Rational Design,\nSynthesis, and Evaluation of Rofecoxib-Based\nPhotosensitizers for the NIR Imaging and Photo-Oxidization of Aβ\nAggregates

The photo-oxidation of amyloid-β (Aβ) protein\ncatalyzed\nby Aβ-targeting photosensitizers shows high potential in treating\nAlzheimer’s disease (AD). Herein, we report the first example\nof photosensitizers based on the rofecoxib scaffold, in which rational\nintroduction of the electron-absorbing pyridinium/quinolinium moiety\nto the skeleton of rofecoxib could not only extend the absorption\nand emission wavelengths but also increase the efficiency of singlet\noxygen (<sup>1</sup>O<sub>2</sub>) production. The emission wavelengths\nof <b>R-S-MP</b>, <b>R-S-MC</b>, and <b>R-S-MQ</b> are red-shifted to 860 nm, which might benefit the NIR imaging of\nAβ aggregates with low photoscattering and autofluorescence.\nIn addition, <b>R-S-MP</b> can identify Aβ plaques in\nbrain sections of AD mice and detect abnormal viscosity environments,\nfacilitating the pathological study of Alzheimer’s disease.\nMost importantly, upon complexation with Aβ plaques, <b>R-S-MP</b> and <b>R-S-MC</b> could produce high singlet oxygen (<sup>1</sup>O<sub>2</sub>) under light irradiation, which can achieve\nthe specific photo-oxidation of Aβ protein. Our optimized photosensitizers\ncould change the conformation of β-rich Aβ protein and\nenhance its clearance through the lysosomal pathway, leading to the\nreduction of the Aβ-mediated neurotoxicity. All these excellent\ncharacteristics of our dual-functional photosensitizers for simultaneous\nimaging and photo-oxidation of Aβ aggregates suggest their promising\nprospects in pathological research in AD.