Fuchigami Takeshi, Haradahira Terushi, Fujimoto Noriko, Okauchi Takashi, Maeda Jun, Suzuki Kazutoshi, Suhara Tetsuya, Yamamoto Fumihiko, Sasaki Shigeki, Mukai Takahiro, Yamaguchi Hiroshi, Ogawa Mikako, Magata Yasuhiro, Maeda Minoru
Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Nucl Med Biol. 2008 Feb;35(2):203-12. doi: 10.1016/j.nucmedbio.2007.10.007.
High-affinity iodine- and ethyl-C-5 substituted analogs of 4-hydroxy-3-(3-[11C]methoxyphenyl)-2(1H)-quinolone ([11C]4HQ) were synthesized as new positron emission tomography radioligands for the glycine-binding sites of the N-methyl-d-aspartate (NMDA) ion channel. Although both radioligands showed high in vitro specific binding to rat brain slices, their binding characteristics were quite different from each other. 5-Ethyl-[11C]4HQ (5Et-[11C]4HQ) showed higher in vitro binding in the forebrain regions than in the cerebellum, bindings that were strongly inhibited by both glycine-site agonists and antagonists. In contrast, 5-iodo-[11C]4HQ (5I-[11C]4HQ) showed a homogeneous in vitro binding throughout the brain, which was inhibited by antagonists but not by agonists. This difference in in vitro binding between 5Et-[11C]4HQ and 5I-[11C]4HQ was quite similar to that previously observed between [11C]L-703,717 and [11C]4HQ, both glycine-site antagonists. In vivo brain uptakes of these 11C-labeled 4-hydroxyquinolones were examined in mice. Initial brain uptakes of 5Et- and 5I-[11C]4HQ at 1 min after intravenous injections were comparable to that of [11C]4HQ, but they were 1.3-2.1 times higher than that of [11C]L-703,717. The treatment with an anticoagulant, warfarin, only slightly increased the initial uptakes of [11C]4HQ and 5Et-[11C]4HQ in contrast to [11C]L-703,717. The in vivo regional brain distributions were slightly different between the two radioligands. Pretreatment with nonradioactive ligand (2 mg/kg) slightly inhibited the binding of 5Et-[11C]4HQ (16-36% inhibition) but not that of 5I-[11C]4HQ. In this study, it was found that a small structural change in [11C]4HQ resulted in a major change in binding characteristics and distributions, suggesting the existence of two binding sites for [11C]4-hydroxyquinolones on the NMDA ion channel - agonist-sensitive and agonist-insensitive (or antagonist-preferring) sites.
合成了4-羟基-3-(3-[11C]甲氧基苯基)-2(1H)-喹诺酮([11C]4HQ)的高亲和力碘代和乙基-C-5取代类似物，作为用于N-甲基-D-天冬氨酸(NMDA)离子通道甘氨酸结合位点的新型正电子发射断层扫描放射性配体。尽管两种放射性配体在体外均显示出与大鼠脑切片的高特异性结合，但其结合特性彼此差异很大。5-乙基-[11C]4HQ(5Et-[11C]4HQ)在前脑区域的体外结合高于小脑，甘氨酸位点激动剂和拮抗剂均强烈抑制这种结合。相比之下，5-碘-[11C]4HQ(5I-[11C]4HQ)在全脑显示出均匀的体外结合，其被拮抗剂抑制但不被激动剂抑制。5Et-[11C]4HQ和5I-[11C]4HQ之间的这种体外结合差异与先前在两种甘氨酸位点拮抗剂[11C]L-703,717和[11C]4HQ之间观察到的差异非常相似。在小鼠中检查了这些11C标记的4-羟基喹诺酮的体内脑摄取。静脉注射后1分钟时，5Et-[11C]4HQ和5I-[11C]4HQ的初始脑摄取与[11C]4HQ相当，但比[11C]L-703,717高1.3-2.1倍。与[11C]L-703,717相比，用抗凝剂华法林治疗仅略微增加了[11C]4HQ和5Et-[11C]4HQ的初始摄取。两种放射性配体之间的体内区域脑分布略有不同。用非放射性配体(2mg/kg)预处理略微抑制了5Et-[11C]4HQ的结合(抑制率为16-36%)，但未抑制5I-[11C]4HQ的结合。在本研究中，发现[11C]4HQ中的一个小结构变化导致结合特性和分布发生重大变化，表明在NMDA离子通道上存在两个[11C]羟基喹诺酮的结合位点——激动剂敏感位点和激动剂不敏感(或拮抗剂优先)位点。
