Wu Chunying, Pike Victor W, Wang Yanming
Department of Medicinal Chemistry, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
Curr Top Dev Biol. 2005;70:171-213. doi: 10.1016/S0070-2153(05)70008-9.
Tremendous efforts have been made in the search for a cure or effective treatment of Alzheimer's disease (AD) to develop therapies aimed at halting or reversing amyloid plaque deposition in the brain. This necessitates in vivo detection and quantification of amyloid plaques in the brain for efficacy evaluation of anti-amyloid therapies. For this purpose, a wide array of amyloid-imaging probes has been developed, mainly for in vivo studies based on positron emission tomography and single photon emission computed tomography. This review provides a full account of the development of amyloid-imaging agents. The in vitro binding properties and in vivo pharmacokinetic profiles of all amyloid-imaging agents so far reported are comprehensively and uniquely surveyed. Emphasis is placed on the development of small-molecule probes based on amyloid dyes, such as Congo red and thioflavin T. Compared to large biomolecules, these small-molecule probes have been systematically investigated through extensive structure activity relationship studies. Many of the probes show favorable properties for in vivo studies. As a result, three lead compounds, termed PIB (Pittsburgh-Compound B, [(11)C]6-OH-BTA-1), FDDNP (2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile), and SB-13 (4-N-methylamino-4'-hydroxystilbene), have been identified and evaluated in human subjects. Preliminary studies have indicated that these lead compounds exhibit a characteristic retention in AD subjects that is consistent with the AD pathology, thus proving the concept that amyloid deposits in the brain can be readily detected and quantified in vivo. The progress to date paves the way for further investigation in various aspects of AD research. Once developed, these amyloid-imaging agents could be used as biomarkers to aid in early and definitive diagnosis of AD, facilitate drug discovery and development, and allow pathophysiological studies of the disease mechanism. Furthermore, the success in the development of amyloid-imaging agents helps with the development of imaging agents for in vivo studies of other AD pathologies in particular and of neurodegenerative disorders in general.
为了研发旨在阻止或逆转大脑中淀粉样蛋白斑块沉积的疗法，人们在寻找阿尔茨海默病（AD）的治愈方法或有效治疗手段方面付出了巨大努力。这就需要在体内检测和定量大脑中的淀粉样蛋白斑块，以便对抗淀粉样蛋白疗法进行疗效评估。为此，人们开发了各种各样的淀粉样蛋白成像探针，主要用于基于正电子发射断层扫描和单光子发射计算机断层扫描的体内研究。本综述全面介绍了淀粉样蛋白成像剂的发展情况。对迄今报道的所有淀粉样蛋白成像剂的体外结合特性和体内药代动力学概况进行了全面且独特的调查。重点介绍了基于淀粉样蛋白染料（如刚果红和硫黄素T）的小分子探针的开发。与大分子相比，这些小分子探针已通过广泛的构效关系研究进行了系统研究。许多探针在体内研究中表现出良好的特性。结果，确定了三种先导化合物，即PIB（匹兹堡化合物B，[(11)C]6-OH-BTA-1）、FDDNP（2-(1-[6-[(2-[(18)F]氟乙基)(甲基)氨基]-2-萘基]亚乙基)丙二腈）和SB-13（4-N-甲基氨基-4'-羟基芪），并在人体受试者中进行了评估。初步研究表明，这些先导化合物在AD受试者中表现出与AD病理学一致的特征性滞留，从而证明了在体内可以轻松检测和定量大脑中淀粉样蛋白沉积的概念。迄今为止的进展为AD研究的各个方面的进一步研究铺平了道路。一旦开发成功，这些淀粉样蛋白成像剂可作为生物标志物，有助于AD的早期和明确诊断，促进药物发现和开发，并允许对疾病机制进行病理生理学研究。此外，淀粉样蛋白成像剂开发的成功有助于开发用于体内研究其他AD病理学特别是一般神经退行性疾病的成像剂。
