双芳叉类双光子荧光探针的设计、合成及其在Aβ斑块成像中的应用

项目名称： 双芳叉类双光子荧光探针的设计、合成及其在Aβ斑块成像中的应用

项目编号： No.21502056

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 环境科学、安全科学

项目作者： 颜金武

作者单位： 华南理工大学

项目金额： 21万元

中文摘要： 目前尚无药物可以有效治疗阿尔茨海默症（AD）。在AD早期阶段甚至临床前阶段进行诊断，将有利于AD的防治。开发双光子荧光探针，对Aβ斑块进行实时荧光成像，在AD患者的早期诊断以及Aβ相关的基础研究领域都具有重要的研究和应用价值。基于双芳叉结构以及供体-受体-供体的探针原理，我们设计、合成了一系列新型的Aβ斑块双光子荧光探针。前期实验表明，部分化合物发射波长达到近红外区，并可以特异性地结合Aβ聚集体，其荧光信号显著增强；AD转基因小鼠离体脑切片成像实验表明，化合物可以透过血脑屏障，在体内特异性地结合Aβ斑块。在此基础上，本项目将进一步优化并合成双芳叉类探针化合物，并系统评价其光学性能以及对Aβ斑块的单/双光子成像能力，旨在开发一类激发和发射波长均达到近红外区的、性能优异的Aβ斑块双光子探针；并阐明该类探针与Aβ聚集体的结合模式与构效关系，为设计靶向Aβ斑块的新型双光子荧光探针提供新思路。

中文关键词： 双光子探针；双芳叉；阿尔茨海默病；淀粉样蛋白斑块；荧光成像

英文摘要： No disease-modifying treatments are currently available to reverse or stop the progress of Alzheimer’s disease (AD). Early diagnosis in the preclinical or early clinical stages of AD would be beneficial for the prevention and treatment of this disease. Real-time imaging Amyloid-β (Aβ) plaque with two-photon excited fluorescent probes is of great significance in the early clinical diagnosis of AD, and also the Aβ-related basic research field. We recently designed and synthesized a series of novel Aβ plaque two-photon probes based on the donor-acceptor-donor bis-arylidene scaffold. Preliminary results indicated that some probes could give near infrared (NIR) emission and specifically bind to Aβ aggregation with significant enhancement of fluorescent intensity. Ex vivo fluorescence observation of brain slices from AD Tg mice after injection of the probe revealed that our probes could penetrate the blood-brain barrier and detect the Aβ deposits in vivo. Based on the work above, we will further optimize and synthesize bis-arylidene compounds, and systematically evaluate their optical properties and ability to image and detect Aβ deposits by one/two-photon excited fluorescence technique. Our work aimed at developing Aβ plaque two-photon probes with NIR exciting and emission wavelength and other excellent properties, clarifying their binding mode and structure–activity relationship, and providing strategy for the development of novel Aβ plaque two-photon probes.

英文关键词： two-photon probe;bis-arylidene;Alzheimer’s disease ;Amyloid-β plaque;fluorescent imaging