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

Area of Science:

• Neuroimaging
• Radiochemistry
• Biochemistry

Background:

• Tau PET tracers are crucial for diagnosing Alzheimer's disease (AD) and other tauopathies.
• Current tracers like PM-PBB3 have limitations including photoisomerization and cross-reactivity with amyloid fibrils.

Purpose of the Study:

• To develop an improved tau PET tracer with enhanced photostability, sensitivity, and selectivity.
• To evaluate the novel tracer BMP-7, featuring a 2-methyl-butadiene scaffold, for its ability to detect pathological tau.

Main Methods:

• Synthesis and characterization of the novel tau probe BMP-7.
• Assessment of BMP-7's photostability using HPLC assays.
• Evaluation of BMP-7's sensitivity and selectivity in brain sections from transgenic AD and tauopathy mouse models.
• In vivo blood-brain barrier penetration and tau binding studies.

Main Results:

• BMP-7 exhibits remarkable photostability, with no significant degradation after 6 hours of light exposure.
• BMP-7 shows 4.9-fold greater selectivity and increased sensitivity for pathological tau compared to PM-PBB3.
• BMP-7 binds to phosphorylated tau conformations and demonstrates effective in vivo brain penetration and target engagement.

Conclusions:

• BMP-7 represents a significant advancement in tau PET tracer technology due to its improved photostability and enhanced detection capabilities.
• BMP-7 shows strong potential for clinical development in imaging tau pathologies, including Alzheimer's disease.