Next-Gen ¹⁸F-Relay Reagent: Optimising [¹⁸F]Ethanesulfonyl Fluoride

Conventional nucleophilic radiofluorination requires azeotropic drying to generate reactive [¹⁸F]fluoride, introducing time delays and activity losses. [¹⁸F]Fluoride relay reagents such as [¹⁸F]triflyl fluoride ([¹⁸F]TfF) and [¹⁸F]ethenesulfonyl fluoride ([¹⁸F]E=SF) have recently emerged as efficient alternatives that bypass this step. Here, we introduce [¹⁸F]ethanesulfonyl fluoride ([¹⁸F]E-SF) as a new relay reagent and benchmark its production and radiolabelling performance against [¹⁸F]TfF and [¹⁸F]E=SF. [¹⁸F]E-SF was prepared from commercially available 2,4,6-trichlorophenyl-1-ethanesulfonate (TCP-ethane) using a microlitre-scale radiofluorination approach, enabling direct distillation and SPE trapping of the product. Under optimised conditions, [¹⁸F]E-SF was obtained in 76 ± 23% RCY (n = 6), compared with 27 ± 6% (n = 2) for [¹⁸F]E=SF and up to 97 ± 2% (n = 3) for [¹⁸F]TfF using an optimised literature-based protocol. Subsequent model labelling reactions demonstrated effective aliphatic nucleophilic substitution to [¹⁸F]fluoroethyl tosylate ([¹⁸F]FEtOTs) and aromatic nucleophilic substitution to [¹⁸F]fluorobenzaldehyde with high radiochemical conversion. These results establish [¹⁸F]E-SF as a robust and operationally simple relay reagent with high production yields from a commercially available precursor. It is compatible with SPE trapping and achieves production yields comparable to [¹⁸F]E=SF and [¹⁸F]TfF, respectively, warranting future automated production for supporting the potential use of [¹⁸F]E-SF in streamlined and decentralised ¹⁸F-labelling workflows.