Automation of Copper-Mediated ¹⁸F-Fluorination of Aryl Pinacol Boronates Using 4-Dimethylaminopyridinium Triflate

Abstract

Currently, the copper-mediated radiofluorination of aryl pinacol boronates (arylBPin) using the commercially available, air-stable Cu(OTf)2Py4 catalyst is one of the most efficient synthesis approaches, greatly facilitating access to a range of radiotracers, including drug-like molecules with nonactivated aryl scaffolds. Further adjustment of this methodology, in particular, the [18F]fluoride recovery step for the routine preparation of radiotracers, has been the focus of recent research. In our recent study, an organic solution of 4-dimethylaminopyridinium trifluoromethanesulfonate (DMAPOTf) was found to be an efficient PTC for eluting radionuclides retained on the weak anion exchange cartridge, Oasis WAX 1cc, employing the inverse sorption–elution protocol. Notably, the following Cu-mediated radiofluorination of arylBPin precursors in the presence of the Cu(OTf)2(Py)4 catalyst can be performed with high efficiency in the same solvent, bypassing not only the conventional azeotropic drying procedure but any solvent replacement. In the current study, we aimed to translate this methodology, originally developed for remote-controlled operation with manual interventions, into the automated synthesis module on the TRACERlab automation platform. The adjustment of the reagent amounts and solvents allowed for high efficiency in the radiofluorination of a series of model arylBPin substrates on the TRACERlab FXFE Pro synthesis module, which was adapted for nucleophilic radiofluorinations. The practical applicability of the developed radiofluorination approach with DMAPOTf elution was demonstrated in the automated synthesis of 6-L-[18F]FDOPA. The radiotracer was obtained with an activity yield (AY; isolated, not decay-corrected) of 5.2 ± 0.5% (n = 3), with a synthesis time of ca. 70 min on the TRACERlab FX N Pro automation platform. The obtained AY was comparable with one reported by others (6 ± 1%) using the same boronate precursor, while a slightly higher AY of 6-L-[18F]FDOPA (14.5 ± 0.5%) was achieved in our previous work using commercially available Bu4NOTf as the PTC.

Keywords

• PET
• [¹⁸F]fluoride
• Cu mediated
• pyridinium sulfonates
• 6-L-[¹⁸F]FDOPA
• automation