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

摘要

We prepared the 2,16α- and 4,16α-difluoroestradiols and their 11β-methoxy derivatives via two different pathways.nThe first route permits large scale synthesis and characterization of the final products while the second route wasnselected to allow for fluorination as a final step to facilitate labeling with the short-lived [18F]fluorine. The formernroute involves successive electrophilic fluorinations of intermediate bistrimethylsilyl enol ethers and 16α-fluoroestronesnfollowed by reduction of the 17-ketone and chromatographic separation of the isomeric products. The second routenproceeds via electrophilic substitution of estrone or 11β-methoxyestrone with N-fluoropyridinium salt to give then2- and 4-fluoro derivatives followed by conversion to the reactive 16β,17β-cyclic sulfates. Stereoselective openingnof the cyclic sulfates via nucleophilic fluorination with Me4NF and subsequent removal of the protecting ether andnsulfate groups via rapid hydrolysis in acidic ethanol, gave the desired 16α-fluoro derivatives. The latter procedure isnreadily adapted for radiolabeling with 18F by substituting Me4NF for 18Fu0002 in acetonitrile. Preliminary biologicalndata suggest that the addition of both a 4-fluoro and 11β-methoxy group onto 16α-[18F]fluoroestradiol (FES)nmay provide an improved radiopharmaceutical for positron emission tomography (PET) imaging of estrogennreceptor densities in breast cancer patients.