Development of Off‐On Near‐Infrared Fluorescent Probes for Sensitive In Vivo Imaging of Amyloid‐β Species with Enhanced Pharmacokinetics

Abstract The fluorescent imaging of pathologically accumulated β‐amyloid (Aβ) proteins is of significant importance to the diagnosis of Alzheimer's disease (AD). In the paper, we prepare two new NIR probes, NIR‐1 and NIR‐2 , through hydrophilic modification of introducing water‐soluble bioactive groups such as polyethylene glycol (PEG) and morpholine to tune in vivo pharmacokinetics for specific detection of soluble and insoluble Aβ species. The in vitro assessments confirm that both NIR‐1 and NIR‐2 display strong near‐infrared (NIR) fluorescence (FL) enhancement upon interaction with Aβ 42 monomers, oligomers or aggregates (λ em >670 nm) and show highly sensitive, rapid and selective response towards Aβ 42 species. After i. v. injection, each probe showed fast blood‐brain barrier (BBB) penetration and immediately produced intense FL signals in the brain of APP/PS1 AD model mice at 10 min. Moreover, compared with NIR‐2 , NIR‐1 bearing a hydrophilic PEG chain displayed not only more rapid clearance but also lower background signal to efficiently distinguish APP/PS1 mice and wild‐type mice with higher signal‐to‐background ratio, which was further validated by ex vivo histological staining of brain tissues. Therefore, due to its excellent pharmacokinetics, NIR‐1 shows great promise as an effective NIR probe for specific detection of Aβ species.