SYNTHESIS, RECEPTOR-BINDING AND BIODISTRIBUTION OF THE GEM-21-CHLORO-21-IODOVINYLESTRADIOL DERIVATIVES

Radioiodinated 11beta-methoxy-(17alpha,20E)iodovinylestradiol (11beta-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 (17alpha,20Z-chloro)21-chloro-21-iodovinylestradiol (4a) and several derivatives featuring 11beta-methoxy (4b), 11beta-ethoxy (4c) or 7alpha-methyl (4d) substituents. All gem-dihalogen derivatives 4a-d were prepared from the 17alpha-chloroethynyl precursors. The intermediate chlorostannylvinyl derivatives were obtained using tri-n-butyltin hydride and palladium acetate catalyst. Compounds 4a and 4b were labeled with I-125 via their corresponding tin intermediates and their tissue distribution was studied in immature female rats. Addition of a 21-Cl to the 17alpha-ethynylestradiols reduced ER binding affinity, except for the 11beta-substituted analogs which showed a pronounced increase. Surprisingly, addition of a 21-Cl to the (17alpha,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.