). Aliquots of

each fraction were analyzed by TLC (SiO2-6, C6H6) and for radioactive content. Fractions 13-17 contai ned 423 vCi of methyl -18-i odo-13-[ 23"?TeItel1 ura-17- octadecenoic acid. The product showed a major radioactive component that 1052343 24

co-chromatographed with authenic (6) on TLC analysis (Rf 0.50; SiOz-G, C-,H6). The product was refluxed for 60 rnin under argon in EtOH (20 mL) containing 2 ml of 1N NaOH. The hydrolysis product was obtained as described for (6) to yield

245 VCi of 18-iodo-13-[123mTe]t~llura-17-octadecenoic acid ([l 23Te]-13).

5-[ 12511-1,5-Di iodo-l-pentene ([12511-9).

Method A. The boronic acid (8) was dissolved in dry THF (10 mL) under argon and the solution cooled to -78OC. After the addition of 2 mL of a 1M- methanolic solution of NaOAc (2 mol), 0.8 mol of [1251]-IC1 (20 mCi) in CC14 (2 mL) was ' added dropwise and the solution stirred for 10 min at -78OC. After warming to -3O"C, an aqueous solution of Na2S203 was added to decolorize the iodine monochl oride. The reaction mixture was diluted with H20, and extracted with pentane. The organic layer was washed four times with H20, dried over

Na2S01, and the solvent removed under argon. Analysis of the crude product by TLC (Si02-G; 5% EtCXc-pet eth) demonstrated the presence of a major radioactive product co-chromatographing with 1,s-diiodo-l-pentene (Rf 0.78) and two additional products, R,- 0.65, and Rf 0.60. The crude product was chromatqraphed on silicic acid by elution (20 mL fractions) with pet eth (1-20) and 5% Et20-pet eth (21-40). The homogeneous 5-[1251]-1,5-diiodo-1- pentene ([12sI]-9; 2.5 mCi) was eluted in fractions 8-13 (See Figure 3). Fractions 25-35 contained significant amounts (10.1 di) of an unknown

component. The 5-E' 23 11-9 showed a single radioactive component (98%) on thin-layer radiochromatographic analysis (Si02-G, pet eth) that co-chromatographed with a 1,5-di iodo-l-pentene standard (Rf 0.57).

I052344 25

Method 8.

A THF-H20 mixture (l:l, 2 mL) of the 5-iodo-1-penten-1-yl boronic acid (8;

23.9 mg, 0.1 mnol) was cooled to O°C. After the addition of 15 mg of Na-I, Na[1251] (2.5 mCi) was added. Chloramine-T (45 mg, 0.2 mnol) was added in 1 ml of the THF-H20 mixture and the solution stirred for 15 min. After dilution with Et20, the reaction mixture was washed with dilute NaHS03 (25 mL) and then H20

(3X). After drying over anhyd. Na2S04, the organic layer was evaporated under argon to give an oil that was chromatographed on Si02. Elution with pet eth (25 mL fractions) gave the [12511-9 in fractions 8-13 which were combined to give 3.32 mCi (37%).

18-[1251]Iodo-13-Tellura-17-0ctadecenoic Acid (C12511-13).

~~ ~ Method A. (Scheme 11) The ditelluride (11; 67.3 mg, 0.1 mnol) was dissolved in EtOH (5 mL) and refluxed under argon with 1N- NaOH (1 mL) for 1 h. The mixture was cooled and reduced with NaBH4 to a colorless solution of the sodium tellurol . The [1251]-9 (2.5 di, 0.1 mol) was combined with 41 mg of carrier 1,5-diodo-l-pentene

(0.23 mnol total in 5 ml of dry THF and added dropwise to the above tellurol solution. After stirring for 1 h at room temperature, the solution was poured

into H2O and washed with pet eth. The aqueous layer was acidified with 10%

H2SO4 and the product obtained as described for 13 to give 18-[1251]iodo-13- tel lura-17-octadecenoic acid.

Method 8. (Scheme 111) The ditelluride (10; 68 mg, 0.1 mol) was dissolved in 10 ml of EtOH and reduced under argon with NaBH4 with warning in a H20 bath. The colorless solution was cooled to room temperature and 5-[ 251]-1,5-di iodo-1-pentene 26

(9; 3.32 mCi; prepared as described in 8, above) addscl in EtOH. The mixture was stirred at room temperature for 1 h, diluted with H20 and extracted with Et20

(2X). The combined organic extracts were washed with H20 (3X), dried over anhyd. Na2SO4 and the solvent evaporated under argon. The oily product was

dissolved in C6H6 and applied to an Si02-8 column. Fractions 25 mL in voluine were eluted with Cgfl~. Fractions 3-6 were combined to give 1.5 nCi (55%) of methyl -18-C1251]iodo-13-tellura-17-octadecenoate (112511-15) TLC (CSH6), one radioactive spot (Ri 0.50) co-chromographing with authentic (11). Ethanolic- basic hydrolysis in the usual manner gave 18-[1251]iodo-13-tellura-17-octadecenoic acid ([12511-13).

