J.M e d .
Chem. 1984,27, 149-155
149
I [X = 3-(methoxycarbonyl)-l-naphthyl],87871-41-8; I (X = I (X = 3-CH20C6H4-3'-NHCOCHa), 79508-86-4; I (X = 33-CH$CBH6), 80239-83-4;I (X = 3-CHaC&-3'-CH3), 87739-85-3; CH~OCBH~-~'-NHCSNH~), 79508-87-5; I (X = 3-CH2OC6H4-3'I (X = 3-CH2SeC6HS),87739-79-5; I (X = 3-SCH2CBHS),87739"CONH2), 70579-43-0; I [X = ~-CH~OCBH~-~'-(CH~)~CH~], 83-1; I (X = 3-SCH2C6H4-4'-C1),87739-84-2; DHFR, 9002-03-3. 87739-81-9; 1[X = 3-(methoxycarbonyl)-2-naphthyl], 87871-40-7;
Adrenal Medulla Imaging Agents: A Structure-Distribution Relationship Study of Radiolabeled Aralkylguanidines' Donald M. Wieland,* Thomas J. Mangner, Muthiah N. Inbasekaran, Lawrence E. Brown, and Jiann-long Wut Division of Nuclear Medicine, T h e University of Michigan Medical Center, Ann Arbor, Michigan 48109 Received M a r c h 9, 1983
Fourteen 12SI-labeledaralkylguanidines were synthesized and evaluated as potential imaging agents for the adrenal medullae and tumors of adrenomedullary origin. These guanidines are radiotracer analogues of guanethidine, an antihypertensive agent thought to mediate neuron blockade by uptake into adrenergic nerves. Dog adrenal medullae were used as a model to test radiotracer affinity for catecholamine storage tissue. Tissue distribution studies revealed that a number of radioiodinated guanidines showed pronounced localization in the adrenal medullae following intravenous injection, in certain cases exceeding that of either (-)-[3H]norepinephrine or [14C]guanethidine. (m-[12SI]Iodobenzyl)guanidine(m-IBG, 2b) gave the best combination of high concentration and selectivity. The low adrenomedullary affinity observed with [I4C]guanidine and m-[12sI]iodobenzylaminedemonstrates the uniqueness of the aralkylguanidine structure. Preliminary evidence suggests that 2b is a storage analogue of norepinephrine. ['=I]2a is now being used clinically in imaging and radiotherapy of catecholamine tumors, such as pheochromocytoma.
An imaging agent for the adrenal medulla and its diseases has been actively pursued for more than a d e ~ a d e . ~ - l ~ Recent efforts in our laboratory to develop a clinically useful agent have focused on radioiodinated analogues of the antihypertensive drug guanethidine. This drug inhibits the release of norepinephrine from adrenergic nerve endings, as well as depletes neuronal stores of norepinephrine.14J5 Both of these effects involve the direct action of guanethidine on the adrenergic nerves.16 If the adrenal medulla is considered a specialized sympathetic ganglion," then compounds known to have an affinity for adrenergic nerves might be expected to localize in the adrenal medulla. Studies in dogs in the early 1960'5,however, showed that pharmacological doses of guanethidine, although rapidly depleting the heart and spleen of norepinephrine, had little effect on the catecholamine content of the adrenal medulla.l8Jg Nonetheless, our initial studies revealed that [14C]guanethidinehad a high affinity for the dog adrenal medulla. Although guanethidine is not readily labeled with a y-emitting radionuclide suitable for use in scintigraphy, pharmacologically active analogues such as benzylguanidines can be readily labeled by substitution of radioiodine on the