Flexible multidentate benzyldiamine derivatives with high affinity for beta-amyloid in cerebral amyloid angiopathy
Flexible multidentate benzyldiamine derivatives with high affinity for beta-amyloid in cerebral amyloid angiopathy
复制标题
灵活的多齿苯甲基二胺衍生物，对脑淀粉样血管病中的β-淀粉样蛋白具有高亲和力。
DOI：
10.1007/s11030-020-10098-y
复制
发表时间：
2021
影响因子：
3.8
通讯作者：
Jia Jianhua
中科院分区：
文献类型：
--
作者：
He Yujia;Fu Tingting;Li Yuying;Xue Weiwei;Cui Mengchao;Wang Liang;Niu Mengda;Peng Zhiping;Jia Jianhua
摘要脑淀粉样血管病（cerebral amyloid angiopathy， CAA）常见于老年人，其病理特征是β-淀粉样蛋白（β）在脑动脉和毛细血管壁沉积。本研究设计并合成了四种柔性多齿苯二胺衍生物，作为脑血管a β沉积的潜在探针。在体外抑制实验中，配体18 - 21对a β聚集体具有较高的亲和力，亲和度分别为1.45±0.53 nM、1.68±0.35 nM、1.16±0.23 nM和1.72±0.19 nM。与单体、化合物9 - 12或苯二胺衍生物的结合亲和力显著提高，证明了多齿方法的适用性。通过分子对接技术探索了这些新型a β试剂的作用机制，从理论上验证了多齿苯二胺衍生物对a β聚集体的高亲和性。此外，配体18 - 21的分子质量超过700道尔顿，很难穿透血脑屏障。因此，这些配体可用于区分CAA与另一种a β相关疾病阿尔茨海默病。为了将这些配体转化为正电子发射断层成像剂，我们尝试了放射性合成[18F]18。虽然放射性标记不是很成功，但初步结果表明，这些新提出的多齿苯二胺衍生物可能用作脑淀粉样血管病的潜在a β显像剂。图形抽象
AbstractCerebral amyloid angiopathy (CAA) commonly found in the aged is pathologically characterized byβ-amyloid (Aβ) deposition in the walls of arteries and capillaries of brain. In this study, four flexible multidentate benzyldiamine derivatives as potential probes for cerebrovascular Aβdeposition were designed and synthesized. In in vitro inhibition assays, the ligands18–21displayed high affinities for Aβaggregates withKivalues of 1.45 ± 0.53 nM, 1.68 ± 0.35 nM, 1.16 ± 0.23 nM and 1.72 ± 0.19 nM, respectively. A significant improvement in the binding affinity over the monomer, compounds9–12or benzyldiamine derivatives, demonstrated the applicability of the multidentate approach. The underlying mechanism of these novel Aβagents was explored by molecular docking technique, which theoretically verified the high affinities of the multidentate benzyldiamine derivatives for Aβaggregates. Moreover, the molecular masses of the ligands18–21are more than 700 Dalton, which are believed to be hardly capable of penetrating blood brain barrier. In this regard, these ligands could be used to distinguish CAA from Alzheimer’s disease which is another Aβ-related disorder disease. To convert these ligands to positron emission tomography imaging agents, we attempted to radiosynthesize [18F]18. Though the radiolabeling was not very successful, the preliminary results suggested that these newly proposed multidentate benzyldiamine derivatives may be used as potential Aβimaging agents in cerebral amyloid angiopathy.Graphic abstract