Probing Alzheimer's Pathology: Exploring the Next Generation of FDDNP Analogues for Amyloid Β Detection
BIOMEDICINE & PHARMACOTHERAPY(2024)
摘要
Fluorescent probes are a powerful tool for imaging amyloid beta (A beta) plaques, the hallmark of Alzheimer's disease (AD). Herein, we report the synthesis and comprehensive characterization of 21 novel probes as well as their optical properties and binding affinities to A beta fibrils. One of these dyes, 1Ae, exhibited several improvements over FDDNP, an established biomarker for A beta- and Tau-aggregates. First, 1Ae had large Stokes shifts (138-213 nm) in various solvents, thereby reducing self-absorption. With a high quantum yield ratio (phi(dichloromethane/methanol) = 104), 1Ae also ensures minimal background emission in aqueous environments and high sensitivity. In addition, compound 1Ae exhibited low micromolar binding affinity to A beta fibrils in vitro (Kd = 1.603 mu M), while increasing fluorescence emission (106-fold) compared to emission in buffer alone. Importantly, the selective binding of 1Ae to A beta 1-42 fibrils was confirmed by an in cellulo assay, supported by ex vivo fluorescence microscopy of 1Ae on postmortem AD brain sections, allowing unequivocal identification of A beta plaques. The intermolecular interactions of fluorophores with A beta were elucidated by docking studies and molecular dynamics simulations. Density functional theory calculations revealed the unique photophysics of these rod-shaped fluorophores, with a twisted intramolecular charge transfer (TICT) excited state. These results provide valuable insights into the future application of such probes as potential diagnostic tools for AD in vitro and ex vivo such as determination of A beta 1-42 in cerebrospinal fluid or blood.
更多查看译文
关键词
Alzheimer’s disease,Amyloid β,Fluorophore,Solvatochromism,Synthesis,Photophysics
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要