In Vivo Evaluation of (11)C-labeled Three Radioligands for Glycine Transporter 1 in the Mouse Brain

OBJECTIVE: Glycine transporter 1 (GlyT-1) is one of the most attractive therapeutic targets for schizophrenia. There is great interest in developing radioligands for in vivo imaging of GlyT-1 in the brain using positron emission tomography. Here, we report the properties of three novel non-sarcosine-based radioligands [(11)C]CHIBA-3007, [(11)C]CHIBA-3009, and [(11)C]CHIBA-3011, for GlyT-1 imaging in the mouse brain in vivo. METHODS: The three radioligands were synthesized by N-[(11)C] methylation of the corresponding desmethyl precursor. A pharmacological characterization of these radioligands for in vivo imaging of GlyT-1 in the brain was conducted using male ddY mice. RESULTS: [(11)C]CHIBA-3009 and [(11)C]CHIBA-3011 were scarcely incorporated into the brain, whereas [(11)C]CHIBA-3007 showed slight but considerable brain uptake. Regional brain uptake of [(11)C]CHIBA-3007 (medulla oblongata>cerebellum>cortex) was similar to the distribution of the GlyT-1 protein. However, pretreatment with CHIBA-3007 (1 mg/kg) or the GlyT-1 selective inhibitor ALX5407 (N-[(3R)-3-([1,1'-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine) (30 mg/kg) did not significantly decrease brain uptake of [(11)C]CHIBA-3007, suggesting low specific binding to GlyT-1. Pretreatment with cyclosporin A significantly increased brain uptake of [(11)C]CHIBA-3009 and [(11)C]CHIBA-3011, suggesting a role for P-glycoprotein in the brain uptake of these ligands. All three radioligands were rapidly degraded intact forms were 3-18% in plasma and 15-74% in the brain at 15 min after injection. CONCLUSION: The results suggest that these three radioligands are not suitable for in vivo imaging of GlyT-1 in the brain because of low brain uptake and rapid metabolism. Further structural refinement is necessary to enhance brain uptake.