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.

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

“…Our previous metadynamics simulations for CBD and AD tau protofibrils also indicated very high binding for PMPBB3 . Recently, Qi et al identified that PMPBB3 has the top rank of hydrophobic contacts against other tracers to the 3R/4R chronic traumatic encephalopathy (CTE) tau protofibrils . These results indicated that the combination of buta-1,3-dienyl and benzothiazole in the scaffold of PMPBB3 and PBB3 is a good strategy for binding to the surface sites on both 3R/4R and 4R tau fibrils.…”

“…35 Recently, Qi et al identified that PMPBB3 has the top rank of hydrophobic contacts against other tracers to the 3R/4R chronic traumatic encephalopathy (CTE) tau protofibrils. 48 These results indicated that the combination of buta-1,3-dienyl and benzothiazole in the scaffold of PMPBB3 and PBB3 is a good strategy for binding to the surface sites on both 3R/4R and 4R tau fibrils. The use of 1,3-butadiene to connect the benzothiazole and pyridine rings leads to a longer linear scaffold compared to CBD2115, which is believed to be beneficial for contacting with more fibril chains.…”

Flortaucipir tau PET findings from former professional and college American football players in the DIAGNOSE CTE research project

“…35 This is also confirmed in this study where only patchy and moderately elevated FTP SUVR was observed in former football players and does not follow the typical spatial pattern of tau deposition in clinical/preclinical AD patients. Examination of other tau PET tracers [36][37][38] is warranted, as is the development of tracers specifically targeting CTE tau based on knowledge gained through recent cryo-EM findings, 21,22 as well as studies of molecular docking and dynamics simulations. 31 PET imaging of other pathways such as neuroinflammation 39 in the individuals exposed to substantial RHI is warranted.…”

Structure-guided design of pyridinyl-indole 4R-tau PET radiotracers: Development of [18F]OXD-2314 for human use

“…The BBB score also predicts potential improvement by modifying the topological polar surface area (TPSA). While the pKa and hydrogen bonding potential of the indole nitrogen in OXD-2115 has been shown to contribute to target a nity, 33 modifying the overall number of HBDs, TPSA, and molecular size are potential ways of improving brain uptake for new pyridinyl-indole analogues of OXD-2115 while maintaining a nity for 4R-tau aggregates. CNS MPO (3.6/6.0) and CNS PET MPO (1.7/6.0) predicted OXD-2314 to be as equally likely to penetrate the BBB as OXD-2115.…”

“…32 Additionally, OXD-2115 was computationally shown to have favorable binding characteristics for CTE tau proto brils. 33 OXD-2115 represents a new structural scaffold for 4R-tau PET radiotracer development with high selectivity for 4Rtau aggregates over Aβ plaques, a-synuclein deposits, and other CNS targets.…”