Virtual screening and fragment growth strategy for developing near-infrared fluorescent probes to detect Aβ in Alzheimer's disease model

Abstract

Amyloid fibrils are well-established biomarkers of Alzheimer's disease (AD), and the development of novel near-infrared fluorescent (NIRF) probes for early detection of β-amyloid can help differentiate AD from other neurodegenerative conditions. In this study, we report the discovery of an effective NIRF probe, probe 6–4, through a combined approach of virtual screening and fragment growth. Probe 6–4 binds strongly to Aβ oligomers and aggregates, showing robust fluorescent properties with an emission maximum near 650 nm when bound to Aβ aggregates and oligomers. It exhibits high sensitivity, with a nearly 100-fold increase in fluorescence intensity, and strong affinity (K_d = 9.4 nM for oligomers and 12.5 nM for aggregates). In vivo and ex-vivo NIRF imaging studies further demonstrated that probe 6–4 can distinguish AD transgenic model mice from wild-type controls. Overall, probe 6–4 proves to be a potent and efficient tool for detecting Aβ aggregates and oligomers in the brain, validating the effectiveness of combining virtual screening and fragment growth in developing NIRF probes for AD research.