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

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, [11C]-CHDI-180R, a benzoxazole derivative, laid the foundation for this effort. Subsequent analogs such as [11C]-CHDI-626 and [18F]-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 [11C]-CHDI-009, [18F]-CHDI-385, and [18F]-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.