Several therapies aimed at lowering mHTT brain levels are currently under clinical evaluation, and there is increasing interest in noninvasive objective markers, such as positron emission tomography (PET) imaging of mHTT, that could directly measure mHTT in the living brain. This mutated gene encodes mutant huntingtin (mHTT) protein that accumulates and plays a pathophysiological role in neuronal dysfunction, selective neurodegeneration, and forebrain atrophy leading to progressive motor, psychiatric, and cognitive impairments in HD patients. Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine (CAG) repeat in exon 1 of the huntingtin ( HTT) gene. With clinical evaluation underway, CHDI-626 PET imaging appears to be a suitable preclinical candidate marker to monitor natural HD progression and for the evaluation of mHTT-lowering therapies. Longitudinal quantification could discriminate between genotypes already at premanifest stage (3 M), showing an age-associated increase in signal in HET mice in parallel with mHTT aggregate load progression, as supported by the post-mortem CHDI-626 autoradiography. Resultsĭespite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. Cross-sectional cohorts at each longitudinal time point were included for post-mortem CHDI-626 autoradiography. Statistical analysis was performed to evaluate temporal and genotypic differences.
MethodsĪfter evaluating radiometabolites and radioligand kinetics, we conducted longitudinal dynamic PET imaging at 3, 6, 9, and 13 months of age (M) in wild-type (WT, n = 17) and heterozygous (HET, n = 23) zQ175DN mice. Here we characterized and longitudinally assessed the novel radioligand CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD. As several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington’s disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression.