Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain
Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain
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DOI：
10.1016/s0024-3205(01)01232-2
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发表时间：
2001-08-17
期刊：
影响因子：
6.1
通讯作者：
Mathis, CA
中科院分区：
文献类型：
--
作者：
Klunk, WE;Wang, YM;Mathis, CA
体内评估沉积在淀粉样斑块(AP肽)或神经原纤维缠结(tau蛋白)中的β-折叠蛋白为阿尔茨海默病(AD)生物标志物的开发提供了一个靶点。为了开发体内的β-片状成像探针，合成并评价了硫代黄素-T(THT)的衍生物。这些化合物缺少带正电荷的四元杂环氮，因此在生理pH下不带电荷。它们的亲油性是它的600倍。这些Tht衍生物与Aβ(1-40)纤维结合的亲和力(K-I=20.2 nM)高于Tht(K-I=890 nM)。未带电的THT衍生物对死后AD脑内的斑块和神经原纤维缠结均进行了染色，显示出对斑块染色的一些偏好。制备了碳-11标记化合物[N-甲基-C-11](6)-Me-BTA-1，并研究了其在Swiss-Webster小鼠体内的脑进入和清除。这种化合物进入大脑的水平与常用的神经受体显像剂相当(注射后2分钟为0.223%ID-kg/g或7.61%ID/g)，并显示出对正常啮齿动物脑组织中自由和非特异性结合放射性的良好清除(脑清除t(1/2)=20分钟)，对淀粉样蛋白的相对高亲和力、对死后AD脑中斑块染色的特异性和神经原纤维缠结，良好的大脑进入和清除能力使[N-甲基-C-11]6-Me-BTA-1有望成为体内正电子发射断层扫描(PET)β片状显像剂的候选药物。(C)2001 Elsevier Science Inc.保留所有权利。
In vivo assessment of the beta-sheet proteins deposited in amyloid plaques (AP peptide) or neurofibrillary tangles (tau protein) presents a target for the development of biological markers for Alzheimer's disease (AD). In an effort to develop in vivo beta-sheet imaging probes, derivatives of thioflavin-T (ThT) were synthesized and evaluated. These compounds lack the positively charged quaternary heterocyclic nitrogen of ThT and are therefore uncharged at physiological pH. They are 600-fold more lipophilic than ThT. These ThT derivatives bind to A beta (1-40) fibrils with higher affinity (K-i = 20.2 nM) than ThT (K-i = 890 nM). The uncharged ThT derivatives stained both plaques and neurofibrillary tangles in post-mortem AD brain, showing, some preference for plaque staining. A carbon-11 labeled compound, [N-methyl-C-11](6)-Me-BTA-1, was prepared, and its brain entry and clearance were studied in Swiss-Webster mice. This compound entered the brain at levels comparable to commonly used neuroreceptor imaging agents (0.223 %ID-kg/g or 7.61 %ID/g at 2 min post-injection) and showed good clearance of free and non-specifically bound radioactivity in normal rodent brain tissue (brain clearance t(1/2) = 20 min), The combination of relatively high affinity for amyloid, specificity for staining plaques and neurofibrillary tangles in post-mortem AD brain, and good brain entry and clearance makes [N-methyl-C-11]6-Me-BTA-1 a promising candidate as an in vivo positron emission tomography (PET) beta-sheet imaging agent. (C) 2001 Elsevier Science Inc. All rights reserved.