Automated Copper‐Mediated Radiofluorination of [ ¹⁸ F]SynVesT‐1: A New Perspective in the Profiling and Control of Chemical Purity

Copper‐mediated radiofluorination (CMRF) of arylstannanes has emerged as a powerful strategy for accessing fluorine‐18 labeled radiotracers. Yet, concerns regarding chemical impurity profiles remain insufficiently addressed. Here, we report the fully automated production of the clinically relevant synaptic vesicle glycoprotein 2A tracer [ ¹⁸ F]SynVesT‐1 on a GE FASTLab module, together with a systematic investigation of the associated impurity profile. Trimethyl‐ and tri(n‐butyl)stannane precursors, as well as nonradioactive analytical standards for all major putative impurities, were synthesized. Automated radiosynthesis afforded [ ¹⁸ F]SynVesT‐1 in 20%–25% nondecay‐corrected radiochemical yield, >99% radiochemical purity, and preserved enantiomeric excess. Comprehensive UPLC‐MS analysis revealed the formation of protodestannylated, hydroxylated, methoxylated, and dimeric side products. Notably, the methoxy‐substituted analog was identified as the major chemical impurity. Systematic variation of fluoride preprocessing conditions and precursor structure demonstrated that both residual methanol and trimethylstannyl leaving groups contribute to methoxylation. Replacement of methanol by n ‐butanol during fluoride processing, combined with a tri( n ‐butyl)stannane precursor, dramatically improved chemical purity. Beyond [ ¹⁸ F]SynVesT‐1, these findings underscore the critical importance of thoroughly investigating the influence of all reaction parameters on the impurity profile in CMRF‐based radiopharmaceutical production.