期刊
ACTA PHARMACOLOGICA SINICA
卷 42, 期 3, 页码 491-498出版社
NATURE PUBL GROUP
DOI: 10.1038/s41401-020-0456-9
关键词
ionotropic glutamate receptors (iGluRs); NMDARs; GluN2B subunit; positron emission tomography (PET); carbon-11
资金
- NSFC [81901802, 81701751, 81871383]
- Postdoctoral Fund of the First Affiliated Hospital, Jinan University [801328]
- Science and Technology Program of Guangzhou [201804010440]
- Project of Innovative Team for the Guangdong Universities [2018KCXTD001]
- National Institutes of Health SIG grant [S10OD025234]
N-methyl-D-aspartate receptors (NMDARs) play important roles in the CNS, with GluN2B being a well-studied subtype. Two GluN2B-selective negative allosteric modulators were synthesized and preclinically evaluated for PET imaging. One PET ligand, [C-11]31, showed moderate specific binding to the GluN2B subtype.
N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to etiopathology of various CNS disorders and neurodegenerative diseases, GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs. Herein, we report the synthesis and preclinical evaluation of two(11)C-labeled GluN2B-selective negative allosteric modulators (NAMs) containingN,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography (PET) imaging. Two PET ligands, namely [C-11]31and [C-11]37(also called N2B-1810 and N2B-1903, respectively) were labeled with [C-11]CH3I in good radiochemical yields (decay-corrected 28% and 32% relative to starting [C-11]CO2, respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/mu mol). In particular, PET ligand [C-11]31demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies. However, because in vivo PET imaging studies showed limited brain uptake of [C-11]31(up to 0.5 SUV), further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据