aromatic ring. In the benzylguanidine series, Short and Darby20have shown that lipophilic aromatic substituents (e.g., CF3,Br, I) can, in certain cases, enhance neuron blocking potency. However, since pharmacological activity may not be the best correlate of adrenal medulla uptake, we report here a structure-distribution relationship (SDR) study of 14 lZ5I-labeled(iodoaralky1)guanidines and 3 [14C]guanidinesin dogs. This study focuses on the structural elements of aralkylguanidines necessary for maximum adrenomedullary uptake and retention. One of the most promising compounds, (m4odobenzyl)guanidine (m-IBG, 2a), when radiolabeled with y-emitting isotopes 1311 or 1231, has shown recent clinical success in imaging diseases of the adrenal medulla.21i22 Chemistry. At the outset of this investigation, attempts were made to synthesize the (iodoaralky1)guanidines by reaction of the appropriate amine with 2methyl-2-thiopseudouea ~ u l f a t e . ~It~was * ~ subsequently Present address: Medi-Physics, Emeryville, CA 94608. 0022-2623/84/1827-0149$01.50/0
found that reaction of the appropriate amine hydrochloride with molten cyanamide gave consistently higher yields of (1) A brief report of part of the present study has appeared: Wieland, D. M.; Brown, L. E.; Mangner, T . J.; et al. Proceedings of the 3rd International Symposium on Radiopharmaceutical Chemistry, J.Labelled Cmpd. Radiopharm. 1981,18,
122. (2) Morales, J. 0.; Beierwaltes, W. H.; Counsell, R. E.; et al. J. Nucl. Med. 1967, 8, 800. (3) Lieberman, L. M.; Beierwaltes, W. H.; Varma, V. M.; et al. J. Nucl. Med. 1969, 10, 93. (4) Anderson, B. G.; Beierwaltes, W. H.; Harrison, T . S.; et al. J. Nucl. Med. 1973, 14, 781. (5) Fowler, J. S.; Ansari, A. N.; Atkins, H. L.; et al. J. Nucl. Med. 1973, 14, 867. (6) ~, Fowler. J. S.: Wolf. A. P.: Christman. R. D.: et al. In
"Radiopharmaceuticals", Subramanian, G.; Rhodes, B. A.; Cooper, J. T., et al., Eds.; Society of Nuclear Medicine: New York, 1975; p 196. (7) Ice, R. D.; Wieland, D. M.; Beierwaltes, W. H.; et al. J. Nucl. Med. 1975,16, 1147. (8) Fowler, J. S.; MacGregor, R. R.; Wolf, A. P. J. Med. Chem. 1976, 19, 356. (9) Counsell, R. E.; Yu, T.; Ranade, V. V.; et al. J. Med. Chem. 1973,16, 1038. (10) Korn, N.; Buswink, A,; Yu, T.; et al. J. Nucl. Med. 1977,18, 87. (11) Wieland, D. M.; Swanson, D. P.; Brown, L. E.; et al. J.Nucl. Med. 1979,20, 155. (12) Wieland, D. M.; Wu, J. L.; Brown, L. E.; et al. J. Nucl. Med. 1980, 21, 349. (13) Wieland, D. M.; Brown, L. E.; Tobes, M. C.; et al. J. Nucl. Med. 1981,22, 358. (14) Chang, C. C.; Chang, J. C.; Su, C. Y. Br. J. Pharmacol. 1967, 30, 213. (15) Giachetti, A.; Hollenbeck, R. A. Br. J. Pharmacol. 1976, 58, 497. (16) For an excellent review, see: Maxwell, R. A.; Wastila, W. B. Handb. Exp. Pharmacol. 1977,39, 161. (17) Stjarne, L. Handb. E x p . Pharmacol. 1972,33, 231. (18) Athos, W. J.; McHugh, B. P., Fineberg, S. E.; et al. J. Pharmacol. 1962, 137, 229. (19) Cass, R.; Kuntzman, R.; Brodie, B. B. Proc. SOC.Exp. Biol. Med. 1960,103, 871. (20) Short, J. H.; Darby, T . D. J. Med. Chem. 1967, IO, 833. (21) Sisson, J. C.; Frager, M. S.; Valk, T. W.; et al. N . Engl. J. Med. 1981, 305, 12. (22) Valk. T . W.: Fraeer. M. S.; Gross, M. D.; et al. Ann. Znt. Med.
