Smart Near-Infrared Fluorescence Probes with Donor-Acceptor Structure for in Vivo Detection of β-Amyloid Deposits
Smart Near-Infrared Fluorescence Probes with Donor-Acceptor Structure for in Vivo Detection of β-Amyloid Deposits
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DOI：
10.1021/ja4052922
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发表时间：
2014-03-05
影响因子：
15
通讯作者：
Saji, Hideo
中科院分区：
文献类型：
--
作者：
Cui, Mengchao;Ono, Masahiro;Saji, Hideo
β-淀粉样蛋白（A β）斑块在脑实质和皮质中的沉积被认为是阿尔茨海默病（AD）的主要病理标志;然而，AD的早期检测仍然存在挑战。在分子成像技术的辅助下，特异性靶向脑中A β斑块的成像剂可能导致AD的早期诊断。在此，我们报告了一系列智能近红外荧光（NIRF）成像探针的设计，合成和评估与供体受体结构桥接的共轭π电子链A β斑块。这些NIRF探针的化学结构与刚果红和硫磺素-T完全不同。具有较长共轭π系统（碳碳双键）的探针在PBS中显示最大发射（>650 nm），其福尔斯落在NIRF探针的最佳范围内。在AD患者和双转基因小鼠的脑切片的荧光染色中，以及在使用A β（1-42）聚集体的体外结合测定中，证明这些探针对A β斑块具有亲和力。选择一种具有高亲和力的探针（k（i）= 37 nM，K-d = 27 nM）用于体内成像。它可以有效地穿透裸鼠的血脑屏障，并迅速从正常大脑中冲洗出来。此外，在静脉注射该探针后，22个月大的APPswe/PSENI小鼠在同一时间段内表现出比对照小鼠更高的相对信号，并且离体荧光观察证实了A β斑块的存在。总之，该探头满足NIRF造影剂在体外和体内检测A β斑块的大部分要求。
The deposition of beta-amyloid (A beta) plaques in the parenchymal and cortical brain is accepted as the main pathological hallmark of Alzheimer's disease (AD); however, early detection of AD still presents a challenge. With the assistance of molecular imaging techniques, imaging agents specifically targeting A beta plaques in the brain may lead to the early diagnosis of AD. Herein, we report the design, synthesis, and evaluation of a series of smart near-infrared fluorescence (NIRF) imaging probes with donor acceptor architecture bridged by a conjugated pi-electron chain for A beta plaques. The chemical structure of these NIRF probes is completely different from Congo Red and Thioflavin-T. Probes with a longer conjugated pi system (carbon carbon double bond) displayed maximum emission in PBS (>650 nm), which falls in the best range for NIRF probes. These probes were proved to have affinity to A beta plaques in fluorescent staining of brain sections from an AD patient and double transgenic mice, as well as in an in vitro binding assay using A beta(1-42) aggregates. One probe with high affinity (k(i) = 37 nM, K-d = 27 nM) was selected for in vivo imaging. It can penetrate the blood-brain barrier of nude mice efficiently and is quickly washed out of the normal brain. Moreover, after intravenous injection of this probe, 22-month-old APPswe/PSENI mice exhibited a higher relative signal than control mice over the same period of time, and ex vivo fluorescent observations confirmed the existence of A beta plaques. In summary, this probe meets most of the requirements for a NIRF contrast agent for the detection of A beta plaques both in vitro and in vivo.