title: Target tissue uptake selectivity of three fluorine-substituted progestins: potential imaging agents for receptor-positive breast tumors.
abstract: We have studied three new fluorine-substituted progestins (1-3) as potential imaging agents for progesterone receptor (PgR)-positive human breast tumors. Two of these are fluorine-substituted analogs of the potent progestin R5020 (promegestone), derived from (21S)-hydroxy R 5020 (RU 27987) and (21R)-hydroxy R 5020 (RU 27988), known metabolites of R 5020, which have affinities for PgR that are 116 and 4%, respectively (relative to R 5020 = 100%). These precursors were protected as their 3,3-dioxolane derivatives and converted to the 21-trifluoromethanesulfonate derivatives. Fluoride ion displacement, followed by acid-catalyzed deprotection, furnished in good yield the epimeric fluoroanalogs, (21S)- and (21R)-fluro R 5020 (1 and 2, affinities for PgR, 11 and 45%, respectively). These compounds were also prepared in 18F labeled form by the same route, in 14-32% overall radiochemical yield (decay corrected; synthesis time 90 min; sp. act. 370-1060 Ci/mmol). In tissue distribution studies in estrogen-primed immature rats, uterus-to-muscle ratios were 4.3 at 1 h for the 21S-epimer and 1.1 for the 21R-epimer, paralleling their relative binding affinities. Considerable metabolic defluorination was observed. The third fluorine-substituted progestin, DU 41165, has a novel retroprogesterone (9 beta, 10 alpha) structure, substituted with fluorine at C-6; its binding affinity is 145% relative to R 5020, and it was prepared in tritium-labeled form by acetylation of DU 41231, the 17 alpha-hydroxy precursor, with [3H]acetic anhydride. In estrogen-primed immature rats, this compound shows uterus-to-muscle ratios of 15 at 1 h, and 18-71 between 2 and 6 h, suggesting that compounds in this retroprogesterone series may be very promising candidates for selective imaging of PgR-positive tissues and tumors.
authors.affiliation: Department of Chemistry, University of Illinois, Urbana 61801.
authors.forename: M G
authors.initials: MG
authors.lastname: Pomper
authors.forename: K G
authors.initials: KG
authors.lastname: Pinney
authors.forename: K E
authors.initials: KE
authors.lastname: Carlson
authors.forename: H
authors.initials: H
authors.lastname: van Brocklin
authors.forename: C J
authors.initials: CJ
authors.lastname: Mathias
authors.forename: M J
authors.initials: MJ
authors.lastname: Welch
authors.forename: J A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging*; D005260:Female; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000000981:diagnostic imaging*; D009649:Norpregnadienes / Q000493:pharmacokinetics*; D011282:Pregnenediones / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011397:Promegestone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
chemical_list: D009649:Norpregnadienes; D011282:Pregnenediones; C064247:21-fluoropromegestone; C012151:DU 41165; D011397:Promegestone