Radioiodinated Tau Imaging Agent III Molecular Modeling, Synthesis, and Evaluation of a New Tau Imaging Agent, [125I]ISAS in Post-Mortem Human Alzheimer's Disease Brain.

放射性碘 Tau 显像剂 III 分子建模,合成,一种新型 Tau 显像剂的评价,[125I] 在死后人类阿尔茨海默病大脑中的 ISAS 。

• 影响指数: 4.927
• 发表时间: 2024 Jul 13
• 来源期刊: Molecules
• DOI: 10.3390/molecules29143308
• PMID: 39064887
• 文章类型: Journal Article
• 中科院分区: Q3
• 作者列表: Sison SA,Paclibar CG,Liang C,Mukherjee J

关键词: Alzheimer’s disease; [125I]INFT; [125I]IPPI; [125I]ISAS; autoradiography; neurofibrillary tangles; post-mortem human Tau

Mesh: Alzheimer Disease / metabolism diagnostic imaging; tau Proteins / metabolism chemistry; Humans; Iodine Radioisotopes / chemistry; Brain / diagnostic imaging metabolism; Radiopharmaceuticals / chemistry chemical synthesis; Models, Molecular; Protein Binding; Binding Sites; Male; Aged; Autopsy; Female

Abstract

Using a molecular modeling approach for Tau-binding sites, we modified our previously reported imaging agent, [125I]INFT, for the potential improvement of binding properties to Tau in an Alzheimer\'s disease (AD) brain. Two new derivatives, namely [125I]ISAS and [125I]NIPZ, were designed, where binding energies at site 1 of Tau were -7.4 and -6.0 kcal/mole, respectively, compared to [125I]INFT (-7.6 kcal/mole). The radiosynthesis of [125I]ISAS and [125I]NIPZ was carried out by using iodine-125 and purified chromatographically to achieve >90% purity. In vitro binding affinities (IC50) for Tau were as follows: INFT = 7.3 × 10-8 M; ISAS = 4.7 × 10-8 M; NIPZ > 10-6 M. The binding of [125I]ISAS to gray matter (GM) correlated with the presence of Tau in the AD brain, confirmed by anti-Tau immunohistochemistry. [125I]NIPZ did not bind to Tau, with similar levels of binding observed in GM and white matter (WM). Four radiotracers were compared and the rank order of binding to Tau was found to be [125I]IPPI > [125I]INFT > [125I]ISAS >>> [125I]NIPZ with GM/WM ratios of [125I]IPPI = 7.74 > [125I]INFT = 4.86 > [125I]ISAS = 3.62 >> [125I]NIPZ = 1.24. The predictive value of Chimera-AutoDock for structurally related compounds binding to the Tau binding sites (measured as binding energy) was good. A binding energy of less than -7 kcal/mole is necessary and less than -8 kcal/mole will be more suitable for developing imaging agents.

摘要

使用Tau结合位点的分子建模方法，我们修改了以前报道的显像剂，[125I]内侧,用于改善阿尔茨海默病（AD）大脑中与Tau的结合特性。两个新的衍生物，即[125I]ISAS和[125I]NIPZ，被设计，其中Tau位点1的结合能为-7.4和-6.0kcal/mol，分别,与[125I]INFT（-7.6千卡/摩尔）相比。通过使用碘-125进行[125I]ISAS和[125I]NIPZ的放射合成,并通过色谱纯化以达到>90%的纯度。Tau的体外结合亲和力（IC50）如下：INFT=7.3×10-8M；ISAS=4.7×10-8M；NIPZ>10-6M。[125I]ISAS与灰质（GM）的结合与AD脑中Tau的存在相关，通过抗Tau免疫组织化学证实。[125I]NIPZ没有绑定到Tau，在GM和白质（WM）中观察到相似的结合水平。比较了四种放射性示踪剂，发现与Tau结合的等级顺序为[125I]IPPI>[125I]INFT>[125I]ISAS>>>[125I]NIPZ，GM/WM比率为[125I]IPPI=7.74>[125I]INFT=4.86>[125I]ISAS=3.62>>[125I]NIPZ=1.24。Chimera-AutoDock对于结构相关的化合物与Tau结合位点结合的预测价值(测量为结合能)是良好的。小于-7kcal/mol的结合能是必要的,并且小于-8kcal/mol将更适合于显影成像剂。