Preclinical evaluation of [¹¹C]CHDI-009R for quantification of mutant huntingtin aggregates

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded trinucleotide repeat in the huntingtin gene (HTT) that subsequently leads to aggregation of the mutant huntingtin (mHTT) protein. Thus, lowering mHTT is a key therapeutic approach used by several candidate therapeutics currently under investigation. Visualization of the efficiency of these therapeutics through in vivo mHTT quantification rises in importance. For positron emission tomography (PET) imaging of mHTT aggregates, it is critical to characterize the in vivo kinetic profile of newly identified mHTT binders to assess their translational application. Here, we report the evaluation of [¹¹C]CHDI-009R, a PET imaging radioligand with higher affinity and selectivity for mHTT aggregates than previously reported radioligands, in the heterozygous zQ175DN mouse model of HD and wild-type littermates at 9 and 3 months of age. [¹¹C]CHDI-009R displayed high stability in plasma and brain, which was reflected in brain kinetics as demonstrated by rapid uptake followed by relatively slow elimination. Kinetic modeling and volume of distribution V_T (IDIF) indicated the radioligand's ability to quantify mHTT aggregation at 9 months of age with clear genotype differentiation (p < 0.0001). [¹¹C]CHDI-009R showed an excellent test-retest reliability in 9-month-old mice (intraclass correlation coefficient: 0.62-0.79). A phenotypic difference in mHTT aggregates was also observed in 3-month-old mice in several brain structures (p < 0.05) and was confirmed with [³H]CHDI-009R autoradiography. Overall, this study suggests [¹¹C]CHDI-009R is a promising radioligand for the detection of cerebral mHTT aggregates in a mouse model of HD and supports its advance to clinical evaluation. KEY MESSAGES: [¹¹C]CHDI-009R clearly differentiated between genotypes at low and high mHTT aggregate stages. [¹¹C]CHDI-009R presented high reproducibility during test-retest imaging. Power analyses suggest [¹¹C]CHDI-009R as suitable marker for early therapeutic interventions.