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

Zhang JC, Toyohara J, Wu J, Ishiwata K, Hashimoto K - Clin Psychopharmacol Neurosci (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

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 [(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.

No MeSH data available.


Related in: MedlinePlus

Radioactivity in the mouse brain and blood after intravenous injection of [11C]CHIBA-3007 (A), [11C]CHIBA-3009 (B) and [11C]CHIBA-3011 (C). Radioactivity was expressed as %ID/g.
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Figure 2: Radioactivity in the mouse brain and blood after intravenous injection of [11C]CHIBA-3007 (A), [11C]CHIBA-3009 (B) and [11C]CHIBA-3011 (C). Radioactivity was expressed as %ID/g.

Mentions: Tissue distribution studies of the three radioligands in the entire body and the regional brain of mice are summarized in Tables 1-3. The three radioligands exhibited a relatively fast clearance rate of radioactivity from the blood within 60 min. The half-lives for blood clearance were 15 min, 15 min, and 5 min for [11C]CHIBA-3007, [11C] CHIBA-3009, and [11C]CHIBA-3011, respectively (Fig. 2). The highest initial uptake (%ID/g) of [11C] CHIBA-3007 occurred in the lung followed by the kidney, heart, pancreas, small intestine, spleen, muscle, liver, blood, and brain sequentially (Table 1). Additionally, [11C]CHIBA-3007 displayed increased radioactivity in the small intestine, which might reflect hepatobiliary clearance of the parent tracers and/or their radioactive metabolites. The highest initial uptake of [11C] CHIBA-3009 was found in the lung followed by the kidney, liver, heart, pancreas, small intestine, spleen, muscle, blood, and brain (Table 2). The highest initial uptake of [11C]CHIBA-3011 was found in the kidney, followed by the spleen, lung, heart, pancreas, small intestine, liver, blood, muscle, and brain (Table 3).


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

Zhang JC, Toyohara J, Wu J, Ishiwata K, Hashimoto K - Clin Psychopharmacol Neurosci (2012)

Radioactivity in the mouse brain and blood after intravenous injection of [11C]CHIBA-3007 (A), [11C]CHIBA-3009 (B) and [11C]CHIBA-3011 (C). Radioactivity was expressed as %ID/g.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569154&req=5

Figure 2: Radioactivity in the mouse brain and blood after intravenous injection of [11C]CHIBA-3007 (A), [11C]CHIBA-3009 (B) and [11C]CHIBA-3011 (C). Radioactivity was expressed as %ID/g.
Mentions: Tissue distribution studies of the three radioligands in the entire body and the regional brain of mice are summarized in Tables 1-3. The three radioligands exhibited a relatively fast clearance rate of radioactivity from the blood within 60 min. The half-lives for blood clearance were 15 min, 15 min, and 5 min for [11C]CHIBA-3007, [11C] CHIBA-3009, and [11C]CHIBA-3011, respectively (Fig. 2). The highest initial uptake (%ID/g) of [11C] CHIBA-3007 occurred in the lung followed by the kidney, heart, pancreas, small intestine, spleen, muscle, liver, blood, and brain sequentially (Table 1). Additionally, [11C]CHIBA-3007 displayed increased radioactivity in the small intestine, which might reflect hepatobiliary clearance of the parent tracers and/or their radioactive metabolites. The highest initial uptake of [11C] CHIBA-3009 was found in the lung followed by the kidney, liver, heart, pancreas, small intestine, spleen, muscle, blood, and brain (Table 2). The highest initial uptake of [11C]CHIBA-3011 was found in the kidney, followed by the spleen, lung, heart, pancreas, small intestine, liver, blood, muscle, and brain (Table 3).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

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 [(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.

No MeSH data available.


Related in: MedlinePlus