J. Med. Chem. 1989,32,609-612
609
Potential Tumor- or Organ-Imaging Agents. 29. Radioiodinated Esters and Amides of 20-Hydroxy- and 20-Aminopregn-5-en-3P-01s T. Haradahira,t S. W. Schwendner, M. Kojima,t and R. E. Counsell* Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, and The Division of Radiopharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812, Japan. Received June 21, 1988 Radioiodinated benzoyl esters and amides of epimeric 20-hydroxy- and 20-aminopregn-5-en-38-01s were synthesized in an effort to find an agent that would be rapidly and selectively taken up by adrenal cortical tissue. Achievement of such a goal would provide a basis for the development of adrenal imaging agents superior to those currently available for clinical use. The iodobenzoyl derivatives were obtained by treating the appropriate epimer with 2-iodobenzoic acid in the presence of dicyclohexylcarbodiimide and 4-(dimethy1amino)pyridine. The resulting esters and amides were readily labeled with radioiodine by isotope exchange with sodium iodide-125 in pivalic acid. Tissue distribution studies in female rats revealed that only the esters displayed appreciable adrenal specificity, and the ester having the same configuration at C-20 as cholesterol was significantly better than the corresponding C-20 epimer.
For the past two decades radioiodinated cholesterol derivatives1+ (Figure 1)have been widely used to scintigraphically visualize adrenals in the diagnosis of a variety of human adrenal disorder^.^^ A major disadvantage of these agents, however, is that 4 to 5 days are normally required following administration in order to obtain satisfactory adrenal images. Thus, there is a need in nuclear medicine for a radiopharmaceutical that could provide adrenal images within 24 h. This would permit the use of the shorter lived iodine-123 (Tlj2= 13 h) rather than the currently used iodine-131 (T1/2= 8 days), which would lead to a concomitant reduction in the radiation dose to the patient. In an effort to achieve this goal, previous papers in this series have explored various radioiodinated esters of cholesterol'* and pregnenolone.+" The pregnenolone esters were particularly interesting since several were shown to reach very high concentrations in the rat adrenal at very early times after administrations. For example, radioiodinated pregnenolone iopanoate was found to produce unusually high levels of radioactivity in the adrenal cortex (23% dose/g) within 0.5 h of iv admini~tration.~ Unfortunately, when this agent was studied in the dog, rapid in vivo hydrolysis of the ester prevented sufficient concentrations from reaching the adrenal.12 In an attempt to overcome the susceptibility of these pregnenolone esters to in vivo hydrolysis, it was decided to explore the possibility of placing the tracer at the 20 rather than the 3 position. Accordingly, the 2-iodobenzoyl derivatives of 20a- and 20P-hydroxy as well as 20a- and 20P-aminopregn-5-en-3P-01 were synthesized, radioiodinated, and analyzed for their ability to accumulate in the rat adrenal.
Chemistry The C-20-iodobenzoates7-10 were synthesized as shown in Scheme I. Pregnenolone 3-THP ether (1) was used as the starting material for preparation of the esters 7 and 8. Reduction of this ether with either LiAlH, or Na in EtOH has been reported to give a mixture of the 20a- and 200-hydroxy derivatives (3 and 4).13J4 In our case, reduction of 1 with Na in 1-propanol (method A) afforded 3 and 4 in a ratio of approximately 2:l after column chromatography. A third product was also isolated, however, whose IR and 'H NMR spectra were very similar to those of 4 and whose elemental analysis agreed with the molecular formula for both 3 and 4. This byproduct was subsequently identified as the l7a-epimer of pregn-5ene-30,20-diol3-THP ether by conversion to known 17at Kyushu
University.
