Rational Design of Long-Circulating Bright Fluorescent Probe for In Vivo Imaging of Amyloid-β Plaques in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques, which serve as crucial biomarkers for disease diagnosis and therapeutic evaluation. While fluorescence imaging has emerged as a powerful technique for Aβ detection, current probes face limitations in clinical application due to insufficient photostability and short blood half-life, resulting in compromised signal-to-noise ratios (SNRs) and imaging resolution. Herein, two bright quinoxalinone-based fluorescent probes (QNO-AD-PEGs) were presented, which incorporate hydrophilic poly(ethylene glycol) (PEG) chains for enhanced biocompatibility and an Aβ-specific N,N-dimethylaminophenyl recognition unit. QNO-AD-PEG1 demonstrated exceptional binding affinity for Aβ₄₂ aggregates (K_d = 42 nM) and a remarkable 49-fold fluorescence enhancement upon target engagement, with a quantum yield (Φ_Aβ) of 11.45%. In vivo imaging revealed that QNO-AD-PEG1 effectively crossed the blood-brain barrier (BBB) and exhibited a prolonged half-life (315 min). Notably, the probe successfully visualized age-dependent Aβ plaque progression in AD mouse models. This study presents a significant breakthrough in molecular imaging for neurodegenerative diseases, offering a versatile tool for both fundamental AD research and potential clinical applications. © 2025 American Chemical Society.