Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
Brain Res. 2010 Nov 11;1360:130-7. doi: 10.1016/j.brainres.2010.08.095.
The α7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. However, there are currently no suitable small molecule radioligands for imaging α7 nAChRs in the brain. In this study, we synthesized the novel radioligand [(125)I]4-iodophenyl 1,4-diazaicyclo[3.2.2]nonane-4-carboxylate ([(125)I]CHIBA-1006), a iodine-derivative of the selective α7 nAChR agonist SSR180711, and studied the characterization of [(125)I]CHIBA-1006 binding to rat brain membranes. The assays of [(125)I]CHIBA-1006 binding to rat brain membranes were performed at 4°C. The presence of a single saturable high-affinity binding component for [(125)I]CHIBA-1006 in the rat brain was shown. Scatchard analysis revealed an apparent equilibrium dissociation constant (K(d)) of 88.2±21.4nM and a maximal number of binding sites (B(max)) of 65.4±6.8fmol/mg protein (mean±SEM, n=4). The specific binding of [(125)I]CHIBA-1006 was inhibited by a number of α7 nAChR-selective ligands (e.g., unlabeled CHIBA-1006, SSR180711, CHIBA-1001, MG624 and A844606), suggesting a similarity among α7 nAChR pharmacological profiles. In contrast, α-bungarotoxin, MLA, and nicotine showed very weak affinity for [(125)I]CHIBA-1006 binding. The regional distribution of [(125)I]CHIBA-1006 binding to crude membranes from dissected regions of the rat brain was different from that of [(125)I]α-bungarotoxin binding, suggesting that [(125)I]CHIBA-1006 binding sites may not be identical to [(125)I]α-bungarotoxin binding sites in the rat brain. The present findings suggest that [(125)I]CHIBA-1006 would be a useful new small molecule radioligand for α7 nAChRs in the brain.
α7 型烟碱型乙酰胆碱受体 (nAChRs) 在精神神经疾病的病理生理学中发挥着重要作用，如精神分裂症和阿尔茨海默病。然而，目前尚无合适的小分子放射性配体可用于在大脑中成像 α7 nAChR。在这项研究中，我们合成了新型放射性配体 [(125)I]4-碘苯基 1,4-二氮杂环[3.2.2]壬烷-4-羧酸酯 ([(125)I]CHIBA-1006)，这是一种选择性 α7 nAChR 激动剂 SSR180711 的碘衍生物，并研究了 [(125)I]CHIBA-1006 与大鼠脑膜结合的特征。在 4°C 下进行 [(125)I]CHIBA-1006 与大鼠脑膜结合的测定。结果表明，在大鼠脑中存在一种用于 [(125)I]CHIBA-1006 的单一可饱和高亲和力结合成分。Scatchard 分析显示，表观平衡解离常数 (K(d)) 为 88.2±21.4nM，最大结合位点 (B(max)) 为 65.4±6.8fmol/mg 蛋白（平均值±SEM，n=4）。[(125)I]CHIBA-1006 的特异性结合受到多种 α7 nAChR 选择性配体的抑制（例如，未标记的 CHIBA-1006、SSR180711、CHIBA-1001、MG624 和 A844606），表明 α7 nAChR 药理学特征相似。相比之下，α-银环蛇毒素、MLA 和尼古丁对 [(125)I]CHIBA-1006 结合的亲和力非常弱。从大鼠脑解剖区域的粗膜中分离出的 [(125)I]CHIBA-1006 结合的区域分布与 [(125)I]α-银环蛇毒素结合的分布不同，这表明 [(125)I]CHIBA-1006 结合位点可能与大鼠脑中的 [(125)I]α-银环蛇毒素结合位点不同。本研究结果表明，[(125)I]CHIBA-1006 将成为大脑中 α7 nAChR 的有用新型小分子放射性配体。
