[I]2-Iodo--[()-{()-1-methylpiperidin-2-yl}(phenyl)methyl]3-trifluoromethyl-benzamide

[I]2-Iodo--[()-{()-1-methylpiperidin-2-yl}(phenyl)methyl]3-trifluoromethyl-benzamide, abbreviated as [I], is a 2-iodo-substituted derivative of SSR504734, which was synthesized by Fuchigami et al. for imaging neuropsychiatric disorders by targeting glycine transporter 1 (GlyT1) (1). Glycine is involved in excitatory and inhibitory neurotransmission in the mammalian central nervous system. Glycine metabolism is controlled by GlyT1 and glycine transporter 2 (GlyT2) (2). GlyT1 is widely distributed in the forebrain areas such as the cortex, hippocampus, and thalamus, as well as glycine-innervated regions such as the spinal cord, brainstem, and cerebellum (1, 3). This expression pattern of GlyT1, especially in the neocortex, is closely related to the distribution of glutamatergic -methyl-d-aspartate receptors (NMDAR). NMDAR dysfunction has been shown to be involved in various disorders such as schizophrenia, stroke, Parkinson’s disease, and Alzheimer’s disease, while glycine modulates excitatory neurotransmission by acting as a necessary co-agonist for NMDAR in the frontal brain areas (4-6). In this process, GlyT1 is considered to play an important role by regulating glycine concentration (5, 7, 8). Because of these findings, pharmacological manipulation of glycine-mediated neurotransmission with GlyT1 inhibitors has become an active field for the development of novel treatments for neuropsychiatric disorders, and evidence has demonstrated the beneficial effect of the inhibitors on the negative and cognitive symptoms of schizophrenia (3, 9). Meaningful progress has also been made in the development of imaging probes for GlyT1 to obtain the disease information and the occupancy of GlyT1 inhibitors (1, 10). Depoortere et al. synthesized the piperidine benzamide derivative 2-chloro--[()-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide (SSR504734) and determined that SSR504734 is a selective and reversible inhibitor of human, rat, and mouse GlyT1 (half-maximal inhibitory concentration (IC) = 18, 15, and 38 nM, respectively) (9). SSR504734 reversibly blocks the cortical uptake of glycine, thus increasing the extracellular levels of glycine in prefrontal cortex, and it exhibits therapeutic activity in schizophrenia, anxiety, and depression models in rats (9). Recently, C-labeled SSR504734 and its derivatives have been shown to exhibit high brain uptake and accumulation in the monkey brain, consistent with the GlyT1 distribution (10). Fuchigami et al. labeled the SSR504734 derivatives for imaging purposes by introducing a radioiodine atom into their 2-position (1). These compounds, especially [I], show high blood–brain barrier permeability and specific brain distribution in GlyT1-rich regions (1). This chapter summarizes the data obtained with [I].