2026-09-20T00:28:24Zhttps://dspace.mit.edu/server/oai/requestoai:dspace.mit.edu:1721.1/1623192025-08-12T03:07:02Zcom_1721.1_7582com_1721.1_7581col_1721.1_131023
Hong, Mei
Angehrn Rodas, Frida Nicole
Massachusetts Institute of Technology. Department of Chemistry
2025-08-11T14:18:11Z
2025-08-11T14:18:11Z
2025-05
2025-06-11T15:13:36.100Z
https://hdl.handle.net/1721.1/162319
https://orcid.org/0000-0002-0502-1877
Aggregation of the tau protein into fibrils is a key feature of Alzheimer's disease (AD) and many other neurodegenerative disorders. Developing small molecules that bind these tau fibrils is important for the diagnosis and treatment of tauopathies. This thesis revolves around a study on the binding sites of a positron emission tomography (PET) ligand, PI-2620, to a recombinant tau construct that adopts the C-shaped AD fold. Using solid state NMR experiments in combination with other techniques such as Transmission Electron microscopy (TEM) as well as docking simulations allowed a better understanding of the binding sites of this PET agent. Specifically, 13C-19F REDOR experiments were used to identify nearby residues to the ligand. PI-2620 was found to bind two primary sites within the C-shaped structure. The docking simulations allowed the proposition of several possible binding poses. Additional 2D NMR experiments suggest that PI-2620 alters the protofilament interfaces. The stoichiometry of PI-2620 binding to tau fibrils was determined to be approximately 20 mol%, with varying degrees of ligand mobility. These findings offer insights into the interaction of this PET tracer with tau fibrils and have implications for the design of improved imaging agents.
S.M.
Massachusetts Institute of Technology
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Solid-State NMR Characterization of a PET Ligand Binding Sites in AD Tau Fibrils
Thesis
application/pdf
Master
Master of Science in Chemistry
Publication
unknown
unknown
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<Abstract>Aggregation of the tau protein into fibrils is a key feature of Alzheimer's disease (AD) and many other neurodegenerative disorders. Developing small molecules that bind these tau fibrils is important for the diagnosis and treatment of tauopathies. This thesis revolves around a study on the binding sites of a positron emission tomography (PET) ligand, PI-2620, to a recombinant tau construct that adopts the C-shaped AD fold. Using solid state NMR experiments in combination with other techniques such as Transmission Electron microscopy (TEM) as well as docking simulations allowed a better understanding of the binding sites of this PET agent. Specifically, 13C-19F REDOR experiments were used to identify nearby residues to the ligand. PI-2620 was found to bind two primary sites within the C-shaped structure. The docking simulations allowed the proposition of several possible binding poses. Additional 2D NMR experiments suggest that PI-2620 alters the protofilament interfaces. The stoichiometry of PI-2620 binding to tau fibrils was determined to be approximately 20 mol%, with varying degrees of ligand mobility. These findings offer insights into the interaction of this PET tracer with tau fibrils and have implications for the design of improved imaging agents.</Abstract>
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