Pharmacological characterization of [³H]CHIBA-3007 binding to glycine transporter 1 in the rat brain.

Glycine transporter-1 (GlyT-1) in glial cells regulates extracellular levels of glycine, which acts as an obligatory co-agonist at the N-methyl-D-aspartate (NMDA) receptors in the brain. In the present study, we developed a novel radioligand, [³H]3-chloro-N-((S)-((R)-1-methylpiperidin-2-yl)(thiophen...

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Autores principales:	Jichun Zhang, Jin Wu, Jun Toyohara, Yuko Fujita, Hongxian Chen, Kenji Hashimoto
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8781b0f9301b4f59b14d94f7f61c2891
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spelling	oai:doaj.org-article:8781b0f9301b4f59b14d94f7f61c28912021-11-18T06:51:27ZPharmacological characterization of [³H]CHIBA-3007 binding to glycine transporter 1 in the rat brain.1932-620310.1371/journal.pone.0021322https://doaj.org/article/8781b0f9301b4f59b14d94f7f61c28912011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21731704/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Glycine transporter-1 (GlyT-1) in glial cells regulates extracellular levels of glycine, which acts as an obligatory co-agonist at the N-methyl-D-aspartate (NMDA) receptors in the brain. In the present study, we developed a novel radioligand, [³H]3-chloro-N-((S)-((R)-1-methylpiperidin-2-yl)(thiophen- 3-yl)methyl)-4- (trifluoromethyl)picolinamide ([³H]CHIBA-3007), for studying GlyT-1 in the brain. The presence of a single saturable high-affinity binding component for [³H]CHIBA-3007 binding to the rat brain membranes was detected. Scatchard analysis revealed an apparent equilibrium dissociation constant (K(d)) of 1.61±0.16 nM and a maximal number of binding sites (B(max)) of 692.8±22.8 fmol/mg protein (mean ± SEM, n = 3). The specific binding of [³H]CHIBA-3007 was inhibited by a number of GlyT-1 inhibitors, such as CHIBA-3007, desmethyl-CHIBA-3007, CHIBA-3008, SSR504734, NFPS/ALX5407, LY2365109 and Org24598, consistent with the pharmacological profiles of GlyT-1 inhibitors. Interestingly, the potency of eight GlyT-1 inhibitors (CHIBA-3007, desmethyl-CHIBA-3007, NFPS/ALX5407, LY2365109, Org24598, SSR504734, sarcosine, and glycine) for blocking in vitro specific binding of [³H]CHIBA-3007 was significantly correlated with the potency of these inhibitors for inhibiting [¹⁴C]glycine uptake in the rat brain membranes. In contrast, the GlyT-2 inhibitor ALX1393 exhibited very weak for [³H]CHIBA-3007 binding. Furthermore, the regional distribution of [³H]CHIBA-3007 binding in the rat brain was similar to the previously reported distribution of GlyT-1. The present findings suggest that [³H]CHIBA-3007 would be a useful new radioligand for studying GlyT-1 in the brain.Jichun ZhangJin WuJun ToyoharaYuko FujitaHongxian ChenKenji HashimotoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 6, p e21322 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jichun Zhang Jin Wu Jun Toyohara Yuko Fujita Hongxian Chen Kenji Hashimoto Pharmacological characterization of [³H]CHIBA-3007 binding to glycine transporter 1 in the rat brain.
description	Glycine transporter-1 (GlyT-1) in glial cells regulates extracellular levels of glycine, which acts as an obligatory co-agonist at the N-methyl-D-aspartate (NMDA) receptors in the brain. In the present study, we developed a novel radioligand, [³H]3-chloro-N-((S)-((R)-1-methylpiperidin-2-yl)(thiophen- 3-yl)methyl)-4- (trifluoromethyl)picolinamide ([³H]CHIBA-3007), for studying GlyT-1 in the brain. The presence of a single saturable high-affinity binding component for [³H]CHIBA-3007 binding to the rat brain membranes was detected. Scatchard analysis revealed an apparent equilibrium dissociation constant (K(d)) of 1.61±0.16 nM and a maximal number of binding sites (B(max)) of 692.8±22.8 fmol/mg protein (mean ± SEM, n = 3). The specific binding of [³H]CHIBA-3007 was inhibited by a number of GlyT-1 inhibitors, such as CHIBA-3007, desmethyl-CHIBA-3007, CHIBA-3008, SSR504734, NFPS/ALX5407, LY2365109 and Org24598, consistent with the pharmacological profiles of GlyT-1 inhibitors. Interestingly, the potency of eight GlyT-1 inhibitors (CHIBA-3007, desmethyl-CHIBA-3007, NFPS/ALX5407, LY2365109, Org24598, SSR504734, sarcosine, and glycine) for blocking in vitro specific binding of [³H]CHIBA-3007 was significantly correlated with the potency of these inhibitors for inhibiting [¹⁴C]glycine uptake in the rat brain membranes. In contrast, the GlyT-2 inhibitor ALX1393 exhibited very weak for [³H]CHIBA-3007 binding. Furthermore, the regional distribution of [³H]CHIBA-3007 binding in the rat brain was similar to the previously reported distribution of GlyT-1. The present findings suggest that [³H]CHIBA-3007 would be a useful new radioligand for studying GlyT-1 in the brain.
format	article
author	Jichun Zhang Jin Wu Jun Toyohara Yuko Fujita Hongxian Chen Kenji Hashimoto
author_facet	Jichun Zhang Jin Wu Jun Toyohara Yuko Fujita Hongxian Chen Kenji Hashimoto
author_sort	Jichun Zhang
title	Pharmacological characterization of [³H]CHIBA-3007 binding to glycine transporter 1 in the rat brain.
title_short	Pharmacological characterization of [³H]CHIBA-3007 binding to glycine transporter 1 in the rat brain.
title_full	Pharmacological characterization of [³H]CHIBA-3007 binding to glycine transporter 1 in the rat brain.
title_fullStr	Pharmacological characterization of [³H]CHIBA-3007 binding to glycine transporter 1 in the rat brain.
title_full_unstemmed	Pharmacological characterization of [³H]CHIBA-3007 binding to glycine transporter 1 in the rat brain.
title_sort	pharmacological characterization of [³h]chiba-3007 binding to glycine transporter 1 in the rat brain.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/8781b0f9301b4f59b14d94f7f61c2891
work_keys_str_mv	AT jichunzhang pharmacologicalcharacterizationof3hchiba3007bindingtoglycinetransporter1intheratbrain AT jinwu pharmacologicalcharacterizationof3hchiba3007bindingtoglycinetransporter1intheratbrain AT juntoyohara pharmacologicalcharacterizationof3hchiba3007bindingtoglycinetransporter1intheratbrain AT yukofujita pharmacologicalcharacterizationof3hchiba3007bindingtoglycinetransporter1intheratbrain AT hongxianchen pharmacologicalcharacterizationof3hchiba3007bindingtoglycinetransporter1intheratbrain AT kenjihashimoto pharmacologicalcharacterizationof3hchiba3007bindingtoglycinetransporter1intheratbrain
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Pharmacological characterization of [³H]CHIBA-3007 binding to glycine transporter 1 in the rat brain.

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