Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 15, Pages 8608-8633Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00955
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Funding
- CHDI Foundation
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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 C-11-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [C-11]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [C-11]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.
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