A 2‐Methyl‐Butadiene Based Probe for Enhancing Photostability and Tau Pathology Detection

Abstract Tau PET tracers are being developed for imaging Alzheimer's disease (AD), primary tauopathies, and potentially screening of cognitively unimpaired elders. A second‐generation tau tracer PM‐PBB3, currently in Phase 3 clinical trials with FDA Fast Track Designation, shows promise as a broad‐spectrum tau imaging agent, but is limited by photoisomerization and binding to amyloid fibrils. Herein, the study reports the development of a better tau probe, BMP‐7, created by strategically introducing a methyl group at position 2 of the butadiene scaffold to enhance its chemical and biological properties. BMP‐7 exhibits remarkable photostability, showing no significant change in HPLC assays after 6 h of light exposure. Critically, BMP‐7 demonstrates increased sensitivity and 4.9‐fold greater selectivity than PM‐PBB3 for detecting tau pathology in brain sections from transgenic mouse models of AD and 4R tauopathies. Specifically, BMP‐7 binds to MC1‐reactive pathological tau conformations requiring both C‐ and N‐terminal phosphorylation, which is abolished by in vitro dephosphorylation. Furthermore, BMP‐7 readily penetrates the blood‐brain barrier and binds to tau pathology in vivo. These studies demonstrate that BMP‐7 bearing 2‐methyl‐butadiene scaffold improves photostability and significantly enhances the sensitivity and selectivity of tau pathology detection, offering substantial advantages for future applications. Therefore, BMP‐7 shows potential for further clinical development.