FLUORINE-18-LABELED PROGESTIN 16A,L7A-DIOXOLANES - DEVELOPMENT OF HIGH-AFFINITY LIGANDS FOR THE PROGESTERONE-RECEPTOR WITH HIGH IN-VIVO TARGET SITE SELECTIVITY

We describe the synthesis and tissue biodistribution of two 21-[fluoro -F-18]progestin 16 alpha,17 alpha-furanyl ketals, potential agents for imaging progesterone receptor (PR)-positive breast tumors in humans, using positron emission tomography. 21-Fluoro-16 alpha,17 yl-methylide ne)dioxy]-19-norpregn-4-ene-3,20-dione (endo-10a) and 21-fluoro-16 alp ha,17 alpha-[(R)-(1'-alpha-furylethylidene) dioxy]-19-norpregn-4-ene-3 ,20-dione (endo-10b) were chosen for radiochemical synthesis from a se ries of seven novel progestin 16 alpha,17 alpha-(furanyldioxolanes) on the basis of their high relative binding affinity to PR (190% and 173 %, respectively, relative to R5020 = 100%), their low nonspecific bind ing (NSB) (log P-o/w = 3.87 and 4.13, respectively), and their resulti ng high binding selectivity indices (BSI; i.e., the ratio of their PR binding affinity to nonspecific binding). Radiochemical synthesis of t hese two species in high radiochemical purity and at high effective sp ecific activity was accomplished by treatment of the corresponding dia stereomerically pure 21-trifluoromethanesulfonates with fluorine-18 an ion. In tissue biodistribution studies in estrogen-primed immature fem ale Sprague-Dawley rats, both [F-18]-endo-10a and [F-18]endo-10b demon strated high PR-selective uptake in the principal target tissues, the uterus and the ovaries, and relatively low uptake in fat and bone. The metabolism at the 21-position in these progestins (as monitored by in vivo defluorination) appears to be less than that in other 21-fluorop rogestins; this may reflect steric inhibition of metabolism at this si te due to the bulk of the furan-substituted dioxolane ring at the 16 a lpha,17 alpha-position. Comparison with other fluorine-18-labeled prog estins shows that the PR-specific uptake in uterine tissue correlates with the BSI of the ligand and that the fat uptake correlates with the NSB of the ligand at high levels of statistical significance. These t wo dioxolanes may prove to be useful as breast tumor-imaging agents in humans.