Synthesis and evaluation of 2-chloro N-[(S)-{(S)-1-[11？C]methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ([11？C]N-methyl-SSR504734) as a PET radioligand for glycine transporter 1

[11？C]N-methyl-SSR504734 was synthesized by N-[11？C]methylation of SSR504734 via [11？C]CH3OTf. In vitro brain distribution of [11？C]N-methyl-SSR504734 was tested in whole-hemisphere autoradiography (ARG) on human brain slices. Initial PET studies were performed using a cynomolgus monkey at baseline and after pretreatment with 0.1 to 1.5？mg/kg of SSR504734. Then, PET studies using rhesus monkeys were performed with arterial blood sampling at baseline and after pretreatment with 1.5 to 4.5？mg/kg SSR504734. Distribution volumes (VT) were calculated with a two-tissue compartment model, and GlyT1 occupancy by SSR504734 was estimated using a Lassen plot approach.[11？C]N-methyl-SSR504734 was successfully synthesized in moderate radiochemical yield and high specific radioactivity. In the ARG experiments, [11？C]N-methyl-SSR504734 showed specific binding in the white matter and pons. In the initial PET experiments in a cynomolgus monkey, [11？C]N-methyl-SSR504734 showed high brain uptake and consistent distribution with previously reported GlyT1 expression in vivo (thalamus, brainstem？>？cerebellum？>？cortical regions). However, the brain uptake increased after pretreatment with SSR504734. Further PET studies in rhesus monkeys showed a similar increase of brain uptake after pretreatment with SSR504734. However, the VT of [11？C]N-methyl-SSR504734 was found to decrease after pretreatment of SSR504734 in a dose-dependent manner. GlyT1 occupancy was calculated to be 45% and 73% at 1.5 and 4.5？mg/kg of SSR504734, respectively.[11？C]N-methyl-SSR504734 is demonstrated to be a promising PET radioligand for GlyT1 in nonhuman primates. The present results warrant further PET studies in human subjects.Glycine is a neurotransmitter of the inhibitory glycine receptors (GlyRs) but also serves as an essential co-agonist of the excitatory N-methyl-D-aspartate (NMDA) receptors [1,2]. It is known that the extracellular glycine concentration is modulated by two glycine transporters (GlyT1 and GlyT