Purpose [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). Methods 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 (VT) using 2-compartment modelling (2TCM) as well as Logan graphical analysis and determined distribution volume ratios relative to cerebellum (DVRCBL). We applied partial volume correction, and assessed test-retest variability in pwHD. Results VT showed considerable intersubject variability among HC (VT(cortex) = 0.68 ± 0.22) and pwHD (VT(cortex) = 0.75 ± 0.26), without any regional significant differences between the groups. VT test-retest variability was high if test and retest scans were performed on the same day, but low (< 10%) if performed one week apart. DVRCBL 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. Conclusion [11C]CHDI-180R VT 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. Registration EudraCT 2018-001862-41 clinicaltrials.gov NCT03810898 <a href="https://clinicaltrials.gov/study/NCT03810898?term=NCT03810898&rank=1">https://clinicaltrials.gov/study/NCT03810898?term=NCT03810898&rank=1</a>

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

期刊论文
发表日期：

2025年6月18日

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Aline Delva,
Michel Koole,
Kim Serdons,
Guy Bormans,
Mette Skinbjerg,
Vinod Khetarpal,
Longbin Liu,
Jonathan Bard,
Robert Doot,
John H. Warner,
Swati Sathe,
Cristina Sampaio,
Andrew Wood,
Koen Van Laere,
Wim Vandenberghe

摘要

Purpose

[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).

Methods

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.

Results

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.

Conclusion

[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.

Registration

EudraCT 2018-001862-41

clinicaltrials.gov NCT03810898 https://clinicaltrials.gov/study/NCT03810898?term=NCT03810898&rank=1