Synthesis and characterization of 11 C-labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors.
Synthesis and characterization of 11 C-labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors.
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DOI：
10.1002/jlcr.3691
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发表时间：
2018-11
影响因子：
1.8
通讯作者：
Takeshi Fuchigami;N. Fujimoto;T. Haradahira;Y. Nojiri;T. Okauchi;J. Maeda;T. Suhara;F. Yamamoto;M. Nakayama;M. Maeda;T. Mukai
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文献类型：
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作者：
Takeshi Fuchigami;N. Fujimoto;T. Haradahira;Y. Nojiri;T. Okauchi;J. Maeda;T. Suhara;F. Yamamoto;M. Nakayama;M. Maeda;T. Mukai
含有 GluN2B 的 NMDA 受体 (NMDAR) 在学习和记忆中发挥着重要作用，尽管它们也与各种脑部疾病有关。在本研究中，我们合成并评估了三种11 C标记的N-苄基脒衍生物2-[11 C]甲氧基苯甲基)肉桂脒([11 C]CBA)、N-(2-[11 C]甲氧基苯甲基)-2-萘脒([11 C]NBA)和N-(2-[11 C]甲氧基苄基)喹啉-3-甲脒 ([11 C]QBA) 作为这些受体的 PET 放射性配体。 11 C-苄基脒是通过用 [11 C]CH3 I 对相应的去甲基前体进行常规甲基化来合成的。使用各种 GluN2B 调节剂和脱靶配体在脑矢状切片中检查了体外结合特征。此外，在正常小鼠中进行了体内脑分布研究。 11 C标记的苄基脒在体外表现出与GluN2B亚基的高特异性结合。特别是，喹啉衍生物[11 C]QBA在对GluN2B富含区域的高脑定位和对GluN2B亚基的特异性方面具有最佳的结合特性。相反，这些 11 C-放射性配体显示大脑分布与生物分布实验中的 GluN2B 表达不一致。大多数放射性标记化合物被鉴定为代谢形式，其中酰胺衍生物似乎是主要种类。尽管这些 11 C 配体与 GluN2B 亚基具有高特异性结合，但代谢稳定性的显着改善对于 NMDAR 的 GluN2B 亚基的成功正电子发射断层扫描 (PET) 成像是必要的。
GluN2B-containing NMDA receptors (NMDARs) play fundamental roles in learning and memory, although they are also associated with various brain disorders. In this study, we synthesized and evaluated three 11 C-labeled N-benzyl amidine derivatives 2-[11 C]methoxybenzyl) cinnamamidine ([11 C]CBA), N-(2-[11 C]methoxybenzyl)-2-naphthamidine ([11 C]NBA), and N-(2-[11 C]methoxybenzyl)quinoline-3-carboxamidine ([11 C]QBA) as PET radioligands for these receptors. The 11 C-benzyl amidines were synthesized via conventional methylation of corresponding des-methyl precursors with [11 C]CH3 I. In vitro binding characteristics were examined in brain sagittal sections using various GluN2B modulators and off-target ligands. Further, in vivo brain distribution studies were performed in normal mice. The 11 C-labeled benzyl amidines showed high-specific binding to the GluN2B subunit at in vitro. In particular, the quinoline derivative [11 C]QBA had the best binding properties in terms of high-brain localization to GluN2B-rich regions and specificity to the GluN2B subunit. Conversely, these 11 C-radioligands showed the brain distributions were inconsistent with GluN2B expression in biodistribution experiments. The majority of the radiolabeled compounds were identified as metabolized forms of which amido derivatives seemed to be the major species. Although these 11 C-ligands had high-specific binding to the GluN2B subunit, significant improvement in metabolic stability is necessary for successful positron emission tomography (PET) imaging of the GluN2B subunit of NMDARs.