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

Positron 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 of ^{11}C radioligands; however, favourable ${}^{18}$F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [${}^{18}$F]CHDI-650 PET radiotracer using a combination of in vivo and in vitro approaches in a mouse model of HD. After characterising [${}^{18}$F]CHDI-650 using in vitro autoradiography, we assessed in vivo plasma 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 [${}^{11}$C]CHDI-180R radioligand. Plasma and brain radiometabolite profiles indicated a suitable metabolic profile for in vivo imaging of [${}^{18}$F]CHDI-650. Both in vitro autoradiography and in vivo [${}^{18}$F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p < 0.0001) despite the poor test-retest reliability. [${}^{18}$F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [${}^{11}$C]CHDI-180R. Overall, [${}^{18}$F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [${}^{18}$F]CHDI-650 represents the first suitable ${}^{18}$F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway.