7 alpha-Methyl- and 11 beta-ethoxy-substitution of [125I]-16 alpha-iodoestradiol: effect on estrogen receptor-mediated target tissue uptake.

The 7 alpha-methyl and 11 beta-ethoxy derivatives of 16 alpha-[125I]iodoestradiol were prepared via halogen exchange with 125I of the corresponding 16 beta-bromoestradiol precursors. The 16 alpha-bromo derivatives were obtained via halogenation of the analogous 17-enol acetate, epimerization to the 16 beta-isomer, and hydride reduction. Stereochemical assignments were based on high resolution 1H NMR. To evaluate the effect of the nature and stereochemistry of the 16-halo substituent on the relative binding affinity for the estrogen receptor, the analogous 16-chloro derivatives were also prepared. The highest binding affinities were observed with the 7 alpha-methyl-16 alpha-haloestradiols, particularly the bromo and chloro derivatives while the 16 alpha-iodo derivatives gave somewhat lower values. Both the 11 beta-ethoxy and 7 alpha-methyl-16 alpha-[125I]iodoestradiols localize in the uteri of immature female rats via a receptor-mediated process. Rapid blood clearance of the 125I-labeled 7 alpha-methyl derivative results in lower 125I uptake by the uterus as well as nontarget organs as compared to the 11 beta-substituted estradiol analogs. However, uterus to blood and nontarget ratios are more favorable for the 7 alpha-methyl-16 alpha-[125I]iodoestradiol as compared to the analogous 11 beta-ethoxy derivatives suggesting that this compound substituted with 123I may be useful for the in vivo imaging of estrogen receptor-rich breast tumors by single photon emission computerized tomography.