Cyclization Enhances Luminescence Efficiency of a Fluorescent Probe for Amyloid-β in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by β-amyloid (Aβ) deposition, imposing significant social and economic burdens globally. Despite extensive efforts have been devoted to developing fluorescent probes for Aβ imaging, further improving the luminescent efficiency of prevailing probes still remains a significant challenge. Herein, we investigated the inner mechanism of constructing high-efficient Aβ probes via a structural cyclization strategy. Based on a typical donor-acceptor Aβ probe (Pro1), three cyclized derivatives (Pro2-Pro4) are designed by incorporating dimethylene, trimethylene, and ethyleneoxy groups into the π-conjugated bridge. It is found that all compounds exhibit high specificity at various binding sites within the Aβ fibril, while Pro4 features preferable hydrogen bond interaction with the fibril. Notably, a significant enhanced fluorescence quantum efficiency is demonstrated in the ethyleneoxy-contained counterpart, primarily due to the decreased nonradiative decay arising from the reduced nonadiabatic electronic coupling, electron-vibration coupling, and vibrational modes mixing. Consequently, the newly designed compound Pro4 achieves both red-shifted emission and optimal luminescent efficiency, making it a promising candidate for Aβ imaging. These findings highlight the feasibility of structural cyclization as an effective approach to improve luminescent efficiency in Aβ-targeted probes, contributing to the development of fluorescent imaging techniques for early AD diagnosis.