The influence of functional groups and their relative position on isotopic exchange between 19F and 18F in aromatic rings.

BACKGROUND: Isotopic exchange with fluorine-18 offers a conceptually simple approach to positron emission tomography (PET) tracer development, as the target compound itself serves as the labeling precursor. RESULTS: In this study, we investigated the influence of functional groups and substituent position on the efficiency of isotopic exchange with fluorine-18. A total of 19 fluorobenzene derivatives were screened under standardized conditions, in dimethyl sulfoxide (175 °C) and dimethylformamide (150 °C) as solvents. Only a subset of compounds underwent efficient exchange; electron-withdrawing substituents strongly promoted isotopic exchange, with ortho and para isomers generally being more reactive than meta-analogues. The kinetics of the exchange in dimethyl sulfoxide were quantified for fluorobenzonitriles, nitrofluorobenzenes, and fluorobenzaldehydes. Nonlinear regression analysis indicated more rapid apparent exchange for the ortho- and para-substituted nitrile and nitro derivatives, together with higher apparent plateaus (≥84-94%), consistent with an SNAr-like mechanism involving stabilization of the Meisenheimer intermediate. By contrast, meta isomers were significantly less reactive, and no exchange was detected for 3-fluorobenzaldehyde. Fluorobenzaldehydes also showed lower overall apparent plateaus and signs of thermal instability in dimethyl sulfoxide. Full-scale labeling confirmed the feasibility of high molar activity, with isolated 2-[18F]fluorobenzonitrile obtained at 121 ± 37 GBq/µmol. Although radiochemical yield (5.84±2.23%, decay-corrected to the addition of tetraethylammonium [18F]fluoride) and radiochemical purity (88.6 ± 3.9%) remained modest, these results demonstrate that isotopic exchange can provide molar activities within the range required for PET radiopharmaceuticals. CONCLUSIONS: These findings clarify the functional group and positional influences on fluorine-19/fluorine-18 isotopic exchange, highlighting the potential of this strategy to streamline PET tracer development by circumventing the need for precursor development and extensive reaction optimization.