0 1984 American Chemical Society
150 Journal of Medicinal Chemistry, 1984, Vol. 27, No. 2
Wieland et al.
Table I. Characteristics of Guanidinium Salts R'
compd
position of I
N-R~
R'
n R2 mp, "C formulaa crystn solvent yield, % la ortho H O H 230-232e CSH,,IN;0.5H,SO, CH,OH 63 2a meta H O H 164-1 6 5 CsH,,IN,~0.5H,S04 H,O 84 3a para H O H 260-262' C8H,,IN,~0.5H,S0, H,O 64 4a meta H 0 CH, 217-220 C,,H,,IN,~HCl EtOH/Et,O 43 5a para H 0 CH, 247-249 C,,H,,IN,~HCl EtOH/Et,O 56 6a meta H 1 H 177-179 C,H ,,IN,~O.5H,SO, EtOH/H,O 42 7a para H 1 H 228-229 C9H,,IN,~0.5H,SO, H,O 30 (+)-8a meta CH, 0 H 279-281 C,HlzIN,~0.5H,S0, EtOH/H,O 70 (+ )-8aC CH, meta 0 H 281-283 C,H ,,IN,.O. 5H,S04 EtOH/H,O (-)-8ad CH, 0 H meta 279-280 C,H,,IN,~O.SH,SO, EtOH/H,O (lt)-9a CH, 0 H para 267-269 C,H,,IN,.0.5H,S04 EtOH/H,O 76 10a 3,4-I, H O H 266-268 C,H,I,N3~0.5H,S0, H,O/EtOH 44 lla 3,5-I, H O H 273-275g C,H,I,N3~0.5H,SO, H,O 39 12a [( rn-iodopheny1)guanidinel 247-248 C,H81N,~0.5H,S0, EtOH/H,O 29 a Microanalyses were within lt0.3% of theoretical values. Isolated yields starting from the respective amine. [MID -40.1" (H,O). [MID 21.6" (H,O). e LiteraturelOmp 229-231. f Literatureaomp258-260 "C. Decomposes.
pure guanidines. Lower reaction temperatures (120-135 more convenient to handle. The findings reported in this "C) and shorter reaction times (2-4 h) than those suggested study, however, are equally applicable to other radioiodine in the l i t e r a t ~ r e were ~ ~ l ~utilized. ~ Workup of the cyanisotopes (e.g., 1231 and I3lI). amide reaction was modified from that reported by Short Initially, the radiosyntheses of the lZI-labeled guanidines and Darby.2O The water-soluble guanidine hydrochlorides listed in Table I1 represented a formidable task. The were converted to their respective bicarbonate ~ a l t s , ~ ~ "cold" , ~ ~ or nonradioactive iodoguanidines posed no synthetic and the precipitates were isolated and then acidified with difficulty-the precursor amines are either commercially available or readily synthesized. Optimally, radioiodine 2 N sulfuric acid. The resulting sulfate salts were recrystallized to obtain analytically pure compounds, which should be introduced in the final synthetic step, preferably were used in subsequent radiolabeling experiments. Atby an isotopic exchange technique. However, at the outset tempts were not made to maximize yields, a notable exof this investigation, no method existed to exchange label ception being 2a. iodo aromatics that were not activated either by strong The N',"'-dimethyl-N-benzylguanidines 4a and 5a were electron-withdrawingor -donating groups. Indeed, our first synthesized by the method of King and Tonkina2' For attempts to exchange label 2a with NalZ5Ifailed under all radiolabeling experiments, the hydriodide salts of the classical exchange condition^.