(17α,20E/Z)-iodovinyl- and 16α-iodo-18-homoestradiol derivatives:: synthesis and evaluation for estrogen receptor imaging

Three new I-125-radioiodinated estrogens featuring a 13 beta-ethyl instead of the natural 13-methyl group, i.e. 18-homoestradiols, were synthesized and evaluated as potential estrogen receptor imaging agents. The 16 alpha-iodo-18-methylestradiol and the I-125-labeled analog were synthesized from the corresponding 16 beta-bromo analog by the halogen-exchange method. The cis-bromohydrin precursor was obtained by bromination of an estrone enolacetate, followed by epimerization and reduction. The isomeric (17 alpha,20E/Z)-iodovinyl-18-methylestradiols were prepared via the vinyltin intermediates. Treatment of 18-methyl-17 alpha-ethynylestradiol with tri-n-butyltin hydride, in the presence of azobisisobutyronitrile as catalyst and heating at 90-100 degrees C afforded the (17 alpha,20E)-tri-n-butylstannyl isomer as the major product. Changing the catalyst for triethyl borane, at room temperature, mainly gave the 20Z-isomer. The nea I-125-labeled analogs were obtained from their corresponding tin intermediates upon treatment with [I-125]NaI in the presence of H2O2. The 16 alpha-[I-125]iodo- and isomeric (17 alpha,20E/Z)-[I-125]iodovinyl-18-methylestradiols were evaluated for estrogen receptor-mediated uterine uptake in immature female rats. Homologation of the C13-methyl group did improve the uterine uptake of the iodovinyl derivatives, but also increased blood retention, resulting in lower target uptake ratios. In the case of the 16 alpha-iodo analog uterine retention decreased upon C13-homologation. (C) 2000 Elsevier Science Inc. All rights reserved.