ChemInform Abstract: Synthesis of 2,16α- and 4,16α-Difluoroestradiols and Their 11β-Methoxy Derivatives as Potential Estrogen Receptor-Binding Radiopharmaceuticals

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.