11-[~~5I]-l,ll-Diiodo-l-undecene ([1251]-19). This 1251-labeled diiodoalkene was pre?ared as described in detail (Method B) for the synthesis of 5-[1251]- 1,5-diiodo-l-pentene ([12511-9). The ll-iodo-l-undecen-l-yl boronic acid (18, 324 mg, 0.1 mol) was dissolved in a mixture of THF-H20 (l:l, 3 mL) and cooled

to O'C. After t'ne addition of Na-[12511 (10 Ki) in H20 (15 mL) containing carrizr Na-I (15 ng), chloramine-T (45 mg, 0.2 mol) in 2 mL of the WF-H20 mixture vias added to the solution which was stirred at 0°C for 15 min. The product was obtained as usual, and purified by chromatography with pet eth on Si02 to give 2.69 mCi (27%) of [12511-9.

18-[ 1 251310do-7-Tel lura-17-Octadecenoic Acid [[ 2511-24). Methyl -18-[1251]iodo- 7-tell ur3-17-octadecenoate ([lZ5I]-23) was prepared as described for methyl- 18-[12511iodo-13-tzllura-17-octadecenoate ([12511-15); Method B, Scheme 111. After NaBH4 reduction of ditelluride (21; 75 mg, 0.3 mol) to a colorless solution of the tellurol (18) at room temperature, the ll-[1251~-l,ll-diiodo- l-undecene ([12511-19;2.69 nCi) was added in EtOH and the mixture stirred 1 h.

105234b 27

The product was worked-up in the usual manner as for [1251]-15 and chromatographed on Si02 to give 547 VCi of [1251]-23, homogeneous upon thin-layer radiochromatographic analysis, Rf 0.50 (C6Hs ). Basic hydrolysis in the usual manner gave 532 pCi (97%) of 18-~12511iodo-7-tellura-17-octadecenoic acid ([1251]-24) showing a single radioactive component on TLC, Rf 0.27 (4% MeOH-CHC13). The product was stored under argon in sealed amber break-sealed tubes at 0°C until fgriher use.

13-[ 123mlel-T21 luraheptadecanoic (134 23"TelTHDA). The 123mTe-labeled fatty acid was pripared by basic hydrolysis of the purified fatty acid methyl obtained by simul taneous butyl bromi de and methyl -12-bromododecanoate acid alkylation of Na2i12"el generated by NaBH4 reduction of 123mTe. The details of the chemical synthesis and properties of this tellgrium fatty acid will be report34 el sewhere.

1052341 ACKNOWLEDGEMENTS

Research sponsored by the Office of Health and Environmental Research, U.S. Department of Energy under contract W-7405-eng-25 with the Union Carbide Corporation and supported by USPHS grant HL-27012 from the National Institutes of Health. The authors also thank E. 8. Cunningham, K. R. Ambrose and D. L. Filer for performing some of the tissue distribution studies, and L. S. Ailey for typing the manuscript.

1052348 29

ELEMENTAL ANALYSES

Compound Calcd. Found 5-Iodo-i-penten-l-yl -boronic C, 24.92 25.02 acid (8) H, 4.33 4.20 C5Hl a02IB I, 53.09 52.91

C, 18.64 18.85 H, 2.51 2.66 I, 78.86 77.04

18-Iodo-13-tel lura-17- C, 39.09 39.18 octadecenoic acid (13) H, 5.99 6.07 I, 24.32 24.24

1l-Iodo-l-undecyne (17) C, 47.50 47.25 CllH19I H, 6.83 6.69

11-Io&-l-undecen-l-yl C, 40.80 40.72 boronic acid (18) H, 6.79 6.96 c 1 1H2 2WI

1,ll-Di iodo-l-undecene (19) C, 32.55 32.70 H, 4.93 4.97

18-Iodo-7-tell ura-17- C, 39.02 39.02 octadecenoic acid (24) H, 5.99 5.99 c 17H3 10ZTel I, 24.32 24.32

I052349 30

FIGURE LEGEND

Fig. 1. Structures of iodinated long-chain fatty acids.

Fig. 2. Expanded 1100-1500 Hz frequency region o the 200 .'Blz proton nuclear magnetic resonance spectrum of 18-iodo-13-tell ura-17-octadecenoic acid, demonstrating the characteri stic ABX2 coup1 i ng pattern of the terminal vinyl iodide moiety: J{YAHg) = 14.4 Hz, trans coupling; J(HBHx2) = 7.2 Hz. The small peak at 1232 Hz is from an unknown impurity. 31

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1. Knapp, F. F., Jr.; Goodman, M. M.; Elmaleh, 0. R.; Okada, R. D.; Strauss,

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