18F-ASEM, a radiolabeled antagonist for imaging the α7-nicotinic acetylcholine receptor with PET.
18F-ASEM, a radiolabeled antagonist for imaging the α7-nicotinic acetylcholine receptor with PET.
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DOI：
10.2967/jnumed.113.132068
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Dannals RF
中科院分区：
文献类型：
--
作者：
Horti AG;Gao Y;Kuwabara H;Wang Y;Abazyan S;Yasuda RP;Tran T;Xiao Y;Sahibzada N;Holt DP;Kellar KJ;Pletnikov MV;Pomper MG;Wong DF;Dannals RF
α7-烟碱胆碱能受体 (α7-nAChR) 是大脑通讯的关键介质，与多种中枢神经系统疾病有关。目前可用的 α7-nAChR PET 放射性配体均不适用于定量 PET 成像，主要是由于特异性结合不足。本研究的目的是评估 [18F]ASEM ([18F]JHU82132) 作为 PET 的 α7-nAChR 放射性配体的潜力。体外评估了 ASEM 的抑制结合测定和受体功能特性。在 DISC1 小鼠（解剖）和狒狒（PET）中评估基线和封锁时 [18F]ASEM 的大脑区域分布。 ASEM 是 α7-nAChR 的拮抗剂，具有高结合亲和力 (Ki = 0.3 nM)。 [18F]ASEM 很容易进入狒狒大脑并专门标记 α7-nAChR。 [18F]ASEM 在富含 α7-nAChR 的大脑区域中的体内特异性结合率为 80-90%。 SSR180711是一种α7-nAChR选择性部分激动剂，以剂量依赖性方式阻断狒狒脑中[18F]ASEM的结合，表明[18F]ASEM的结合是由α7-nAChR介导的，并且放射性配体适合药物评价研究。在狒狒基线研究中，[18F]ASEM的大脑区域分布容积（VT）值为23（丘脑）、22（岛叶）、18（海马）和14（小脑），而在结合选择性（封锁）扫描中，所有区域VT值均降至小于4。狒狒大脑中的区域结合电位（BPND）值范围为3.9至6.6。突变型 DISC1 小鼠（一种精神分裂症啮齿动物模型）中 [18F]ASEM 的体内脑结合和 α7-nAChR 表达显着低于对照动物，这与之前的人类尸检数据一致。 [18F]ASEM有望作为一种具有合适成像特性的放射性示踪剂，用于定量人脑中的α7-nAChR。
The α7-nicotinic cholinergic receptor (α7-nAChR) is a key mediator of brain communication and has been implicated in a wide variety of central nervous system disorders. None of the currently available PET radioligands for α7-nAChR are suitable for quantitative PET imaging, mostly due to insufficient specific binding. The goal of this study was to evaluate the potential of [18F]ASEM ([18F]JHU82132) as an α7-nAChR radioligand for PET. Inhibition binding assay and receptor functional properties of ASEM were assessed in vitro. The brain regional distribution of [18F]ASEM in baseline and blockade were evaluated in DISC1 mice (dissection) and baboons (PET). ASEM is an antagonist for the α7-nAChR with high binding affinity (Ki = 0.3 nM). [18F]ASEM readily entered the baboon brain and specifically labeled α7-nAChR. The in vivo specific binding of [18F]ASEM in the brain regions enriched with α7-nAChRs was 80–90%. SSR180711, an α7-nAChR selective partial agonist, blocked [18F]ASEM binding in the baboon brain in a dose-dependent manner, suggesting that the binding of [18F]ASEM was mediated by α7-nAChRs and the radioligand was suitable for drug evaluation studies. In the baboon baseline studies, the brain regional volume of distribution (VT) values for [18F]ASEM were 23 (thalamus), 22 (insula), 18 (hippocampus) and 14 (cerebellum), whereas in the binding selectivity (blockade) scan, all regional VT values were reduced to less than 4. The range of regional binding potential (BPND) values in the baboon brain was from 3.9 to 6.6. In vivo cerebral binding of [18F]ASEM and α7-nAChR expression in mutant DISC1 mice, a rodent model of schizophrenia, was significantly lower than in control animals, which is in agreement with previous post-mortem human data. [18F]ASEM holds promise as a radiotracer with suitable imaging properties for quantification of α7-nAChR in the human brain.
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影响因子：
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作者：
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