Rational Design, Synthesis, and Evaluation of Rofecoxib-Based Photosensitizers for the NIR Imaging and Photo-Oxidization of Aβ Aggregates.

The photo-oxidation of amyloid-β (Aβ) protein catalyzed by Aβ-targeting photosensitizers shows high potential in treating Alzheimer's disease (AD). Herein, we report the first example of photosensitizers based on the rofecoxib scaffold, in which rational introduction of the electron-absorbing pyridinium/quinolinium moiety to the skeleton of rofecoxib could not only extend the absorption and emission wavelengths but also increase the efficiency of singlet oxygen (1O2) production. The emission wavelengths of R-S-MP, R-S-MC, and R-S-MQ are red-shifted to 860 nm, which might benefit the NIR imaging of Aβ aggregates with low photoscattering and autofluorescence. In addition, R-S-MP can identify Aβ plaques in brain sections of AD mice and detect abnormal viscosity environments, facilitating the pathological study of Alzheimer's disease. Most importantly, upon complexation with Aβ plaques, R-S-MP and R-S-MC could produce high singlet oxygen (1O2) under light irradiation, which can achieve the specific photo-oxidation of Aβ protein. Our optimized photosensitizers could change the conformation of β-rich Aβ protein and enhance its clearance through the lysosomal pathway, leading to the reduction of the Aβ-mediated neurotoxicity. All these excellent characteristics of our dual-functional photosensitizers for simultaneous imaging and photo-oxidation of Aβ aggregates suggest their promising prospects in pathological research in AD.