Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand
Authors:
- 14 July 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (15) , 8608-8633
Abstract
Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of 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. With a strategy to identify 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 post-mortem human HD samples. PET imaging studies with 11C-labelled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand side labelled 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.Keywords
Funding Information
- CHDI Foundation
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