Preclinical evaluation of the novel [18F]CHDI-650 PET ligand for non-invasive quantification of mutant huntingtin aggregates in Huntington’s disease

Abstract

AbstractPurposePositron emission tomography (PET) imaging of mutant huntingtin (mHTT) aggregates is a potential tool to monitor disease progression as well as the efficacy of candidate therapeutic interventions for Huntington’s disease (HD). To date, the focus has been mainly on the investigation of11C radioligands; however, favourable18F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [18F]CHDI-650 PET radiotracer using a combination ofin vivoandin vitroapproaches in a mouse model of HD.MethodsAfter characterising [18F]CHDI-650 usingin vitroautoradiography, we assessedin vivoplasma and brain radiotracer stability as well as kinetics through dynamic PET imaging in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 months of age. Additionally, we performed a head-to-head comparison study at 3 months with the previously published [11C]CHDI-180R radioligand.ResultsPlasma and brain radiometabolite profiles indicated a suitable metabolic profile forin vivoimaging of [18F]CHDI-650. Bothin vitroautoradiography andin vivo[18F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p<0.0001) despite the poor test-retest reliability. [18F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [11C]CHDI-180R.ConclusionOverall, [18F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [18F]CHDI-650 represents the first suitable18F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway.