Enhancement of Binding Affinity for Amyloid Aggregates by Multivalent Interactions of 99mTc-Hydroxamamide Complexes
Enhancement of Binding Affinity for Amyloid Aggregates by Multivalent Interactions of 99mTc-Hydroxamamide Complexes
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DOI：
10.1021/mp400499y
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发表时间：
2014-04-01
影响因子：
4.9
通讯作者：
Saji, Hideo
中科院分区：
文献类型：
--
作者：
Iikuni, Shimpei;Ono, Masahiro;Saji, Hideo
淀粉样蛋白聚集体的沉积被认为是淀粉样变进展的早期阶段。一种能够对淀粉样蛋白聚集体成像的成像探针能够早期诊断淀粉样变性，并有助于开发新的医学治疗方法。对淀粉样蛋白聚集体的高结合亲和力对于开发有用的分子成像探针至关重要。本文描述了一种新的策略，以提高靶向淀粉样蛋白聚集体显像剂的结合亲和力。我们设计并合成了具有二价淀粉样配体的新型tc -99m-羟酰胺（Tc-99m-Ham）复合物，并以β -淀粉样肽（a β(1-42)）聚集体为模型，评估了它们与淀粉样聚集体的结合亲和力。体外抑制实验表明，二价Tc-99m-Ham复合物对淀粉样蛋白聚集体的结合亲和力远高于单价复合物。Tg2576小鼠体外放射自显影显示，二价Tc-99m-Ham复合物与小鼠大脑中的A β斑块特异性结合，这反映在抑制实验的结果中。初步结果表明，基于二价Tc-99m-Ham复合物的新分子设计可能是开发针对淀粉样蛋白聚集体的成像探针的合理选择。
Deposition of amyloid aggregates has been regarded as an early stage of amyloidosis progression. An imaging probe that can image amyloid aggregates enables the early diagnosis of amyloidosis and contributes to the development of new medical therapies. High binding affinity for amyloid aggregates is essential to develop a useful molecular imaging probe. This article describes a new strategy to enhance the binding affinity of imaging agents targeting amyloid aggregates. We designed and synthesized novel Tc-99m-hydroxamamide (Tc-99m-Ham) complexes with a bivalent amyloid ligand and evaluated their binding affinity for amyloid aggregates by using beta-amyloid peptide (A beta(1-42)) aggregates as a model. In vitro inhibition assay indicated that bivalent Tc-99m-Ham complexes had much higher binding affinity for amyloid aggregates than monovalent complexes. In vitro autoradiography using Tg2576 mice showed the specific binding of bivalent Tc-99m-Ham complexes to A beta plaques in the mouse brain, as reflected in the results of the inhibition assay. The preliminary results suggest that a new molecular design based on bivalent Tc-99m-Ham complexes may be reasonable to develop an imaging probe targeting amyloid aggregates.