Oxohexestrol derivatives labeled with fluorine-18. Synthesis, receptor binding and in vivo distribution of two non-steroidal estrogens as potential breast tumor imaging agents

Abstract We have prepared two non-steroidal estrogens in the 2-oxohexestrol series labeled with the positron-emitting radionuclide fluorine-18, 1-fluoro-5-oxohexestrol ( 4 ) and 1-fluoro-2-oxohexestrol ( 5 ). We anticipated that the polar ketone function at the interior of these ligands would reduce their level of non-specific binding, which might increase the selectivity of their uptake in vivo . The two compounds were prepared by total synthesis: compound 4 was prepared in fluorine-18 labeled form by [ 18 F]fluorine ion displacement on a suitably protected methanesulfonate precursor followed by deprotection under acidic hydrogenolytic conditions; the isomer 5 was prepared from a protected α-keto trifluoromethanesulfonate precursor with deprotection under basic conditions as the final step. The binding affinity of these hexestrol derivatives for the estrogen receptor was determined by competitive radiometric binding assays at 0 and 25 °C, and their lipophilicity (as octanol-water partition coefficients, log P values) and non-specific binding were estimated. The log P values determined by a reversed phase HPLC method were higher, relative to estradiol, than those calculated by the fragment method of Rekker. In tissue distribution studies in immature (50 g) rats, both of these compounds showed selective uptake in estrogen target tissues. At 1 h, activity in the uterus reached the level of 2.5–3.0% of the injected dose per gram tissue, with uterus-to-blood and uterus-to-muscle ratios of 14–20 and 8–14, respectively. The uptake efficiency and selectivity of these fluoro-oxohexestrols in principal estrogen target tissues is less than that of fluorine-18 labeled steroidal estrogens we have prepared previously, but their receptor-mediated uptake in certain secondary target tissues is substantial. The specific and non-specific components of target tissue uptake of these two compounds appear to be directly related to their non-specific binding and their binding selectivity.