Synthesis of b-TVBT 2 analogues for detection of protein aggregates involved in Alzheimer's disease

Small fluorescent probes serve as the primary tools for studying protein aggregates that occur in neurodegenerative diseases including Alzheimer’s disease (AD). Research on amyloid pathology benefits from bi-thiophene-vinyl-benzothiazole (bTVBT) analogues because their conjugated backbones produce unique photophysical characteristics. The development of probes for biological targets continues as an active area of research. In this project, a library of bTVBT analogues was synthesized by modifying the R1 moiety of the bTVBT2 scaffold to study their optical properties and binding characteristics. Among this library, 18 new analogues with phenyl, pyridyl and fused heterocyclic R1 cores were successfully synthesized through a two-step synthetic method. The first Suzuki coupling reactions produced aldehyde intermediates at yields between 19% and 89% while the subsequent condensation reactions produced final products with yields between 5% and 57%. Then the research examined how R1 core modifications affected photophysical responses through spectral detection and differentiation of protein aggregates in AD. The staining of AD brain tissue showed that meta-substituted analogues together with some pyridinyl-based compounds failed to bind specifically but a major portion of synthesized probes including para-substituted phenyl analogues and one meta-substituted phenyl derivative (Ligand 9) successfully stained protein aggregates. The effective probes showed discrimination between Aβ plaques and neurofibrillary tangles (NFTs) while most of them displayed strong tau selectivity. This research describes the synthesis of bTVBT2 analogue libraries while showing their photophysical properties and their application in staining AD brain tissue to identify potential candidates for future development.