OXOHEXESTROL DERIVATIVES LABELED WITH F-18 - SYNTHESIS, RECEPTOR-BINDING AND IN-VITRO DISTRIBUTION OF 2 NONSTEROIDAL ESTROGENS AS POTENTIALBREAST-TUMOR IMAGING AGENTS

We have prepared two non-steroidal estrogens in the 2-oxohexestrol ser ies labeled with the positron-emitting radionuclide fluorine-18, 1-flu oro-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 b y total synthesis: compound 4 was prepared in fluorine-lb labeled form by [F-18]fluorine ion displacement on a suitably protected methanesul fonate precursor followed by deprotection under acidic hydrogenolytic conditions; the isomer 5 was prepared from a protected a-keto trifluor omethanesulfonate precursor with deprotection under basic conditions a s the final step. The binding affinity of these hexestrol derivatives for the estrogen receptor was determined by competitive radiometric bi nding assays at 0 and 25 degrees C, and their lipophilicity (as octano l-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 th e fragment method of Rekker. In tissue distribution studies in immatur e (50 g) rats, both of these compounds showed selective uptake in estr ogen 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 upta ke efficiency and selectivity of these fluoro-oxohexestrols in princip al estrogen target tissues is less than that of fluorine-18 labeled st eroidal estrogens we have prepared previously, but their receptor-medi ated uptake in certain secondary target tissues is substantial. The sp ecific and non-specific components of target tissue uptake of these tw o compounds appear to be directly related to their non-specific bindin g and their binding selectivity.