Optimization of quinolinium-carbazole theranostics for the improved photooxidation of β-amyloid aggregates with the variation of conjugation site

Alzheimer's disease (AD), the most prevalent neurodegenerative condition, is characterized by a gradual decline in cognitive function and memory loss. Presently, it ranks as the fifth leading cause of death worldwide. Photodynamic therapy, with its operational flexibility, noninvasive approach, and high spatial and temporal resolution, has emerged as an innovative therapeutic method, enhancing therapeutic efficacy and minimizing systemic toxicity. In this work, we have designed two donor-π-acceptor (D-π-A) type photosensitizers targeting amyloid, differing in the donor and acceptor junction sites. Surprisingly we found that by altering the junction site of the donor and acceptor from the 2-position to the 3-position of carbazole, the binding affinity and singlet oxygen efficiency of compound 3-QM16 improved compared to compound 2-QM16. This modification facilitated β-amyloid imaging and photooxidative therapy. Our study might shed light on the further optimization of the photooxidation performance of photosensitizers on misfolded proteins.