Flavonoid‐Derived Probes for the Detection of Islet Amyloid Polypeptide Aggregates

Abstract Type‐2 diabetes (T2D) is a growing global health crisis, with over 90% of diabetes cases attributed to this condition. Misfolding and aggregation of islet amyloid polypeptide (IAPP) is a hallmark of early T2D, contributing to pancreatic β‐cell dysfunction. While significant progress has been made in developing sensors for amyloids implicated in neurodegeneration, fluorescent probes for detecting IAPP aggregates remain limited. We report a series of flavonoid derivatives designed for enhanced IAPP fibril detection. The probes feature modifications, including methoxy substitution at C7 and varying amines at C4, which enhance their binding affinity for IAPP fibrils compared to the widely used Thioflavin T (ThT). The leading probes, F4 and MF1 , exhibited over 10‐fold increased binding affinity compared to ThT, alongside ratiometric fluorescence due to excited‐state intramolecular proton transfer. F4 and MF1 were applied to image IAPP aggregates in pancreatic β‐cells and zebrafish tissue sections, where both probes demonstrated specific imaging of IAPP fibrils. These probes also demonstrated reduced fluorescence when IAPP monomers were incubated with inhibitors, indicating fibril disassembly. Our results position F4 and MF1 as promising tools for exploring the pathological role of IAPP aggregation in diabetes and for high‐throughput screening of IAPP aggregation inhibitors.