| Literature DB >> 32662649 |
Longbin Liu1, Michael E Prime2, Matt R Lee1, Vinod Khetarpal1, Christopher J Brown2, Peter D Johnson2, Patricia Miranda-Azpiazu3, Xuemei Chen4, Daniel Clark-Frew2, Samuel Coe2, Randall Davis4, Anthony Dickie2, Andreas Ebneth2, Simone Esposito5, Elise Gadouleau2, Xinjie Gai2, Sebastien Galan2, Samantha Green2, Catherine Greenaway2, Paul Giles2, Christer Halldin3, Sarah Hayes2, Todd Herbst1, Frank Herrmann6, Manuela Heßmann6, Zhisheng Jia3, Alexander Kiselyov1, Adrian Kotey2, Thomas Krulle2, John E Mangette4, Richard W Marston2, Sergio Menta5, Matthew R Mills2, Edith Monteagudo5, Sangram Nag3, Martina Nibbio5, Laura Orsatti5, Sabine Schaertl6, Christoph Scheich6, Joanne Sproston2, Vladimir Stepanov3, Marie Svedberg3, Akihiro Takano3, Malcolm Taylor2, Wayne Thomas2, Miklós Toth3, Darshan Vaidya2, Katarina Vanräs3, Derek Weddell2, Ian Wigginton2, John Wityak1, Ladislav Mrzljak1, Ignacio Munoz-Sanjuan1, Jonathan A Bard1, Celia Dominguez1.
Abstract
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.Entities:
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Year: 2020 PMID： 32662649 DOI： 10.1021/acs.jmedchem.0c00955
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446