Isoindolinone-Derived PET Tracers for Molecular Imaging of mHTT Aggregates in Huntington’s Disease

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High Resolution Image Download MS PowerPoint Slide Mutant huntingtin (mHTT) aggregates represent a key pharmacodynamic biomarker of Huntington’s disease (HD). The development of positron emission tomography (PET) tracers targeting mHTT addresses a critical unmet need by enabling the noninvasive quantification of pathological burden in vivo . The first-generation tracer, [ 11 C]CHDI-180R, a benzoxazole derivative, laid the foundation for this effort. Subsequent analogs such as [ 11 C]CHDI-626 and [ 18 F]CHDI-650 were developed to improve in vivo performance; however, key challenges including limited metabolic stability and suboptimal selectivity persisted. To address these limitations, a recent study introduced a new class of isoindolinone-derived candidate tracers, including [ 11 C]CHDI-009, [ 18 F]CHDI-385, and [ 18 F]CHDI-386, identified through systematic structure–activity relationship (SAR) optimization. These next-generation tracers exhibit markedly enhanced binding affinity, selectivity, and translational potential, offering valuable tools to investigate mHTT pathology and its role in HD progression.

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