A simplified, robust protocol for [18F]fluoride elution under mild conditions to enhance late-stage aromatic radiofluorinations

Abstract

Abstract Direct radiofluorination of base-sensitive PET precursors is challenging due to the harsh reaction conditions of traditional fluorine-18 radiochemistry. In particular, the presence of inorganic bases with a relatively high conjugate p K a (e.g. K 2 CO 3 ) and phase-transfer catalysts (e.g. Kryptofix 2.2.2), and/or the need for azeotropic removal of elution solvents during fluorine-18 workup have been detrimental to reaction yields. This has limited the practical applicability of base-sensitive but clinically interesting radiotracers and, ultimately, their accessibility for patient care. By lowering alkalinity and eliminating the need for phase-transfer catalysts and azeotropic drying, we speculated that radiochemical conversions (RCCs) and yields (RCYs) would substantially be improved. We demonstrate that this can be achieved by using a weak anion exchange cartridge for trapping fluorine-18. No preconditioning is required, and fluorine-18 is easily eluted directly into the reaction vessel using a solution of weak base and organic solvent, the types of which can be adjusted to the specific requirements of the desired reaction. We demonstrate the general applicability of the procedure using various elution solutions and base-sensitive, copper-mediated radiofluorinations. As proof of concept, we markedly improve RCCs and RCYs for base-labile tetrazine precursors. To demonstrate its versatility, we expand the procedure to other types of radiofluorination reactions, including non-metal-mediated and isotopic exchange reactions.