Abstract
PurposeAs 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. Here we characterized and longitudinally assessed the novel radioligand [11C]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD.MethodsAfter 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. Statistical analysis was performed to evaluate temporal and genotypic differences. Cross-sectional cohorts at each longitudinal time point were included for post-mortem [3H]CHDI-626 autoradiography.ResultsDespite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. 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 [3H]CHDI-626 autoradiography.ConclusionWith clinical evaluation underway, [11C]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.
Highlights
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 [1, 2]
We have recently reported the development of a novel high-affinity radioligand, CHDI-626, that targets mutant huntingtin (mHTT) and lacks significant affinity towards amyloid plaques, representing a potential candidate for mHTT positron emission tomography (PET) imaging in the clinic [16, 17]
Striatal volume of distribution (VT) (IDIF) values calculated with Logan plot considering 15-min acquisition in 10 M animals displayed higher values for HET mice compared to WT littermates (+ 50 ± 3.4%, p < 0.0001) (Fig. 3f), highlighting the capability of [11C]CHDI-626 in discriminating between genotypes given the differences in target expression
Summary
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 [1, 2]. Our objective in this study was to evaluate kinetic modelling properties and to perform a longitudinal quantification of the novel radioligand [11C]CHDI-626 for mHTT PET imaging using the zQ175DN knock-in HD mouse model [18, 19]. This model displays hallmarks of mHTT-containing neuropil, soma, and intranuclear inclusions increasing from 3 to 12 months of age (M) [20], thereby allowing assessment of disease progression. A longitudinal PET imaging of [11C] CHDI-626 was performed in mice at 3, 6, 9, and 13 M to monitor the disease course and to assess its ability to discriminate between genotypes and mHTT load for clinical application, including monitoring disease progression and potential application in mHTT-lowering therapeutic interventional trials
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