Facile aromatic radiofluorination of [18F]flumazenil from diaryliodonium salts with evaluation of their stability and selectivity

Abstract

Aromatic radiofluorination of the diaryliodonium tosylate precursor with [¹⁸F]fluoride ions has been applied successfully to access [¹⁸F]flumazenil in high radiochemical yields of 67.2 ± 2.7% (decay corrected). The stability and reactivity of the diaryliodonium tosylate precursor plays a key role in increasing the production of ¹⁸F-labelled molecules under the fluorine-18 labelling condition. Various conditions were explored for the preparation of [¹⁸F]flumazenil from different diaryliodonium tosylate precursors. Optimum incorporation of [¹⁸F]fluoride ions in the 4-methylphenyl-mazenil iodonium tosylate precursor (5f) was achieved at 150 °C for 5 min by utilizing 4 mg of the precursor, K_2.2.2/K₂CO₃ complex, and the radical scavenger in N,N-dimethylformamide. This approach was extended to a viable method for use in automated synthesis with a radiochemical yield of 63.5 ± 3.2% (decay corrected, n = 26) within 60.0 ± 1.1 min. [¹⁸F]Flumazenil was isolated by preparative HPLC after the reaction was conducted under improved conditions and exhibited sufficient specific activity of 370–450 GBq μmol⁻¹, with a radiochemical purity of >99%, which will be suitable for human PET studies.