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

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.