|
Title
|
|
|
|
In vivo cerebral imaging of mutant Huntingtin aggregates using ¹¹C-CHDI-180R PET in a nonhuman primate model of Huntington disease
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| Huntington disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine (CAG) trinucleotide expansion in the huntingtin (HTT) gene that encodes the mutant huntingtin protein (mHTT). Visualization and quantification of cerebral mHTT will provide a proxy for target engagement and a means to evaluate therapeutic interventions aimed at lowering mHTT in the brain. Here, we validated the novel radioligand 11C-labeled 6-(5-((5-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazin-3(2H)-one (11C-CHDI-180R) using PET imaging to quantify cerebral mHTT aggregates in a macaque model of HD. Methods: Rhesus macaques received MRI-guided intrastriatal delivery of a mixture of AAV2 and AAV2.retro viral vectors expressing an HTT fragment bearing 85 CAG repeats (85Q, n = 5), a control HTT fragment bearing 10 CAG repeats (10Q, n = 4), or vector diluent only (phosphate-buffered saline, n = 5). Thirty months after surgery, 90-min dynamic PET/CT imaging was used to investigate 11C-CHDI-180R brain kinetics, along with serial blood sampling to measure input function and stability of the radioligand. The total volume of distribution was calculated using a 2-tissue-compartment model as well as Logan graphical analysis for regional quantification. Immunostaining for mHTT was performed to corroborate the in vivo findings. Results: 11C-CHDI-180R displayed good metabolic stability (51.4% ± 4.0% parent in plasma at 60 min after injection). Regional time–activity curves displayed rapid uptake and reversible binding, which were described by a 2-tissue-compartment model. Logan graphical analysis was associated with the 2-tissue-compartment model (r2 = 0.96, P < 0.0001) and used to generate parametric volume of distribution maps. Compared with controls, animals administered the 85Q fragment exhibited significantly increased 11C-CHDI-180R binding in several cortical and subcortical brain regions (group effect, P < 0.0001). No difference in 11C-CHDI-180R binding was observed between buffer and 10Q animals. The presence of mHTT aggregates in the 85Q animals was confirmed histologically. Conclusion: We validated 11C-CHDI-180R as a radioligand to visualize and quantify mHTT aggregated species in a HD macaque model. These findings corroborate our previous work in rodent HD models and show that 11C-CHDI-180R is a promising tool to assess the mHTT aggregate load and the efficacy of therapeutic strategies. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
The Journal of nuclear medicine. - New York
| |
|
Publication
|
|
|
|
New York
:
2023
| |
|
ISSN
|
|
|
|
0161-5505
| |
|
DOI
|
|
|
|
10.2967/JNUMED.123.265569
| |
|
Volume/pages
|
|
|
|
64
:10
(2023)
, p. 1581-1587
| |
|
ISI
|
|
|
|
001103015900015
| |
|
Pubmed ID
|
|
|
|
37591545
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|