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

• Published in: Steroids Vol. 62; no. 12; pp. 750 - 761
• Main Authors: Stalford, Anne C., Maggs, James L., Gilchrist, Thomas L., Park, B.Kevin
• Format: Journal Article
• Language: English
• Published: NEW YORK Elsevier Inc 01.12.1997; Elsevier; Elsevier Science
• Subjects: 16-fluoroestrogen; Animals; Biochemistry & Molecular Biology; Biological and medical sciences; Biotransformation; catecholestrogen; Endocrinology & Metabolism; Estradiol - analogs & derivatives; Estradiol - chemical synthesis; Estradiol - metabolism; Estradiol - pharmacokinetics; estrogen; Fundamental and applied biological sciences. Psychology; Glucuronates - metabolism; Isomerism; Life Sciences & Biomedicine; Male; Mass Spectrometry - methods; metabolism; Oxidation-Reduction; Rats; Rats, Wistar; Science & Technology; Steroid hormones. Cholecalciferol derivatives; Structure-Activity Relationship; Tritium; Vertebrates: endocrinology; catecholestrogen; estrogen; metabolism; 16-fluoroestrogen; RAT; ANALOGS; BREAST-TUMORS; CANCER; AROMATIC HYDROXYLATION; IN-VITRO; POSITRON TOMOGRAPHIC ASSESSMENT; CATECHOL ESTROGEN; BINDING; PET; In vivo; Vertebrata; Mammalia; Rat; Molecular structure; Metabolite; Biotransformation; Rodentia; Catechol estrogen; Metabolism
• ISSN: 0039-128X; 1878-5867
• 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( test-butyldimethylsilyloxy)-[6,7- 3H]estratetraene with N-fluoropyridinium triflate and reduction of 16α β - fluoro[6,7- 3H]estrone with NaBH 4. 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 delivery to the target tissue.