Estrogens labeled with fluorine-I 8 show selective receptor-mediated uptake into estrogen target tissues,' and one agent, 1 6u-[1~F]fluoroestradiol ( l ) , has been used to image estrogen receptor-positive human breast tumors.2 In order to improve on the uptake characteristics of 1, we have examined the effect of 11 p-ethyl and 11 p-methoxy groups, as substituents at this site are known to substantially affect the binding behavior of estr0gens.3~4 The llp-methoxy substituent has been used by us5 and others6-8 to improve the target tissue uptake selectivity of estrogens labeled with the gamma emitters Br-77 and 1-125.1 1 p-Ethyl-1 6a-fluoroestradiol (2) and 1 1 p-methoxy-1 6a-fluoroestradiol (3) were ultimately produced by a facile fluoride ion (or [18F]fluoride ion displacement of the corresponding p-disposed trifluoromethanesulfonates (triflates), as previously described [Scheme 11.9 1-Dehydroadrenosterone serves as a common precursor to the 1 1 p-ethyland 1 1 p-methoxy-bis-triflates, which are prepared in thirteen and eleven steps, respectively, through modification of literature procedures.10 In the key step of the sequence to 2, the palladium-catalyzed hydrogenation (1 atm), a 2.5:1 preference for the desired llp-epimer was observed. We found that trituration (ether) of the epimeric mixture of 3-deprotected estrones effected a clean isomer separation, with the 1 1 p-ethyl epimer remaining as the insoluble component; chromatography has traditionally been employed to achieve this separation.10The receptor binding affinity (RBA), estimated non-specific binding (NSB) and their ratio, the binding selectivity index (BSl),ll for compounds 1-3, are shown in Table I, together with data for the corresponding estradiols. To assure attainment of equilibrium, the binding assay was conducted for 18 h at 25OC, rather than 4OC.12 The Ilp-ethyl substituent in estradiol and 2 elevates the RBA 9-11 fold; although the NSB also is increased, the BSI values are greatly elevated. The 1 lp-methoxy substituted in estradiol and 3 lowers the RBA, but the NSB is lowered to a greater extent, so that the BSI values are still higher than E2 and 1, respectively.
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