pregnenolone. Butenandt and co-worker~'~J~ have shown that 170,20-ketosteroidssuch as pregnenolone are partially isomerized to their l7a-epimers by refluxing in alkaline solution. Therefore, we believe the 17a byproduct arose in our preparation by initial isomerization at C-17 followed by reduction of the C-20 carbonyl. When the reduction of 1 was performed with NaBH, (method B) only 3 and 4 were isolated in a ratio of 1:15. Acylation of the 20-hydroxy (3 and 4) and 20-amino (5 and 6) steroids with 2-iodobenzoic acid in the presence of dicyclohexylcarbodiimide (DCC) and a catalytic amount of 4-(dimethy1amino)pyridine(DMAP) followed by removal of the THP protecting group furnished the desired C-20-iodobenzoates 7-10 in excellent overall yields. Radioiodinations of 7-10 for in vivo tissue distribution were performed by isotope exchange with Na'=I in pivalic acid as reported previously." Radiochemical yields for the radioiodinated steroids were estimated by TLC of the reaction mixtures and ranged from 89% to 94%. Radioiodinated products were purified by column chromatogCounsell, R. E.; Ranade, V. V.; Blair, R. D.; Beierwaltes, W. H.; Weinhold, P. A. Steroids 1970, 16, 317. Kojima, M.; Maida, M.; Oguiva, H.; Nita, K.; Ito, T. J. Nucl. Med. 1975, 16, 542. Basmadjian, G. P.; Hetzed, R. R.; Ice, R. D.; Beierwaltes, W. H. J. Labeled Compds. Radiopharm. 1975,11,427. Britton, K. E. In The Adrenal Gland; Raven Press: New York, 1979; pp 309-322. Beierwaltes, W. H.; Sisson, J. C.; Shapiro, B. Spec. Top. Endocrinol. Metab. 1987, 6, 1. Gross, M. D.; Valk, T. W.; Swanson, D. P.; Thrall, J. H.; Grekin, R. I.; Beienvaltes, w. H. Sem. Nucl. Med. 1987, 11, 128. Counsell, R. E.; Seevers, R. H.; Korn, N.; Schwendner, S. W. J. Med. Chem. 1981,24, 5. Seevers, R. H.; Schwendner, S. W.; Swayze, S. L.; Counsell, R. E. J. Med. Chem. 1982,25, 618. Seevers, R. H.; Groziak, M. P.; Weichert, J. P.; Schwendner, S. W.; Longino, M. A.; Counsell, R. E. J. Med. Chem. 1982,25, 1500. VanDort, M.; Schwendner, S. W.; Skinner, R. W. S.; Gross, M. D.; Counsell, R. E. Steroids 1984,44, 85. VanDort, M.; Schwendner, S. W.; Counsell, R. E. Steroids 1987, 49, 531. Longino, M. A.; Schwendner, S. W.; VanDort, M.; Skinner, R. W. S.; Gross, M. D.; Counsell, R. E. In Proceedings of the 4th International Symposium on Radiopharmacology; Pergamon Press: Toronto, 1986; pp 290-297. Irmscher, K.; Kraemer, J. H.; Halpaap, H. Steroids 1966, 7, 557. Takahashi, T.; Otake, A.; Yamada, H.; Tsuji, J. Tetrahedron Lett. 1985, 26, 69. Butenandt, A.; Mamoli, L. Ber. 1935, 68, 1847. Butenandt, A.; Fleischer, G. Ber. 1937, 70, 96. Weichert, J. P.; VanDort, M. E.; Groziak, M. P.; Counsell, R. E. Appl. Radiat. Isot. 1986, 37, 907.
0022-262318911832-0609$01.50/0 0 1989 American Chemical Society
610 Journal of Medicinal Chemistry, 1989, Vol. 32, No. 3
Haradahira et al.
Scheme Io CH3
I
c=x
THPO
Lu
w
THPO
HO
u
1x=o 2 X=NOH
(a) Na + 1-PrOH (method A) or NaBH,
+ MeOH (method B);(b) 2-IC6H4COOH+ DCC + DMAP/CH2C12; (c) p-TsOHITHF + EtOH.
Table I. Distribution of Radioactivity” at 0.5 and 24 h after Intravenous Administration of C-20 Iodobenzoates and Iodobenzamides to Female Rats (n = 4) time, compound h tissue standardbVc 7 8 9 10 0.5 adrenal 17.89 f 0.90 10.04 f 0.34 6.83 f 0.64 2.49 f 0.07 1.66 f 0.14 0.59 f 0.03 blood 2.35 f 0.11 0.25 f 0.02 0.10 f
