Isoindolinone-Based PET Tracers for Imaging Mutant Huntingtin Aggregates

Area of Science:

• Neuroscience
• Molecular Biology
• Radiochemistry

Background:

• Huntington's disease (HD) is a neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the mutant Huntingtin gene (mHTT).
• mHTT aggregates in the brain are a key pathological feature and potential biomarker in HD.
• Developing in vivo imaging tools is crucial for understanding HD progression and evaluating therapeutics.

Purpose of the Study:

• To develop novel Positron Emission Tomography (PET) imaging tracers targeting mHTT aggregates.
• To identify potent and selective isoindolinone-based ligands for PET imaging of Huntington's disease.
• To evaluate the structure-activity relationship (SAR) of new tracers for potential use in human studies.

Main Methods:

• Synthesis and characterization of a series of isoindolinone compounds.
• In vitro and in vivo evaluation of tracer binding affinity and selectivity in HD mouse models.
• Assessment of tracer binding in post-mortem human brain tissue from individuals with HD.
• Structure-activity relationship (SAR) analysis to optimize tracer properties.

Main Results:

• Identified a series of isoindolinone derivatives with significantly higher binding potential (BP) compared to first-generation ligands.
• Demonstrated increased tracer binding in HD mouse models and post-mortem HD brain tissue.
• Selected three lead candidate tracers ([11C]CHDI-009, [18F]CHDI-385, and [18F]CHDI-386) for further development.

Conclusions:

• Novel isoindolinone-based PET tracers show promise for imaging mHTT aggregates in Huntington's disease.
• These tracers can serve as valuable pharmacodynamic biomarkers for disease progression and therapeutic intervention.
• The developed tracers represent a significant advancement in the development of in vivo tools for HD research.