GSK-1018921

The current interest in developing Glycine transporter Type 1 (GlyT‐1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT‐1 PET molecular imaging tool to aid drug development and dose selection. We report on [11C]GSK931145 as a novel GlyT‐1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma‐occupancy relationship of the GlyT‐1 inhibitor GSK1018921. Human PET studies were performed to determine the test–retest reproducibility of [11C]GSK931145 and the plasma‐occupancy relationship of GSK1018921. [11C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction (fP: 0.8 vs. 8%) and delivery (K1: 0.025 vs. 0.126 ml cm−3min−1) were significantly lower in humans. Test–retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR(VT): 29–38%), but was improved using a pseudo reference tissue model (VAR(BPND): 16–23%). GSK1018921 EC50estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively. Synapse, 2011. © 2011 Wiley‐Liss, Inc.