Efficient automated production of [¹⁸F]flumazenil through aromatic fluorination of an iodonium salts precursor

Objectives [¹⁸F]Flumazenil has been useful radiopharmaceutical for the assessment of the cBZR concentration in the brain. Although the NO₂-mazenil was known as the general precursor of [¹⁸F]flumazenil, its radiochemical yield in automatic production was poor for clinical research. As an alternative radiosynthetic pathway to label of [¹⁸F]flumazenil, we synthesized an iodonium salt precursor. In this study, we describe aromatic radiofluoriantion with iodonium salt-precursor in a commercial module and compared the labeling efficiencies between nitro-precursor and iodonium salt-precursor.

Methods An iodonium salt precursor was prepared from commercially available isatoic anhydride in five steps. Fully automated preparation of [¹⁸F]flumazenil was performed through aromatic fluorination of a nitro- or an iodonium salt-precursor, respectively using the TracerLab FX-FN module . To optimize the fluorine-18 incorporation condition, the labeling was investigated in various temperatures, amounts of precursor and solvents. The final product, [¹⁸F]flumazenil, was isolated by HPLC purification and then reformulated by solid-phase purification for clinical injectable 10% EtOH/saline.

Results The radiosynthesis of [¹⁸F]flumazenil using nitro-precursor was not sufficient to obtain the desired activity for clinical research compare to iodonium salt-precursor in fully automated system. Optimal labeling condition of [¹⁸F]flumazenil showed when iodonium salt-precursor was used. The best condition was that 10 mg of iodonium salt-precursor in DMF (1 mL) was incubated at 150 °C for 15 min with 40% TBAHCO₃ (10 μL). [¹⁸F]Flumazenil was obtained about 12-15% radiochemical yield (d.c., n=11) within total synthesis time of 70 min. In PET imaging study, [¹⁸F]flumazenil showed a good correlation with reported image.

Conclusions We developed the advanced [¹⁸F]flumazenil radiosynthesis using novel iodonium salt-precursor and showed more increased radiochemical yield than nitro-precursor