Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand

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 <b>1</b>, 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 <b>1</b> in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [¹¹C]-<b>1R</b> (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [¹¹C]-<b>1R</b> is now being advanced to human trials as a first-in-class HD PET radiotracer.