Dimethylamino-fluorenes:: ligands for detecting β-amyloid plaques in the brain
Dimethylamino-fluorenes:: ligands for detecting β-amyloid plaques in the brain
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DOI：
10.1016/s0969-8051(03)00050-7
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发表时间：
2003-08-01
影响因子：
3.1
通讯作者：
Kung, HF
中科院分区：
文献类型：
--
作者：
Lee, CW;Kung, MP;Kung, HF
大脑中 β-淀粉样蛋白 (Abeta) 斑块的形成是阿尔茨海默病 (AD) 发病机制的一个主要因素。检测大脑中的 Abeta 斑块可能有助于早期诊断和监测疾病的进展。合成并表征了一系列基于芴的新型 Abeta 聚集体特异性配体，芴是简单且刚性的三环分子。从2-或3-氨基芴1a-1f开始，氨基以优异的产率转化为N,N-二甲基氨基(2a-2f)。结果发现，7-碘-2-N,N-二甲基氨基芴 (2f) 对预先形成的 Abeta40 聚集体表现出极高的结合亲和力 (K-i = 0.9 nM)。使用从含有 [I-125]2f 的转基因小鼠 (Tg2576) 获得的脑切片进行的体外放射自显影研究显示，与 Abeta 斑块具有极高的特异性结合。当用硫磺素-S（Abeta 斑块的常用荧光染料）染色时，同一切片也显示出等效的标记。当[1251]2f静脉注射到正常小鼠体内时，它表现出极好的脑摄取能力。综上所述，数据表明 [I-125]2f 可用作体内成像剂来检测大脑中的 Abeta 斑块。 (C) 2003 Elsevier Inc. 保留所有权利。
Formation of beta-amyloid (Abeta) plaques in the brain is a major contributing factor in the pathogenesis of Alzheimer's disease (AD). Detection of Abeta plaques in the brain will be potentially useful in early diagnosis and monitoring the progression of the disease. A series of novel Abeta aggregate-specific ligands based on fluorenes, which are simple and rigid tricyclic molecules, are synthesized and characterized. Starting with 2- or 3-aminofluorenes, 1a-1f, the amino group was converted to the N,N-dimethylamino group (2a-2f) in excellent yield. It was found that 7-iodo-2-N,N-dimethylaminofluorene (2f) showed an extremely high binding affinity to preformed Abeta40 aggregates (K-i = 0.9 nM). In vitro autoradiography study using brain sections obtained from transgenic mice (Tg2576) with [I-125]2f showed exquisitely high specific binding to Abeta plaques. The same section also displayed an equivalent labeling when stained by Thioflavin-S, a commonly used fluorescent dye for Abeta plaques. When [1251]2f was injected intravenously into normal mice, it exhibited an excellent brain uptake. Taken together the data suggest that [I-125]2f may be useful as an in vivo imaging agent to detect Abeta plaques in the brain. (C) 2003 Elsevier Inc. All rights reserved.