[3H]Chiba-1001(methyl-SSR180711) has low in vitro binding affinity and poor in vivo selectivity to nicotinic alpha-7 receptor in rodent brain
[3H]Chiba-1001(methyl-SSR180711) has low in vitro binding affinity and poor in vivo selectivity to nicotinic alpha-7 receptor in rodent brain
复制标题
DOI：
10.1002/syn.21513
复制
发表时间：
2012-04-01
期刊：
影响因子：
2.3
通讯作者：
Maier, Donna L.
中科院分区：
文献类型：
--
作者：
Ding, Min;Ghanekar, Smita;Maier, Donna L.
神经烟碱型乙酰胆碱受体(NAChR)激动剂活性于α-7(α-7)受体亚型，是治疗精神分裂症、阿尔茨海默病和其他精神障碍认知障碍的潜在药物。SSR180711是一种α-7选择性部分激动剂，已被证明可以改善临床前认知。一种新的正电子发射断层扫描(PET)放射性配体11C-Chiba1001是SSR180711的类似物。我们用氚标记千叶-1001，以评估其作为临床前放射配基工具的实用性。在体外，在表达人α-7受体的HEK239细胞膜和天然大鼠海马膜上，[~3H]Chiba-1001与α-7受体的结合亲和力都很低(Kd=120-180 nM)。α-7选择性配体AZD0328、ARR17779和MLA不抑制[~3H]Chiba-1001结合(Ki>；10,000 nM)。在大鼠海马膜上，Chiba-1001和SSR180711抑制[~3H]Chiba-1001结合(Ki分别为220和230 nM)，与文献报道一致。放射性配基的体内结合谱在正常大鼠、野生型小鼠和α-7基因敲除小鼠脑中进行了检测。我们发现[~3H]Chiba-1001在大鼠和小鼠的大脑中缺乏足够和特异的大脑区域摄取。AZ11637326、AZD0328或MLA对动物的放射性配基结合没有明显的抑制作用。我们的结果表明，[~3H]Chiba-1001在体外对α-7nAChRs的亲和力较低，在啮齿类动物的脑内对α-7区域和药物选择性较差。Synapse，2012年。(C)2011年威利期刊公司。
Neuronal nicotinic acetylcholine receptor (nAChR) agonists active at the alpha-7 (alpha-7) receptor subtype are potential therapeutics for cognitive deficits in schizophrenia, Alzheimer's disease, and other mental disorders. SSR180711, an alpha-7 selective partial agonist, has been shown to improve preclinical cognition. A novel positron emission tomography (PET) radioligand, 11C-Chiba1001, is a close analog of SSR180711. We labeled Chiba-1001 with tritium in order to evaluate its utility as a preclinical radioligand tool. In vitro, the binding affinity of [3H]Chiba-1001 at the alpha-7 receptor was low (Kd = 120-180 nM) in both HEK239 cell membranes expressing human alpha-7 receptor and in native rat hippocampus membranes. The alpha-7 selective ligands AZD0328, ARR17779, and MLA did not inhibit [3H]Chiba-1001 binding (Ki > 10,000 nM). In rat hippocampal membranes, Chiba-1001 and SSR180711 inhibited [3H]Chiba-1001 binding (Ki = 220 and 230 nM, respectively), consistent with the literature reports. The in vivo binding profile of the radioligand was examined in normal rat, wild type mouse, and alpha-7 knockout mouse brain. We found that [3H]Chiba-1001 lacks adequate and specific brain regional uptake in rat and mouse brain. No significant inhibition of the radioligand binding was obtained following pretreatment of the animal with AZ11637326, AZD0328, or MLA. Our results indicate that [3H]Chiba-1001 has low affinity for alpha-7 nAChRs in vitro and poor alpha-7 regional and pharmacological selectivity in the rodent brain. Synapse, 2012. (c) 2011 Wiley Periodicals, Inc.