Target tissue uptake selectivity of three fluorine-substituted progestins: potential imaging agents for receptor-positive breast tumors.
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.
Pomper
M G
MG
Department of Chemistry, University of Illinois, Urbana 61801.
Pinney
K G
KG
Carlson
K E
KE
van Brocklin
H
H
Mathias
C J
CJ
Welch
M J
MJ
Katzenellenbogen
J A
JA
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
D009649:Norpregnadienes; D011282:Pregnenediones; C064247:21-fluoropromegestone; C012151:DU 41165; D011397:Promegestone