A sulfur-atom-enhanced strategy for NIR imaging of soluble and insoluble amyloid-β species

Soluble Aβ oligomers, more neurotoxic than monomers and plaques, are the predominant drivers of Alzheimer's disease in its earliest phase. However, the severe scarcity of effective molecular design principles for constructing soluble Aβ oligomer-targeted imaging probes severely hampers early-stage Alzheimer's diagnosis and pathological mechanistic dissection. Herein, we propose a sulfur-atom hybridization enhancement strategy to boost the binding ability of probes towards Aβ species, especially soluble Aβ oligomers and successfully engineer a fluorescence (FL) intensity amplifying (91-fold) D-π-A probe F-BSTH-NM for Aβ oligomers. Specifically, we initially develop a novel non-planar chromophore by changing the CC of quinoline into C-S to improve the interaction towards Aβ species. Then, optimizing the π-bridge to improve sulfur content and integrating electron donor group to extend the emission into near-infrared (NIR) window and simultaneously enhance desirable targetability and binding affinity. The rational designed F-BSTH-NM exhibits larger FL turn-on ratios as well as NIR emissions after binding to Aβ species, especially Aβ oligomers. Moreover, the proper lipophilicity (cLogP = 2.61) enable itself with desirable BBB penetration ability, and in vivo NIR fluorescent imaging reveals that probe F-BSTH-NM is capable of differentiating transgenic (Tg) AD mice from normal controls. The ex vivo histology experiment demonstrate that F-BSTH-NM could co-localization with both plaque cores and oligomer-enriched peripheries, suggesting that F-BSTH-NM could serve as a potential imaging tool for the early diagnosis of AD.