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We prepared the 2,16α- and 4,16α-difluoroestradiols and their 11β-methoxy derivatives via two different pathways. The first route permits large scale synthesis and characterization of the final products while the second route was selected to allow for fluorination as a final step to facilitate labeling with the short-lived [18F]fluorine. The former route involves successive electrophilic fluorinations of intermediate bistrimethylsilyl enol ethers and 16α-fluoroestrones followed by reduction of the 17-ketone and chromatographic separation of the isomeric products. The second route proceeds via electrophilic substitution of estrone or 11β-methoxyestrone with N-fluoropyridinium salt to give the 2- and 4-fluoro derivatives followed by conversion to the reactive 16β,17β-cyclic sulfates. Stereoselective opening of the cyclic sulfates via nucleophilic fluorination with Me4NF and subsequent removal of the protecting ether and sulfate groups via rapid hydrolysis in acidic ethanol, gave the desired 16α-fluoro derivatives. The latter procedure is readily adapted for radiolabeling with 18F by substituting Me4NF for 18F− in acetonitrile. Preliminary biological data suggest that the addition of both a 4-fluoro and 11β-methoxy group onto 16α-[18F]fluoroestradiol (FES) may provide an improved radiopharmaceutical for positron emission tomography (PET) imaging of estrogen receptor densities in breast cancer patients.

We prepared a new series of 7α-substituted derivatives of 16α-fluoroestradiol, based on the very potent antiestrogen 7α-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}-estra-1,3,5(10)-triene-3,17β-diol (ICI 182,780; Faslodex™). The latter consist of estradiol functionalized with a side chain at the 7α-position, conferring interesting pharmaceutical properties for endocrine therapy of estrogen receptor (ER) positive breast cancer. The considerable advantages of ICI 182,780 over other selective ER-modulators (SERMs) already used in hormonal therapy, lead us to develop three new 16α-fluoro derivatives with potential use in positron emission tomography (PET), for the imaging of ER densities in breast tumors. Introduction of the long side chain at the 7α-position was accomplished by Cu(I)-promoted conjugate addition of a Grignard reagent to 6-dehydro-19-nortestosterone. Subsequent oxidation of the 17-hydoxy group and A-ring aromatization gave a 7α-substituted estrone derivative. Further addition to complete the side chain gave the ICI 182,780 mimics that were converted to the reactive 16β,17β-cyclic sulfates, i.e. the key intermediates for the 18F-labeling reaction. Opening of the cyclic sulfates via nucleophilic fluorination with Me4NF, followed by rapid hydrolysis in acidic ethanol of the protecting ether and sulfate groups, yielded the desired 16α-fluoro PET derivatives of ICI 182,780. The latter procedure is readily adapted for radiolabeling with 18F by substituting Me4NF for 18F− in acetonitrile.