In Vivo Evaluation of 11C-labeled Three Radioligands for Glycine Transporter 1 in the Mouse Brain.
- Author:
Ji Chun ZHANG
1
;
Jun TOYOHARA
;
Jin WU
;
Kiichi ISHIWATA
;
Kenji HASHIMOTO
Author Information
1. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. hashimoto@faculty.chiba-u.jp
- Publication Type:Original Article
- Keywords:
Glycine transporter 1;
Brain;
Positron-emission tomography;
CHIBA-3007;
CHIBA-3009;
CHIBA-3011
- MeSH:
Animals;
Brain;
Cyclosporine;
Glycine;
Glycine Plasma Membrane Transport Proteins;
Humans;
Ligands;
Male;
Methylation;
Mice;
Niacinamide;
P-Glycoprotein;
Plasma;
Positron-Emission Tomography;
Schizophrenia;
Thiophenes
- From:Clinical Psychopharmacology and Neuroscience
2012;10(1):34-43
- CountryRepublic of Korea
- Language:English
-
Abstract:
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 [11C]CHIBA-3007, [11C]CHIBA-3009, and [11C]CHIBA-3011, for GlyT-1 imaging in the mouse brain in vivo. METHODS: The three radioligands were synthesized by N-[11C] 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: [11C]CHIBA-3009 and [11C]CHIBA-3011 were scarcely incorporated into the brain, whereas [11C]CHIBA-3007 showed slight but considerable brain uptake. Regional brain uptake of [11C]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 [11C]CHIBA-3007, suggesting low specific binding to GlyT-1. Pretreatment with cyclosporin A significantly increased brain uptake of [11C]CHIBA-3009 and [11C]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.
