PET imaging with [¹¹C]CHDI-00485180-R, designed as radioligand for aggregated mutant huntingtin, in people with Huntington's disease.

Abstract

[¹¹C]CHDI-00485180-R ([¹¹C]CHDI-180R) is a novel PET radioligand developed to image aggregated mutant huntingtin (mHTT). Data from mouse models of Huntington's disease (HD) and biodistribution studies in healthy volunteers suggested that [¹¹C]CHDI-180R is a promising candidate for in vivo determination of cerebral aggregated mHTT levels using PET. In the iMagemHTT study reported here, we investigated [¹¹C]CHDI-180R kinetic properties and suitability to quantify aggregated mHTT in brains of people with HD (pwHD). A total of 12 pwHD (53.7 ± 6.9y, 5 M/ 7 F, Shoulson-Fahn stage 2) and 12 healthy controls (HC; six young [26.8 ± 3.2y], 2 M/ 4 F; six age-matched [53.7 ± 6.1y],2 M/ 4 F) were included. We conducted dynamic 90 min [¹¹C]CHDI-180R PET imaging with arterial sampling and radiometabolite quantification, and delineated volumes of interest (VOIs) using individual 3D T1-MRI. We calculated total distribution volumes (V_T) using 2-compartment modelling (2TCM) as well as Logan graphical analysis and determined distribution volume ratios relative to cerebellum (DVR_CBL). We applied partial volume correction, and assessed test-retest variability in pwHD. V_T showed considerable intersubject variability among HC (V_T(cortex) = 0.68 ± 0.22) and pwHD (V_T(cortex) = 0.75 ± 0.26), without any regional significant differences between the groups. V_T test-retest variability was high if test and retest scans were performed on the same day, but low (< 10%) if performed one week apart. DVR_CBL showed significantly higher [¹¹C]CHDI-180R relative binding in frontal, temporal, parietal, occipital and composite cortex VOIs (average increase 19.5 ± 6.1%) in pwHD than age-matched HC. [¹¹C]CHDI-180R V_T showed high intersubject variability and relatively low signal-to-background ratio. However, significant differences were found between pwHD and HC using cerebellum as pseudo-reference region. EudraCT 2018-001862-41 clinicaltrials.gov NCT03810898  https://clinicaltrials.gov/study/NCT03810898?term=NCT03810898&rank=1.