^^ A new technique for the guanidines were converted to their respective hydrosynthesis of aryl radioiodides of high specific activity was chloride salts by passage through Amberlite IRA-400 anthen developed, which involves a mild, solid-phase exchange under mildly acidic, oxidizing conditions. The in ion-exchange resin (chloride form). Partial resolution of situ thermal decomposition of (",),SO, facilitates the (+)-(rn-iodo-a-methy1benzyl)guanidine (8a) was achieved exchange.30 The technique has permitted the rapid, by fractional crystallization of its (+I- and (-)-mandelate high-yield radiosyntheses of all the ([1251]iodoaralkyl)salts with subsequent conversion to the respective sulfates. guanidines in Table 11. Exchange reactions were conducted Only five of the precursor amines were unavailable in the solid state at 120-140 "C for 2-4 h with ammonium commercially. rn-Iodophenethylamine was synthesized by sulfate as a promoter. Purification was achieved by disdiborane reduction of (m-iodopheny1)acetonitrile. The solving the reaction mixture in 13.5 mM sodium acetate 3,4-diiodobenzylamine was obtained by iodination of pbuffer (pH 4.5) and passing the solution through a column iodobenzylamine by the Derbyshire method.28 The 33of Cellex-D anion-exchange resin to remove unreacted diiodobenzylamine was synthesized by diiodination of radioiodide. Radiochemical yields ranged from 60 to 98%. p-aminobenzonitrile with iodine monochloride, followed Specific activities were routinely 0.25-0.80 Ci/mmol, alby reductive deamination with nitrous acidlhypothough values as high as 100 Ci/mmol could be achieved phosphorous acid and subsequent reductive of the nitrile if desired, albeit in slightly lower yield. Radiochemical with BH,.Me2S. The iodo-a-methylbenzylamines were purity for all l=I-labeled compounds was greater than 98%, obtained from m-and p-iodoacetophenone, respectively, as determined by radio-TLC (three solvent systems) and, via the Leuckhart reaction.29 in a few select cases, by radio-HPLC. Radiochemistry. In this work the labeling and bioThe hydriodide salts of iodoguanidines 4a and 5a gave distribution studies were performed on compounds labeled poor exchange yields; carrier iodide likely competes with with 1251. This radionuclide is not only less expensive but [ 1251]iodidefor exchange. The respective hydrochloride its long TI,, (60 days) and low y energy (36 keV) make it salts, however, gave good exchange yields. The exchange reaction of Na1251with rn-IBG (2a) was (23) Rathke, B. Ber. Dtsch. Chem. Ges. 1881, 14, 1774. chosen for more detailed purity studies, both radiochemical (24) Braun, C. E. J. Am. Chem. SOC.1933,55,1280. and nonradiochemical. Potential radioactive impurities, (25) Bobeck, R. Justus Liebigs, Ann. Chem. 1931,487, 294. such as [1251]iodide,rn-[1251]iodobenzylamine,(rn-[1251](26) Fielden, R.; Green, A. L.; Willey, G. L. Br. J. Pharmacol. 1965, 24, 395. iodobenzyl)urea, (34-[ 1251]diiodobenzyl)guanidineand (27) King, H.; Tonkin, I. M. J. Chem. SOC.1946, 1063. (28) Barker, I. R. L.; Waters, W. A. J. Chem. SOC.1962, 150. (29) Ingersoll, A. W. In "Organic Syntheses"; Wiley: New York, 1943; Collect. Vol. 11, p 503.
(30) Mangner, T. J.; Wu, J. L.; Wieland, D. M.; et al. J . Org. Chem.
1982,47, 1484.
