Synthesis and characterization of [(125)I]2-iodo N-[(S)-{(S)-1-methylpiperidin-2-yl}(phenyl)methyl]3-trifluoromethyl-benzamide as novel imaging probe for glycine transporter 1.
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In this study, 2-iodo substituted 1-methylpiperidin-2-yl benzamide derivatives were synthesized and evaluated as candidate SPECT imaging agents for glycine transporter 1 (GlyT1). In JAR cells, which predominantly express GlyT1, 2-iodo N-[(S)-{(S)-1-methylpiperidin-2-yl}(phenyl)methyl]3-trifluoromethyl-benzamide (5) showed excellent inhibitory activity of [(3)H]glycine uptake (IC(50)=2.4nM). Saturation assay in rat cortical membranes revealed that [(125)I]5 had a single high affinity binding site with a K(d) of 1.54nM and a B(max) of 3.40pmol/mg protein. In vitro autoradiography demonstrated that [(125)I]5 showed consistent accumulation with GlyT1 expression. The in vitro binding was greatly inhibited by GlyT1 inhibitors but not by other site ligands, which suggested the high specific binding of [(125)I]5 with GlyT1. In the biodistribution and ex vivo autoradiography studies using mice, [(125)I]5 showed high blood-brain barrier permeability (1.68-2.17% dose/g at 15-60min) and similar regional brain distribution pattern with in vitro results. In addition, pre-treatment of GlyT1 ligands resulted in significant decrease of [(125)I]5 binding in the GlyT1-rich regions. This preliminary study demonstrated that radio-iodinated 5 is a promising SPECT imaging probe for GlyT1.
Bioorganic & Medicinal Chemistry, 19(21), pp.6245-6253; 2011
収録刊行物
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- Bioorganic & Medicinal Chemistry
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Bioorganic & Medicinal Chemistry 19 (21), 6245-6253, 2011-11-01
Elsevier BV
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詳細情報 詳細情報について
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- CRID
- 1050850247193215872
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- NII論文ID
- 120006985260
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- NII書誌ID
- AA10938083
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- ISSN
- 09680896
- 14643391
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- HANDLE
- 10069/26394
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- 本文言語コード
- en
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- journal article
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- IRDB
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