Synthesis of 2,16α- and 4,16α-difluoroestradiols and their 11β-methoxy derivatives as potential estrogen receptor-binding radiopharmaceuticals

Abstract

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.