Synthesis, receptor binding and biodistribution of the gem-21-chloro-21-iodovinylestradiol derivatives.

Radioiodinated 11 beta-methoxy-(17 alpha,20E)iodovinylestradiol (11 beta-OMe-IVE2) shows high estrogen receptor (ER)-mediated uterus uptake and good potential as an ER-imaging agent. In order to examine the tolerance of the ER for modification about the iodovinyl substituent, we prepared the (17 alpha,20Z-chloro)21-chloro-21-iodovinylestradiol (4a) and several derivatives featuring 11 beta-methoxy (4b), 11 beta-ethoxy (4c) or 7 alpha-methyl (4d) substituents. All gem-dihalogen derivatives 4a-d were prepared from the 17 alpha-chloroethynyl precursors. The intermediate chlorostannylvinyl derivatives were obtained using tri-n-butyltin hydride and palladium acetate catalyst. Compounds 4a and 4b were labeled with 125I via their corresponding tin intermediates and their tissue distribution was studied in immature female rats. Addition of a 21-Cl to the 17 alpha-ethynylestradiols reduced ER binding affinity, except for the 11 beta-substituted analogs which showed a pronounced increase. Surprisingly, addition of a 21-Cl to the (17 alpha,20E)IVE2 resulted in increased ER binding affinities and augmented ER-mediated uterus uptake, which may result from the pronounced increase in the dipole moment of the molecule. Thus, further modifications at the C-21 position of IVE2 are well tolerated by the ER. However, addition of the 21-Cl also resulted in increased radioiodine uptake by the thyroid, much slower blood clearance and lower uterus to blood/nontarget ratios, suggesting increased in vivo instability of the C--I bond of the gem-chlorine-iodine atoms which may reflect the increase in steric and electronic interference.