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 KD) 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).