Synthesis, receptor binding, and tissue distribution of 7 alpha- and 11 beta-substituted (17 alpha,20E)- and (17 alpha,20Z)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetraene-3,17-diols

Abstract

The 11 beta-methoxy, 11 beta-ethoxy, and 7 alpha-methyl derivatives of the isomeric (17 alpha,20E)- and (17 alpha,20Z)-(iodovinyl)estradiols 3 and 6, and their no-carrier-added [125I]iodovinyl analogues, were evaluated for their relative target-tissue retention and binding affinity for the estrogen receptor. The isomeric iodovinyl and [125I]iodovinyl derivatives were prepared via destannylation of the corresponding tributylstannyl precursors in the presence of H2O2 or chloramine-T, with retention of configuration. The 20Z isomers 6 exhibited slightly higher receptor binding affinities than the 20E isomers 3, with all eight isomeric products giving relative binding affinity values in the 20-50 range. The 11 beta- and 7 alpha-substituted (iodovinyl)estradiols gave substantially higher estrogen receptor-mediated uterus uptake as compared to the nonsubstituted parent molecule. Synergism between the effect of 11 beta- or 7 alpha-substituents and the configuration of the iodovinyl group was evident from the in vivo distribution pattern of [125I]-3 and -6. The best uterus uptake was observed, at 2 h postinjection, with the 20E isomer of 11 beta-methoxy derivative 3b. However, at 5 h postinjection the 20Z isomer 6b reached higher uterus concentrations than the 20E isomer 3b, and furthermore, these values are now comparable to those observed with the 20Z isomer of the 11 beta-ethoxy derivative 6c. In the case of the 7 alpha-methyl derivatives the differences in in vivo stability between the 20E and 20Z isomers was less pronounced, whereas the 20Z isomer 6d reached somewhat higher uterus to blood as well as nontarget ratios.