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Synthesis and preliminary studies of 11C-labeled tetrahydro-1,7-naphthyridine-2-carboxamides for PET imaging of metabotropic glutamate receptor 2
Theranostics ( IF 12.4 ) Pub Date : 2020-9-14 , DOI: 10.7150/thno.42587
Xiaofei Zhang 1, 2 , Yiding Zhang 3 , Zhen Chen 1 , Tuo Shao 1 , Richard Van 4 , Katsushi Kumata 3 , Xiaoyun Deng 1 , Hualong Fu 1 , Tomoteru Yamasaki 3 , Jian Rong 1 , Kuan Hu 3 , Akiko Hatori 3 , Lin Xie 3 , Qingzhen Yu 1 , Weijian Ye 5 , Hao Xu 5 , Douglas J Sheffler 6 , Nicholas D P Cosford 6 , Yihan Shao 4 , Pingping Tang 2 , Lu Wang 1, 5 , Ming-Rong Zhang 3 , Steven H Liang 1
Affiliation  

Selective modulation of metabotropic glutamate receptor 2 (mGlu2) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson's disease (PD), Alzheimer's disease (AD), drug abuse and addiction. Imaging mGlu2 using positron emission tomography (PET) would allow for in vivo quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. In this paper, we aimed to develop a novel specific radioligand derived from negative allosteric modulators (NAMs) for PET imaging of mGlu2./nMethods. A focused small molecule library of mGlu2 NAMs with tetrahydro naphthyridine scaffold was synthesized for pharmacology and physicochemical evaluation. GIRK dose-response assays and CNS panel binding selectivity assays were performed to study the affinity and selectivity of mGlu2 NAMs, among which compounds 14a and 14b were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the in vitro binding specificity and selectivity of [11C]14a and [11C]14b towards mGlu2. In vivo binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [11C]14b as most promising PET mGlu2 PET ligand./nResults. mGlu2 NAMs 14a-14g were synthesized in 14%-20% yields in five steps. NAMs 14a and 14b were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [11C]14a and [11C]14b displayed similar heterogeneous distribution by autoradiography, consistent with mGlu2 expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [11C]14b demonstrated superior binding specificity compared to [11C]14a. Further radiometabolite analysis of [11C]14b showed excellent stability in the brain./nConclusions. Compound 14b exhibited high affinity and excellent subtype selectivity, which was then evaluated by in vitro autoradiography and in vivo PET imaging study after labeling with carbon-11. Ligand [11C]14b, which we named [11C]MG2-1904, demonstrated high brain uptake and excellent in vitro/in vivo specific binding towards mGlu2 with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu2 in vivo derived from NAMs, which represents a promising chemotype for further development and optimization aimed for clinical translation.

中文翻译:

11C标记四氢-1,7-萘啶-2-甲酰胺的合成及用于代谢型谷氨酸受体2 PET成像的初步研究

选择性调节代谢型谷氨酸受体 2 (mGlu 2 ) 代表了一种治疗脑部疾病的新方法,包括精神分裂症、抑郁症、帕金森病 (PD)、阿尔茨海默病 (AD)、药物滥用和成瘾。使用正电子发射断层扫描 (PET) 对mGlu 2进行成像将允许在生理和病理条件下进行体内定量,并通过实现靶点参与研究来促进药物发现。在本文中,我们旨在开发一种源自负变构调节剂 (NAM) 的新型特异性放射性配体,用于 mGlu 2 ./n方法的 PET 成像。合成了具有四氢萘啶支架的mGlu 2 NAM的集中小分子库,用于药理学和理化评价。进行GIRK剂量反应测定和CNS面板结合选择性测定来研究mGlu 2 NAM的亲和力和选择性,其中化合物14a14b被选为PET配体候选物。SD大鼠脑切片的放射自显影用于确认[ 11 C] 14a和[ 11 C] 14b对mGlu 2的体外结合特异性和选择性。然后通过 PET 成像研究体内结合特异性。进行全身生物分布研究和放射性代谢物分析,以证明 [ 11 C] 14b作为最有前途的 PET mGlu 2 PET 配体的药代动力学特性。/n 结果。mGlu 2 NAM 14a-14g通过五步合成,产率为 14%-20%。NAM 14a14b因其在 GIRK 剂量反应测定中的高亲和力而被选为最有前途的配体。通过放射自显影, [ 11 C] 14a和[ 11 C] 14b显示出相似的异质分布,与大脑中mGlu 2 的表达一致。虽然 PET 成像研究显示两种示踪剂均具有良好的脑通透性,但与 [ 11 C] 14a相比,化合物 [ 11 C] 14b表现出更优异的结合特异性。[ 11 C] 14b的进一步放射代谢分析显示其在大脑中具有出色的稳定性。/n结论。化合物14b表现出高亲和力和优异的亚型选择性,并在碳11标记后通过体外放射自显影和体内PET成像研究进行评估。配体 [ 11 C] 14b,我们将其命名为 [ 11 C]MG2-1904,表现出高脑摄取率和对 mGlu 2的出色的体外/体内特异性结合,并且在脑中具有高代谢稳定性。作为概念验证,我们的初步工作展示了在体内可视化源自 NAM 的mGlu 2的成功示例,这代表了一种有前途的化学型,可用于进一步开发和优化以用于临床转化。
更新日期:2020-09-20
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