Automated synthesis of 11β-methoxy-4,16α-[16α-18F]difluoroestradiol (4F-M[18F]FES) for estrogen receptor imaging by positron emission tomography

Addition of both a 4-fluoro and 11β-methoxy group onto 16α-[18F]fluoroestradiol ([18F]FES) yields 11β-methoxy-4,16α-[16α-18F]difluoroestradiol (4F-M[18F]FES) with potential improved properties for positron emission tomography (PET) imaging of estrogen receptor densities in breast cancer patients. In order to provide 4F-M[18F]FES as a radiopharmaceutical for clinical trials, we developed an automated synthesis procedure using 3-O-methoxymethyl-11β-methoxy-4-fluoro-16,17-O-sulfuryl-16-epiestriol as precursor. The radio synthesis involves stereoselective opening of the protected cyclic sulfone precursor via nucleophilic fluorination with [18F]fluoride in acetonitrile. After removal of the protecting ether and 17β-sulphate groups by rapid hydrolysis in acidic ethanol and subsequent reversed-phase HPLC purification, the pure 4F-M[18F]FES was obtained as a sterile physiological saline solution in 45–50% radiochemical yield (decay corrected). The radiochemical purity of the final product was >98% and the effective specific activity (ESA) of 4F-M[18F]FES prepared under optimized conditions was >15,000 Ci/mmol. The total preparation time was 110±5 min and the product was shown to be stable for at least 6 h.