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Isoindolinone-Based PET Tracers for Imaging Mutant Huntingtin Aggregates.

Longbin Liu¹, Peter D Johnson², Matthew R Mills²

¹CHDI Management, Inc., The Company That Manages the Scientific Activities of CHDI Foundation, Inc., 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States.

Journal of Medicinal Chemistry

|July 7, 2025

Summary

This summary is machine-generated.

Researchers developed new PET imaging tracers to detect mutant Huntingtin (mHTT) aggregates, a hallmark of Huntington's disease (HD). These novel isoindolinone tracers show improved binding in HD models and human brain tissue, aiding disease understanding and biomarker development.

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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.