Mechanistic Insights into the Binding of Different Positron Emission Tomography Tracers to Chronic Traumatic Encephalopathy Tau Protofibrils.

ABSTRACT

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, and it is neuropathologically defined as the accumulation of abnormally hyperphosphorylated tau (p-tau). Early detection of p-tau in the brain is of great value in the prevention and treatment of CTE. Previous experimental studies reported that positron emission tomography (PET) technique using several tau tracers are available for imaging certain neurodegenerative diseases. However, few studies have focused on the development of CTE tau tracers. In this work, we performed conventional molecular docking and molecular dynamics simulations to address the binding properties and mechanisms of PET tracers (18F-PM-PBB3, 18F-CBD-2115, 18F-PI-2620, 18F-RO-948, 18F-MK-6240, and 18F-flortaucipir) to CTE tau protofibrils. The results show that the hydrophobic cavity and the top of the concave structure of CTE tau protofibrils are the preferred binding sites for the six tracers, and 18F-PM-PBB3 has the most competitive binding affinity to CTE tau protofibrils. Further investigation into the binding patterns of the six tracers to the CTE tau protofibrils showed that 18F-CBD-2115 and 18F-PM-PBB3 have a high number of H-bonds and hydrophobic contacts with tau protofibrils, resulting in strong hydrogen bonding and hydrophobic interactions; 18F-flortaucipir/18F-PI-2620 and 18F-PI-2620/18F-RO-948 form more intense π-π and cation-π interactions with tau protofibrils, respectively. Subsequently, we conducted a detailed analysis of the binding mechanism of 18F-PM-PBB3 to CTE tau protofibrils. The benzothiazole ring of 18F-PM-PBB3 exhibits stronger π-π stacking and cation-π interactions with tau protofibrils than the pyridine ring and forms a more concentrated T-shaped π-π stacking pattern. This study contributes to understanding the binding mechanism of PET tracers to CTE tau protofibrils and provides new insights into the design of potential novel tracers.