Maeda Jun, Suhara Tetsuya, Kawabe Kouichi, Okauchi Takashi, Obayashi Shigeru, Hojo Junko, Suzuki Kazutoshi
Brain Imaging Project, National Institute of Radiological Sciences, Chiba, Japan.
Synapse. 2003 Mar;47(3):200-8. doi: 10.1002/syn.10169.
Although [(11)C]Ro15-4513 and [(11)C]flumazenil both bind to the central benzodiazepine (BZ) receptors, the distributions of the two ligands are not identical in vivo. Moreover, the in vivo pharmacological properties of [(11)C]Ro15-4513 have not been thoroughly examined. In the present study, we examined the pharmacological profile of [(11)C]Ro15-4513 binding in the monkey brain using positron emission tomography (PET). [(11)C]Ro15-4513 showed relatively high accumulation in the anterior cingulate cortex, hippocampus, and insular cortex, with the lowest uptake being observed in the pons. Accumulation in the cerebral cortex was significantly diminished by the BZ antagonist flumazenil (0.1 mg/kg, i.v.), but not that in the pons. Using the pons as a reference region, the specific binding of [(11)C]Ro15-4513 in most of the cerebral cortex including the limbic regions clearly revealed two different affinity sites. On the other hand, specific binding in the occipital cortex and cerebellum showed only a low affinity site. Zolpidem with affinity for alpha1, alpha2, and alpha3 subunits of GABA(A)/BZ receptor fully inhibited [(11)C]Ro15-4513 binding in the occipital cortex and cerebellum, while only about 23% of the binding was blocked in the anterior cingulate cortex. Diazepam with affinity for alpha1, alpha2, alpha3, and alpha5 subunits inhibited the binding in all brain regions. Since Ro15-4513 has relatively high affinity for the alpha5 subunit in vitro, these in vivo bindings of [(11)C]Ro15-4513 can be interpreted as the relatively high accumulation in the fronto-temporal limbic regions representing binding to the GABA(A)/BZ receptor alpha5 subunit.
尽管[(11)C]Ro15 - 4513和[(11)C]氟马西尼均与中枢苯二氮䓬（BZ）受体结合，但这两种配体在体内的分布并不相同。此外，[(11)C]Ro15 - 4513的体内药理学特性尚未得到充分研究。在本研究中，我们使用正电子发射断层扫描（PET）研究了[(11)C]Ro15 - 4513在猴脑中的结合药理学特征。[(11)C]Ro15 - 4513在前扣带回皮质、海马和岛叶皮质中显示出相对较高的积聚，而在脑桥中的摄取最低。BZ拮抗剂氟马西尼（0.1 mg/kg，静脉注射）可显著减少[(11)C]Ro15 - 4513在大脑皮质中的积聚，但对脑桥中的积聚无影响。以脑桥作为参考区域，[(11)C]Ro15 - 4513在包括边缘区域在内的大部分大脑皮质中的特异性结合清楚地显示出两个不同的亲和力位点。另一方面，[(11)C]Ro15 - 4513在枕叶皮质和小脑中的特异性结合仅显示出一个低亲和力位点。对GABA(A)/BZ受体的α1、α2和α3亚基具有亲和力的唑吡坦完全抑制了[(11)C]Ro15 - 4513在枕叶皮质和小脑中的结合，而在前扣带回皮质中仅约23%的结合被阻断。对α1、α2、α3和α5亚基具有亲和力的地西泮抑制了所有脑区的结合。由于Ro15 - 4513在体外对α5亚基具有相对较高的亲和力，[(11)C]Ro15 - 4513的这些体内结合可解释为在额颞边缘区域的相对较高积聚，代表与GABA(A)/BZ受体α5亚基的结合。
