Radioiodinated Benzyloxybenzene Derivatives: A Class of Flexible Ligands Target to 尾-Amyloid Plaques in Alzheimer鈥檚 Brains

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• 作者：Yanping Yang ; Mengchao Cui ; Xiaoyang Zhang ; Jiapei Dai ; Zhiyong Zhang ; Chunping Lin ; Yuzhi Guo ; Boli Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：6030-6042
• 全文大小：767K
• ISSN：1520-4804

文摘

Benzyloxybenzene, as a novel flexible scaffold without rigid planarity, was synthesized and evaluated as ligand toward A尾 plaques. The binding site calculated for these flexible ligands was the hydrophobic Val18_Phe20 channel on the flat surface of A尾 fiber. Structure鈥揳ctivity relationship analysis generated a common trend that binding affinities declined significantly from para-substituted ligands to ortho-substituted ones, which was also quantitatively illustrated by 3D-QSAR modeling. Autoradiography in vitro further confirmed the high affinities of radioiodinated ligands [¹²⁵I]4, [¹²⁵I]24, and [¹²⁵I]22 (K_i = 24.3, 49.4, and 17.6 nM, respectively). In biodistribution, [¹²⁵I]4 exhibited high initial uptake and rapid washout property in the brain with brain_2聽min/brain_60聽min ratio of 16.3. The excellent in vitro and in vivo biostability of [¹²⁵I]4 enhanced its potential for clinical application in SPECT imaging of A尾 plaques. This approach could also allow the design of a new generation of A尾 targeting ligands without rigid and planar framework.