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Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand

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posted on 2020-08-04, 13:57 authored by Longbin Liu, Michael E. Prime, Matt R. Lee, Vinod Khetarpal, Christopher J. Brown, Peter D. Johnson, Patricia Miranda-Azpiazu, Xuemei Chen, Daniel Clark-Frew, Samuel Coe, Randall Davis, Anthony Dickie, Andreas Ebneth, Simone Esposito, Elise Gadouleau, Xinjie Gai, Sebastien Galan, Samantha Green, Catherine Greenaway, Paul Giles, Christer Halldin, Sarah Hayes, Todd Herbst, Frank Herrmann, Manuela Heßmann, Zhisheng Jia, Alexander Kiselyov, Adrian Kotey, Thomas Krulle, John E. Mangette, Richard W. Marston, Sergio Menta, Matthew R. Mills, Edith Monteagudo, Sangram Nag, Martina Nibbio, Laura Orsatti, Sabine Schaertl, Christoph Scheich, Joanne Sproston, Vladimir Stepanov, Marie Svedberg, Akihiro Takano, Malcolm Taylor, Wayne Thomas, Miklós Toth, Darshan Vaidya, Katarina Vanräs, Derek Weddell, Ian Wigginton, John Wityak, Ladislav Mrzljak, Ignacio Munoz-Sanjuan, Jonathan A. Bard, Celia Dominguez
Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington’s disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.