Virtual screening and fragment growth strategy for developing near-infrared fluorescent probes to detect Aβ in...

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.