Fuchigami Takeshi, Fujimoto Noriko, Haradahira Terushi, Nojiri Yumiko, Okauchi Takashi, Maeda Jun, Suhara Tetsuya, Yamamoto Fumihiko, Nakayama Morio, Maeda Minoru, Mukai Takahiro
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
J Labelled Comp Radiopharm. 2018 Dec;61(14):1095-1105. doi: 10.1002/jlcr.3691. Epub 2018 Nov 18.
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 C-labeled N-benzyl amidine derivatives 2-[ C]methoxybenzyl) cinnamamidine ([ C]CBA), N-(2-[ C]methoxybenzyl)-2-naphthamidine ([ C]NBA), and N-(2-[ C]methoxybenzyl)quinoline-3-carboxamidine ([ C]QBA) as PET radioligands for these receptors. The C-benzyl amidines were synthesized via conventional methylation of corresponding des-methyl precursors with [ C]CH 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 C-labeled benzyl amidines showed high-specific binding to the GluN2B subunit at in vitro. In particular, the quinoline derivative [ 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 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 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.
含GluN2B的N-甲基-D-天冬氨酸受体（NMDARs）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碳-11标记的N-苄基脒衍生物2-([¹¹C]甲氧基苄基)肉桂脒([¹¹C]CBA)、N-(2-[¹¹C]甲氧基苄基)-2-萘脒([¹¹C]NBA)和N-(2-[¹¹C]甲氧基苄基)喹啉-3-甲脒([¹¹C]QBA)作为这些受体的正电子发射断层扫描（PET）放射性配体。碳-11苄基脒是通过用[¹¹C]CH₃I对相应的去甲基前体进行常规甲基化反应合成的。使用各种GluN2B调节剂和非靶向配体在脑矢状切片中检查体外结合特性。此外，在正常小鼠中进行了体内脑分布研究。碳-11标记的苄基脒在体外对GluN2B亚基显示出高特异性结合。特别是，喹啉衍生物[¹¹C]QBA在对富含GluN2B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，在生物分布实验中，这些碳-11放射性配体的脑分布与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形式。尽管这些碳-11配体对GluN2B亚基具有高特异性结合，但对于NMDARs的GluN2B亚基进行成功的正电子发射断层扫描（PET）成像，代谢稳定性仍需显著提高。