Journal of Medicinal Chemistry, 1984, Vol. 27, No. 2 151
Radiolabeled Aralkylguanidines Table 11. SDR Data on Radiolabeled Guanidines in Dogs'
adrenal medulla concn
[adrenal medulla]/ 30 min 72 hr [liver] at 72 h 1.3 i 0 . l c 13OC H 1.7 i 0.1 0 lb ortho H 13.0 i 1.5 720 H 5.4 i 0.7 0 2b meta H 545 13.9 i 1.6 H 0 3.2 i. 0.6 3b para H 0 0.4 i. 0.0 4b meta H CH, 0.1 i 0.0 0 5b para H CH, 190 1 4.8 f 0.7 H 4.4 i 0.3 6b meta H 200 1 2.4 i 0.6 H 1.4 i 0.2 7b para H 430 7.3 f 1.0 0 5.4 f 0.4 H meta CH3 (+)-8b 390 9.3 f 0.9 0 H 4.2 i 0.5 meta CH3 ( + )-8b 300 7.3 i 1.6 H 0 6.4 i 1.2 meta CH, (-)-8b 190 7.2 i. 0.5 H 0 2.9 i 0.1 para CH3 (i)-9b 115 4.9 f 0.1 H 0 2.1 i 0.3 3,4-I, H 10b 5.2 0.5 ?: 0.0 H 0 0.4 ~t0.0 3,5-I, H llb 45 1.3 i 0.3 3.0 i 0.1 1 2 b [(m-iodopheny1)guanidinel 70 5.1 i 0.6 2.6 ~t 0.8 13 ( ['4C]guanethidine)d 1.4e 0.2 It O.Od 0.2 i 0.0 1 4 ( [I4C]guanidine) 8.1 i. 2.2 2700 9.3 i. 0.8 15 ( [ l4C]benzylguanidine) f 0.2 i 0.0 16 [( m-iodobenzyl)amine] 8.0 i. 0.6 13.8 i 0.5 1 7 [(-)-[3H]norepinephrine] ' Tissue distribution data for all compounds in 18 selected tissues can be obtained upon request from the author. Concentration is given in percent kilogram dose per gram, plus or minus the standard error of the mean; N ranged from 4 to 12. 48 h. [ 2-(Octahydro-l-azocinyl)ethyl] [ I4C]guanidine sulfate. e 2 h. [methyZ-'4C]Benzylguanidine.g L - [ ~ - ~ H ( N ) ] Norepinephrine. compd
position of radioiodine
R'
n
R2
N,"-bis(m- [1261]iodobenzyl)urea, were shown to be absent by separate synthesis and analysis by radi~-HPLC.~lThe absence of the radiochemical impurities is also evidence for their absence as the respective nonradiolabeled impurities, since they have been shown in separate experiments to undergo radioiodide exchange under the reaction conditions employed. To further demonstrate the nonradiochemical purity of m-[1251]IBG(2b),a mock exchange reaction using Na12'I was conducted. The chemical purity (>98%) of m-IBG (2a) was then determined by HPLC using ultraviolet detection (254 nm). The four iodo aromatics listed above, as well as benzylguanidine, were shown to be absent under the HPLC conditions employed. Scrambling of the radioiodine label during the exchange process did not occur (95% of the extracted radioactivity is unchanged 3b.12 A similar study of 2b using radio-HPLC has shown that >98% of the adrenomedullary radioactivity at 24 h postinjection is due to unchanged 2b.31The in vivo stability of the carbon-iodine bond in the 1251-labeled compounds in Table I1 was good, as indicated by low concentrations of radioactivity in the thyroid, an organ that efficiently sequesters iodide. By comparison of the thyroid concentrations of radioactivity obtained with lb-3b and 6b-12b to a standard graph of thyroid radioactivity concentration vs. time in dogs injected intravenously with Na1251,we estimate that at 24 h postinjection none of these compounds show >4% deiodination. However, at 72 h, the values ranged from 3 to 25%; compounds 3b, 6b, and 10b in particular showed a high degree of deiodination at this time interval. Holzbauer, M.; Sharman, D. F. Handb. Exp. Pharmacol. 1972, 33, 110.
Winkler, H.; Smith, A. D. Handb. E x p . Pharmacol. 1972,33, 900.
