[18F]Fluoroacetaldehyde, a new reagent for direct radiofluoroalkylation

1864 Objectives: The objectives of this work is to develop a new fluorination agent for labelling proteins and peptides in higher yields, shorter times and simpler methods than currently available agents. [18F]Fluoroacetaldehyde was produced by partial oxidation of [18F]Fluoroethyltosylate obtained by fluorination with [18F]fluoride of ethylene di-p-toluenesulfonate. [18F]Fluoroacetaldehyde was characterized after reaction with benzylamine. Methods: Cyclotron produced [18F]HF-water solution added to potassium bicarbonate and Kryptofix 222. After addition of 1 mL of acetonitrile the mixture was dried under argon at 110oC.To the dried Kryptofix/[18F]fluoride complex was added to a solution of ethylene di-p-toluenesulfonate in 0.3mL acetonitrile and the mixture was heated to 110oC. The radioactive yield of [18F]Fluoroethyltosylate (75 to 88%) was assessed by radioTLC. After evaporation of the solvent at room temperature and under argon, [18F]Fluoroethyltosylate was then partially oxidized to [18F]Fluoroacetaldehyde by reaction at 150oC. The radioactive yield of the oxidation reaction was 42-64%. Results: [18F]Fluoroacetaldehyde was characterized after reaction with benzylamine to give N-[18F]Fluoroethylbenzylamine which was analysed by HPLC. The reductive N-alkylation of benzylamine, 3.5 µL (32 µmol), took place in a ready-to-use commercial (Aldrich) cyanoborohydride phosphate buffered saline solution into which [18F]Fluoroacetaldehyde was distilled. The solution is made up of 0.02 M sodium phosphate, pH 7.5, containing 0.2 M sodium chloride and 3.0 g/L sodium cyanoborohydride. After 20 min the yield of the reaction at 80oC was 88% but only 27% at 50oC. A more hydrophilic molecule might give a better yield at low temperature. Stable N-Fluoroethylbenzylamine was synthesized following a different synthesis route. Fluoro-2-ethylamine was reacted with benzaldehyde in a reductive N-alkylation using sodium cyanoborohydride. The product of the reaction was characterized by mass spectroscopy and NMR and served as a reference compound. N-[18F]Fluoroethylbenzylamine was analysed by HPLC under reverse phase conditions found for the reference compound: C18 column (Waters semi prep. 30 x 0.7 cm) with phosphate buffer (pH 7.4) – acetonitrile (70:30 ) as eluent. A flow rate of 6 mL/min gave a retention time of 14 min. N-[18F]Fluoroethylbenzylamine co-eluted with the reference compound as a shoulder free peak. Conclusions: [18F]Fluoroacetaldehyde was produced, in a two steps reaction and in one pot, with an overall radioactive yield ranging from 31 to 56%. The advantage of using this reagent in reductive N-alkylation reaction is that the conditions are mild, phosphate buffered saline and low temperature, and might be used for protein radiolabelling.