A closer look at the synthesis of 2-[¹⁸F]fluoroethyl tosylate to minimize the formation of volatile side-products

Background: 2-[¹⁸F]Fluoroethyltosylate ([¹⁸F]FEtOTs) is a well-known ¹⁸F-fluoroalkylating agent widely used to synthesize radiotracers for positron emission tomography. The widespread use of [¹⁸F]FEtOTs is due in part to its low volatility when compared to other halide and sulfonate building blocks. In this work, the radioactive volatile side-products formed during the synthesis of [¹⁸F]FEtOTs were identified and characterized for the first time, and an optimization of the reaction conditions to minimize their formation was proposed.

Results: In order to characterize the volatiles produced during [¹⁸F]FEtOTs synthesis, the reaction mixtures of both cold FEtOTs and [¹⁸F]FEtOTs were co-injected onto the HPLC system. The radioactive peaks corresponding to the volatile compounds were collected, analyzed through headspace gas chromatography mass spectrometry sampler (HS-GC–MS) and identified as vinyl fluoride ([¹⁹F]VF) and 2-fluoroethanol ([¹⁹F]FEOH). By using a rotatable central composite design with a two-level full factorial core of two factors (2²), it was determined that temperature and time are independent variables which affect the generation of [¹⁸F]VF and [¹⁸F]FEOH during the radiosynthesis of [¹⁸F]FEtOTs. In addition, in order to reduce the formation of the volatiles ([¹⁸F]VF and [¹⁸F]FEOH) and increase the yield of [¹⁸F]FEtOTs, it was demonstrated that the molar ratio of base to precursor must also be considered.

Conclusion: [¹⁸F]VF and [¹⁸F]FEOH are volatile side-products formed during the radiosynthesis of [¹⁸F]FEtOTs, whose yields depend on the reaction time, temperature, and the molar ratio of base to precursor. Therefore, special care should be taken during the radiosynthesis and subsequent reactions using [¹⁸F]FEOTs in order to avoid environmental contamination and to improve the yield of the desired products.