Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Huntington's disease (HD) is a genetic disorder caused by CAG trinucleotide repeat expansion in the huntingtin (HTT) gene.
• Misfolding and aggregation of mutant huntingtin (mHTT) protein are central to HD pathology.
• Development of imaging tools and therapeutics targeting mHTT aggregates is crucial for HD research.

Purpose of the Study:

• To conduct an in-depth pharmacological investigation of PET tracers CHDI-180 and CHDI-626.
• To evaluate the binding characteristics, affinity, and selectivity of these tracers for mHTT aggregates.
• To assess their potential as imaging agents for Huntington's disease.

Main Methods:

• In vitro and ex vivo radiometric binding assays using recombinant HTT and brain homogenates.
• Autoradiography studies on brain sections from HD mouse models and post-mortem human samples.
• Assessment of binding selectivity against proteins implicated in Alzheimer's disease and spinocerebellar ataxia.

Main Results:

• CHDI-180 and CHDI-626 demonstrated specific binding to mHTT aggregates in HD mouse models.
• Binding of tracers correlated with age and disease progression in HD models.
• CHDI-180 and CHDI-626 showed no significant binding to beta-amyloid plaques in Alzheimer's disease samples, indicating high selectivity.

Conclusions:

• CHDI-180 and CHDI-626 are effective PET tracers for specifically imaging mHTT aggregates in Huntington's disease.
• These tracers possess high selectivity, distinguishing mHTT from other protein aggregates relevant to neurodegenerative diseases.
• The developed tracers hold promise for both in vivo imaging and potential therapeutic strategies in HD.