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A second\u2010generation tau tracer PM\u2010PBB3, currently in Phase 3 clinical trials with FDA Fast Track Designation, shows promise as a broad\u2010spectrum 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\u20107, created by strategically introducing a methyl group at position 2 of the butadiene scaffold to enhance its chemical and biological properties. BMP\u20107 exhibits remarkable photostability, showing no significant change in HPLC assays after 6 h of light exposure. Critically, BMP\u20107 demonstrates increased sensitivity and 4.9\u2010fold greater selectivity than PM\u2010PBB3 for detecting tau pathology in brain sections from transgenic mouse models of AD and 4R tauopathies. Specifically, BMP\u20107 binds to MC1\u2010reactive pathological tau conformations requiring both C\u2010 and N\u2010terminal phosphorylation, which is abolished by in vitro dephosphorylation. Furthermore, BMP\u20107 readily penetrates the blood\u2010brain barrier and binds to tau pathology in vivo. These studies demonstrate that BMP\u20107 bearing 2\u2010methyl\u2010butadiene scaffold improves photostability and significantly enhances the sensitivity and selectivity of tau pathology detection, offering substantial advantages for future applications. Therefore, BMP\u20107 shows potential for further clinical development.<\/jats:p>","DOI":"10.1002\/adhm.202502450","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T06:24:09Z","timestamp":1753770249000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A 2\u2010Methyl\u2010Butadiene Based Probe for Enhancing Photostability and Tau Pathology Detection"],"prefix":"10.1002","volume":"14","author":[{"given":"Anyang","family":"Sun","sequence":"first","affiliation":[{"name":"Laboratory of Neurodegenerative Diseases and Molecular Imaging Shanghai University of Medicine and Health Sciences  Shanghai 201318 P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guanglei","family":"Lv","sequence":"additional","affiliation":[{"name":"Laboratory of Neurodegenerative Diseases and Molecular Imaging Shanghai University of Medicine and Health Sciences  Shanghai 201318 P. R. 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