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

Abstract

BackgroundIsotopic 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.ResultsIn 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.ConclusionsThese 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.