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Amyloid fibrils are associated with many neurodegenerative diseases. In situ and in vivo visualization of amyloid fibrils is important for medical diagnostics and requires fluorescent probes with both excitation and emission wavelengths in the far-red and NIR region, and simultaneously with high binding-affinity to amyloid fibrils and the ability to cross the blood-brain barrier, which, however, remain a challenge. Here, we rationally design and synthesize an excellent polarity-sensitive two-photon excited NIR fluorophore (TZPI) based on a donor (D)-acceptor (A)-ion compound. The electron-rich carbazole group and the ionic pyridinium bromide group, linked by an electron-poor π-conjugated benzothiadiazole group, ensure strong near infrared (NIR) emission. Furthermore, the lipophilic carbazole together with the benzothiadiazole group facilitates docking of the probe in the hydrophobic domains of amyloid aggregates with the dissociation constant K  d = 20 nM and 13.5-fold higher binding affinity to insulin fibrils than the commercial probe ThT. On association with the amyloid fibrils, the tiny decrease in polarity leads to a large increase in its NIR emission intensity with an on-off ratio &gt; 10; meanwhile, the TZPI probe exhibits a quantum yield of up to 30% and two-photon absorption cross-section values of up to 467.6 GM at 890 nm. Moreover, the application of TZPI in two-photon imaging is investigated. The ultrahigh binding affinity, the strong NIR emission, the good two-photon absorption properties, the high photo-stability, the appropriate molecular mass of 569 Da and the lipophilicity with log  P = 1.66 ± 0.1 to cross the BBB make TZPI promising as an ideal candidate for detecting amyloid plaques in vivo .

Polarity-active NIR probes with strong two-photon absorption and ultrahigh binding affinity of insulin amyloid fibrils