A Practical Method for the Preparation of (18)F-Labeled Aromatic Amino Acids from Nucleophilic [(18)F]Fluoride and Stannyl Precursors for Electrophilic Radiohalogenation

In a recent contribution of Scott et al., the substrate scope of Cu-mediated nucleophilic radiofluorination with [(18)F]KF for the preparation of (18)F-labeled arenes was extended to aryl- and vinylstannanes. Based on these findings, the potential of this reaction for the production of clinically relevant positron emission tomography (PET) tracers was investigated. To this end, Cu-mediated radiofluorodestannylation using trimethyl(phenyl)tin as a model substrate was re-evaluated with respect to different reaction parameters. The resulting labeling protocol was applied for (18)F-fluorination of different electron-rich, -neutral and -poor arylstannyl substrates in RCCs of 16–88%. Furthermore, this method was utilized for the synthesis of (18)F-labeled aromatic amino acids from additionally N-Boc protected commercially available stannyl precursors routinely applied for electrophilic radiohalogenation. Finally, an automated synthesis of 6-[(18)F]fluoro-l-m-tyrosine (6-[(18)F]FMT), 2-[(18)F]fluoro-l-tyrosine (2-[(18)F]F-Tyr), 6-[(18)F]fluoro-l-3,4-dihydroxyphenylalanine (6-[(18)F]FDOPA) and 3-O-methyl-6-[(18)F]FDOPA ([(18)F]OMFD) was established furnishing these PET probes in isolated radiochemical yields (RCYs) of 32–54% on a preparative scale. Remarkably, the automated radiosynthesis of 6-[(18)F]FDOPA afforded an exceptionally high RCY of 54 ± 5% (n = 5).