Isoindolinone-Based PET Tracers for Imaging Mutant Huntingtin Aggregates

Huntington's disease (HD) is caused by the repeat expansion of the CAG trinucleotide in the mutant Huntingtin gene (mHTT) within the exon1 region, resulting in an expanded polyglutamine-containing mHTT exon1 protein that serves as the source of the hallmark mHTT aggregates in people with HD (PwHD). To better understand aggregation formation during disease progression and its utility as a pharmacodynamic biomarker, we have been targeting mHTT aggregates for developing PET imaging tracers and have identified a series of isoindolinones that show significantly higher binding potential (BP, a ratio of Bmax over K_D) in HD mouse models as well as increased binding in HD post-mortem brains, compared to first generation ligands. We present the structure-activity relationship (SAR) work leading to three candidate tracers progressed for human studies: [¹¹C]CHDI-009 (6), [¹⁸F]CHDI-385 (29) and [¹⁸F]CHDI-386 (30).