Kirschner, A. S.;Ice, R. D.; Beierwaltes, W. H. J. Nucl. Med. 1975,16,248.
Bisson, G. M.; Muscholl, E. Nauyn-Schmedebergs Arch. Exp. Pathol. Pharrnacol. 1962,244,185. McMartin, C.;Rondel, R. K.; Vinter, J.; et al. Clin. Pharmacol. Ther. 1970,11,423. Turnbull. L.B.: Tene. L.:, Newman., J.:, et al. Drug- Metab. D i m .
Wieland et al.
Since a homogeneous distribution of a radiochemical evenly throughout the body would result in a concentration of 0.1% kg dose/g in all body it can be seen that many of the guanidines show high affinity for the adrenal medulla. In screening for potential adrenomedullary radiopharmaceuticals, high concentrations of radioactivity in the adrenal medulla are desirable, as well as low concentrations in surrounding organs, such as adrenal cortex, kidneys, liver, intestines, stomach, and gallbladder. The liver is particularly troublesome because of its large size (2600 times heavier than the adrenal medulla) and high metabolic activity. Thus the 72-h adrenal medulla to liver concentration ratio is given in Table I1 as an index of the degree of selectivity of the radiolabeled compounds for the adrenal medulla. Markedly high concentration ratios were obtained for a majority of the radiolabeled guanidines evaluated. The following observations can be made based on the data in Table 11: (1)Of the radioiodinated compounds, 2b shows the best combination of high retention and pronounced selectivity for the adrenal medulla. (2) Two structural modifications of 2b result in a striking diminution in adrenomedullary affinity, methyl substitution on the N’,N” atoms (e.g., 4b and 5b) and incorporation of a second iodine atom in the 5-position (llb). (3) The low values obtained with [14C]guanidine (14) and rn-[lz5I]iodobenzylamine (16) stress the combined importance of both the aralkyl and guanidino portions of rn-IBG to adrenomedullary localization. (4) Comparison of 2b with [ 14C]benzylguanidine(15) suggests that incorporation of radioiodine into benzylguanidine increases the 72-h concentration of radioactivity in the adrenal medulla but lowers the adrenal medulla to liver concentration ratio. However, the definitive experiment will be to compare the biodistributions of [methyl-14C]benzylguanidine with [rnethyl-14C]-m-IBGof the same specific activity. In view of the close ontogenetic relationship between chromaffin cells and sympathetic nerves, it is not surprising that the adrenal medulla removes and retains circulating catecholamines. The ability of the adrenal medullae to efficiently accumulate tracer amounts of radioactive catecholamines was first demonstrated by the early work of Axelrod and ~ o - w o r k e r s . ~Although ~ , ~ ~ the adrenomedullary uptake of radioactivity at 30 min from a bolus intravenous injection of (-)-[3H]norepinephrine is higher than that of any radiolabeled guanidine studied, the retention (or more appropriately the net accumulation) of radioactivity in the medullae at 72 h is less than observed with 2b or 3b. Although speculative at this point, this reversal may be due to the continuous release of 2b or 3b into the blood pool from the peripheral adrenergic nerves and partial reuptake in the adrenal medullae. This systemic, steady perfusion is likely a less efficient process in the case of (-)-[3H]norepinephrine due to its rapid metabolism by monoamine oxidase or catechol 0methyltransferase following release from the peripheral adrenergic nerves. Alternatively, the adrenomedullary concentration pattern of the two radiotracers may be due, at least in part, to a slower release of m-IBG (2b) from the adrenal medullae. A potential problem exists in that the three 14C-labeled compounds evaluated in this study have up to 100-fold lower specific activities than the radioiodinated compounds. The specific activity or loading dose of a radio-
I
1976,4,269.
Mahgoub, A.; Idle, J. R.; Dring, L. G.;et al. Lancet 1977,2,584. Medina, M.A.: Giachetti, A.: Shore, P. A. Biochem. Pharmacol. 1969,18, 891.
