Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
ACS Chem Neurosci. 2024 Jun 5;15(11):2233-2242. doi: 10.1021/acschemneuro.4c00053. Epub 2024 May 16.
Detection of amyloid β (Aβ) oligomers, regarded as the most toxic aggregated forms of Aβ, can contribute to the diagnosis and treatment of Alzheimer's disease (AD). Thus, the development of imaging probes for visualization of Aβ oligomers is crucial. However, the structural uncertainty regarding Aβ oligomers makes it difficult to design imaging probes with high sensitivity to Aβ oligomers against highly aggregated Aβ fibrils. In this study, we developed Aβ oligomer-selective fluorescent probes based on triphenylmethane dyes through screening of commercially available compounds followed by structure-activity relationship (SAR) studies on cyclic or acyclic 4-dialkylamino groups. We synthesized 11 triarylmethane-based Aβ oligomer probe (TAMAOP) derivatives. evaluation of fluorescence properties, TAMAOP-9, which had bulky 4-diisobutylamino groups introduced into three benzenes of a twisted triphenylmethane backbone, showed marked fluorescence enhancement in the presence of Aβ oligomers and demonstrated high selectivity for Aβ oligomers against Aβ fibrils. In docking studies using the Aβ trimer model, TAMAOP-9 bound to the hydrophobic surface and interacted with the side chain of Phe. section staining revealed that TAMAOP-9 could visualize Aβ oligomers in the brains of AD model mice. An fluorescence imaging study using TAMAOP-9 showed significantly higher fluorescence signals from the brains of AD model mice than those of age-matched wild-type mice, confirmed by section observation. These results suggest that TAMAOP-9 is a promising Aβ oligomer-targeting fluorescent probe applicable to imaging.
淀粉样 β (Aβ) 寡聚体被认为是 Aβ 最具毒性的聚集形式，可用于阿尔茨海默病 (AD) 的诊断和治疗。因此，开发用于可视化 Aβ 寡聚体的成像探针至关重要。然而，由于 Aβ 寡聚体的结构不确定性，设计对 Aβ 寡聚体具有高灵敏度的成像探针以对抗高度聚集的 Aβ 纤维仍然具有挑战性。在这项研究中，我们通过筛选市售化合物，基于三苯甲烷染料开发了 Aβ 寡聚体选择性荧光探针，并对环状或非环状 4-二烷基氨基进行了构效关系 (SAR) 研究。我们合成了 11 种基于三苯甲烷的 Aβ 寡聚体探针 (TAMAOP) 衍生物。通过荧光性质评估，具有大体积 4-二异丁基氨基引入扭曲三苯甲烷骨架三个苯环的 TAMAOP-9 在存在 Aβ 寡聚体时表现出明显的荧光增强，并对 Aβ 寡聚体具有高选择性，对 Aβ 纤维没有选择性。在使用 Aβ 三聚体模型进行的对接研究中，TAMAOP-9 结合到疏水面并与 Phe 的侧链相互作用。组织染色显示，TAMAOP-9 可在 AD 模型小鼠的大脑中可视化 Aβ 寡聚体。使用 TAMAOP-9 的荧光成像研究显示，AD 模型小鼠大脑的荧光信号明显高于年龄匹配的野生型小鼠，这通过切片观察得到了证实。这些结果表明，TAMAOP-9 是一种有前途的靶向 Aβ 寡聚体的荧光探针，可用于成像。
