The metabolism of 16-fluoroestradiols in vivo: Chemical strategies for restricting the oxidative biotransformations of an estrogen-receptor imaging agent

Article abstract of DOI:10.1016/S0039-128X(97)00116-5

16α-Fluoro-17β-, 16α-fluoro-17α-, and 16β-fluoro-17β-[6,7- ³H]estradiol were prepared from [6,7-³H]estrone via fluorination of 3,17- bis(tert-butyldimethylsilyloxy)-[6,7-³H]estratetraene with N- fluoropyridinium triflate and reduction of 16α/β-fluoro[6,7-³H]estrone with NaBH₄. The three isomers were separated by silica-phase high- performance liquid chromatography. They were administered intravenously (4 μmol/kg) to anaesthetized male rats. Their biliary metabolites (90-97% of dose over 6 h) were characterized by high performance liquid chromatography- mass spectrometry and compared with those of [6,7-³H]17β-estradiol. The four estrogens and their hydroxylated and methoxylated metabolites were excreted as glucuronides. C-16 fluorination blocked C-16 hydroxylation and also the dehydrogenation of the C-17 hydroxyl group. The 16α-17β isomer was extensively glucuronylated at C(O)3 but also underwent aromatic hydroxylation and methoxylation before conjugation. Its C-17 epimer was subject to much greater aromatic hydroxylation but the catecholestrogen was O-methylated to a greater relative extent. The 16β-17β derivative underwent alicyclic as well as substantial aromatic hydroxylation and yielded numerous isomeric glucuronides of O-methylated catechols. Thus, the fluorine exerted complex effects (inhibitory and enhancing) on both localized (D-ring) and distal (A- ring) biotransformations of the estradiol molecule; the direction and magnitude of the effects being dependent upon the stereochemistry at C-16 and C-17. These findings provide structural guidelines for restricting the metabolism of tumor-imaging fluoroestrogens and thereby enhancing their deliver), to the target tissue.