(42) Axelrod, J.; Weil-Malherbe, H.; Tomchick, R. J . Pharmacol. Exp. Ther. 1959,127,251. (43) Whitby, L.G.; Axelrod, J.; Weil-Malherbe, H. J. Pharmacol. Exp. Ther. 1961,132,193.
Journal of Medicinal Chemistry, 1984, Vol. 27,No. 2 153
Radiolabeled Aralkylguanidines
-P
loo
98% radiochemical purity. Qpecific activity of the product was 20.74 Ci/mmol. Tissue Distribution Studies. These were performed on female mongrel dogs (14-22 kg). Animals received 100 pCi of the appropriate 1251-labeledcompound or 50-60 pCi of I4C-labeled compound. For each time interval evaluated, two to six dogs received bolus intravenous injections of radiolabeled compound in 2.0 mL of sterile acetate buffer (pH 4.5). The dogs were sacrificed 30 min or 72 h later by rapid intravenous injection of sodium pentobarbital. Both adrenals were removed from each dog, freed of fat and connective tissue, and immediately placed on dry ice. The adrenals were sliced in halfto expose the medullae, and the medullary tissue was removed with a 2.0-mm Meyhoefer curette. In the l%Istudies, duplicate samples of 18 different organs or tissues from each dog were excised, washed free of blood with saline solution, blotted dry, quickly weighed (15-80 mg), and counted on a Packard 5260 Autogamma counter. For the 14Cor 3H-labeledcompounds, duplicate samples of the same tissues were weighed, oxidized in a P a c h d 306 Tri-Carb sample oxidizer, and then counted in a Packard 3330 liquid scintillation counter with correctionsmade for background and counter efficiency. In order to normalize for differences in animal weights, tissue concentrations are expressed as percent kilogram dose per gram (% kg d ~ s e / g ) . ~ ~
Acknowledgment. This research was supported by DHEW Grant CA-09015 (Cancer Research Training in Nuclear Medicine) and ERDA Contract EY-76-S-02-2031. The authors thank Linder Markham for help in preparing the manuscript. Special thanks to Philip S. Sherman and Susan J. Fisher for technical assistance in the latter stages of this work. We are indebted to John D. Jones and Dr. William Kerr for the use of the radiochemicallaboratories at the Phoenix Memorial Building, University of Michigan. The authors thank Dr. William H. Beierwaltes for support and encouragement during the course of this study. Registry No. la, 16125-86-3;lb, 74075-14-2;2a, 87862-25-7; 2b, 74075-13-1;3a, 14629-13-1;3b, 74075-12-0;4a, 87862-26-8;4b, 87862-27-9; 5a, 87862-28-0;5b, 87862-29-1; 6a, 87862-30-4; 6b, 80664-16-0;7a, 87862-31-5;7b, 80664-17-1; (*)-sa, 87862-32-6; (+)-sa, 87900-85-4;(-)-8a, 87900-86-5;(*)-8b, 80664-14-8; (+)-8b, 80734-43-6; (-)-8b, 80734-42-5; (*)-9a, 87862-33-7; (i)-9b, 80664-15-9; loa, 87862-34-8; lob, 80664-13-7; l l a , 87862-35-9;l l b , 80664-25-1;12a, 87862-36-0; 12b, 80664-18-2;13, 87862-38-2;14, 87862-39-3; 15, 87862-40-6; 16, 87862-41-7; 17, 62600-61-7. Supplementary Material Available: The 24- and 72-h dog thyroid radioactivityconcentrationsof all 1261-labeledcompounds reported in this study and a standard graph of thyroid radioactivity concentration vs. time after injection with Na1261(2 pages). Ordering infdrmation is given on any current masthead page. Also, the tissue distribution data for all compounds in Table I1 in 18 selected tissues can be obtained upon request from the author.
