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Selective inhibition of glycine transporter 1 (GlyT1) has emerged as a potential approach to alleviate N-methyl-d-aspartate receptor (NMDAR) hypofunction in patients with schizophrenia and cognitive decline. ALX5407 is a potent and selective inhibitor of GlyT1 derived from the metabolic intermediate sarcosine (N-methylglycine) that showed antipsychotic potential in a number of animal models. Whereas clinical application of ALX5407 is limited by adverse effects on motor performance and respiratory function, a suitably radiolabeled drug could represent a promising PET tracer for the visualization of GlyT1 in the brain. Herein, [18F]­ALX5407 and the corresponding methyl ester, [18F]­ALX5406, were prepared by alcohol-enhanced copper mediated radiofluorination and studied in vitro in rat brain slices and in vivo in normal rats. [18F]­ALX5407 demonstrated accumulation consistent with the distribution of GlyT1 in in vitro autoradiographic studies but no brain uptake in μPET experiments in naı̈ve rats. In contrast, the methyl ester [18F]­ALX5406 rapidly entered the brain and was enzymatically transformed into [18F]­ALX5407, resulting in a regional accumulation pattern consistent with GlyT1 specific binding. We conclude that [18F]­ALX5406 is a promising and easily accessible PET probe for preclinical in vivo imaging of GlyT1 in the brain.

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