20.500.12556/RUL-166735 Probing Alzheimer's pathology exploring the next generation of FDDNP analogues for amyloid β detection Fluorescent probes are a powerful tool for imaging amyloid β (Aβ) 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 Aβ fibrils. One of these dyes, 1Ae, exhibited several improvements over FDDNP, an established biomarker for Aβ- 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 (φ(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 Aβ fibrils in vitro (K$_d$ = 1.603 µM), while increasing fluorescence emission (106-fold) compared to emission in buffer alone. Importantly, the selective binding of 1Ae to Aβ$_{1–42}$ 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 Aβ plaques. The intermolecular interactions of fluorophores with Aβ 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 Aβ$_{1–42}$ in cerebrospinal fluid or blood. amyloid β fluorophore solvatochromism synthesis photophysics Alzheimer’s disease amiloid beta fluorofor solvatokromizem sinteza fotofizika alzheimerjeva bolezen true false true Angleški jezik Slovenski jezik Članek v reviji 2025-01-23 12:43:23 2025-01-23 12:43:30 2025-01-24 04:05:29 0000-00-00 00:00:00 2024 0 0 19 str. Vol. 175, art. 116616 Jun. 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 54 1950-6007 10.1016/j.biopha.2024.116616 194778883 1-s2.0-S0753332224005006-main.pdf 1-s2.0-S0753332224005006-main.pdf 1 E3EA3BC5B15CAD481202EE5A26CFC761 a12f6ceb799992098bcaec677c8e8f04d109a2ef9cbe925217ca09dfcd692d07 fbbcd311-d97e-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=198563 https://www.sciencedirect.com/science/article/pii/S0753332224005006 0 7a55e682-d97e-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=198561 Fakulteta za kemijo in kemijsko tehnologijo Fakulteta za farmacijo Medicinska fakulteta 0 0 0