Insight into the Binding of First- and Second-Generation PET Tracers to 4R and 3R/4R Tau Protofibrils

Area of Science:

• Neuroscience
• Computational Chemistry
• Radiopharmaceutical Chemistry

Background:

• Primary tauopathies, including progressive supranuclear palsy (PSP), cortical basal degeneration (CBD), and Alzheimer's disease (AD), are characterized by abnormal tau protein aggregation.
• Positron Emission Tomography (PET) tracers are crucial for diagnosing and monitoring these neurodegenerative diseases by targeting tau fibrils.
• Understanding the precise binding mechanisms of existing PET tracers is essential for developing more selective and effective diagnostic agents.

Purpose of the Study:

• To investigate the binding mechanisms of 10 first- and second-generation PET tracers for PSP tau.
• To compare the binding preferences of these tracers across different tauopathies, including PSP, CBD, and AD.
• To elucidate structure-activity relationships and identify key interactions governing tracer binding to tau fibrils.

Main Methods:

• Utilized a combination of computational approaches: molecular docking, molecular dynamics, and metadynamics simulations.
• Evaluated binding interactions, including intermolecular forces, role of polar residues, induced-fit effects, and conformational changes.
• Assessed tracer binding free energies and preferences for specific tau fibril sites.

Main Results:

• Identified PMPBB3 and PBB3 as exhibiting the strongest binding free energies to specific sites on PSP tau fibrils, driven by van der Waals and cation-π interactions.
• Demonstrated that tracers can display different binding preferences based on the distinct folding patterns of tau fibrils in different tauopathies.
• Confirmed known tracer specificities, such as MK6240's preference for AD tau and CBD2115, PI2620, and PMPBB3's classification as 4R tau binders.

Conclusions:

• The study provides a comprehensive understanding of PET tracer binding mechanisms to tau fibrils in various tauopathies.
• Findings highlight the importance of fibril structure and specific interactions in determining tracer selectivity.
• Results will guide the rational design of novel, highly selective PET tracers for improved diagnosis and management of tauopathies.