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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 01-03-2022 | Positron Emission Tomography | Original Article

Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington’s disease

Authors: Daniele Bertoglio, Jeroen Verhaeghe, Alan Miranda, Leonie Wyffels, Sigrid Stroobants, Ladislav Mrzljak, Vinod Khetarpal, Mette Skinbjerg, Longbin Liu, Celia Dominguez, Ignacio Munoz-Sanjuan, Jonathan Bard, Steven Staelens

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 4/2022

Abstract

Purpose

As 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.

Methods

After 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.

Results

Despite 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.

Conclusion

With 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.

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Title: Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington’s disease
Authors: Daniele Bertoglio
Jeroen Verhaeghe
Alan Miranda
Leonie Wyffels
Sigrid Stroobants
Ladislav Mrzljak
Vinod Khetarpal
Mette Skinbjerg
Longbin Liu
Celia Dominguez
Ignacio Munoz-Sanjuan
Jonathan Bard
Steven Staelens
Publication date: 01-03-2022
Publisher: Springer Berlin Heidelberg
Keywords: Positron Emission Tomography
Huntington's Disease
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 4/2022
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-021-05578-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington’s disease

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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