{"doi":"10.2967/jnumed.123.265569","title":"In Vivo Cerebral Imaging of Mutant Huntingtin Aggregates Using<sup>11</sup>C-CHDI-180R PET in a Nonhuman Primate Model of Huntington Disease","abstract":"Huntington disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine (CAG) trinucleotide expansion in the huntingtin (<i>HTT</i>) 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 <sup>11</sup>C-labeled 6-(5-((5-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazin-3(2H)-one (<sup>11</sup>C-CHDI-180R) using PET imaging to quantify cerebral mHTT aggregates in a macaque model of HD. <b>Methods:</b> 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, <i>n</i> = 5), a control HTT fragment bearing 10 CAG repeats (10Q, <i>n</i> = 4), or vector diluent only (phosphate-buffered saline, <i>n</i> = 5). Thirty months after surgery, 90-min dynamic PET/CT imaging was used to investigate <sup>11</sup>C-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&nbsp;vivo findings. <b>Results:</b><sup>11</sup>C-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 (<i>r</i><sup>2</sup> = 0.96, <i>P</i> &lt; 0.0001) and used to generate parametric volume of distribution maps. Compared with controls, animals administered the 85Q fragment exhibited significantly increased <sup>11</sup>C-CHDI-180R binding in several cortical and subcortical brain regions (group effect, <i>P</i> &lt; 0.0001). No difference in <sup>11</sup>C-CHDI-180R binding was observed between buffer and 10Q animals. The presence of mHTT aggregates in the 85Q animals was confirmed histologically. <b>Conclusion:</b> We validated <sup>11</sup>C-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 <sup>11</sup>C-CHDI-180R is a promising tool to assess the mHTT aggregate load and the efficacy of therapeutic strategies.","journal":"Journal of Nuclear Medicine","year":2023,"id":338708,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":301291,"name":"Alison R. Weiss","orcid":"0000-0002-1821-8193","position":1,"is_corresponding":false},{"id":301292,"name":"William A. Liguore","orcid":"0000-0002-6853-1882","position":2,"is_corresponding":false},{"id":349005,"name":"Lauren Martin","orcid":"0009-0003-6450-5411","position":3,"is_corresponding":false},{"id":385185,"name":"Theodore R. Hobbs","orcid":"0000-0002-1717-7115","position":4,"is_corresponding":false},{"id":957994,"name":"John Templon","orcid":null,"position":5,"is_corresponding":false},{"id":894352,"name":"Sathya Srinivasan","orcid":"0000-0002-5386-8722","position":6,"is_corresponding":false},{"id":1071630,"name":"Celia Dominguez","orcid":"0000-0001-6862-1645","position":7,"is_corresponding":false},{"id":891749,"name":"Ignacio Muñoz-Sanjuán","orcid":"0000-0003-0353-3577","position":8,"is_corresponding":false},{"id":891748,"name":"Vinod Khetarpal","orcid":"0000-0002-2175-5117","position":9,"is_corresponding":false},{"id":1071631,"name":"Jeroen Verhaeghe","orcid":"0000-0002-4493-1902","position":10,"is_corresponding":false},{"id":1071632,"name":"Steven Staelens","orcid":"0000-0003-3376-0519","position":11,"is_corresponding":false},{"id":924862,"name":"Jeanne Link","orcid":"0000-0002-9063-0203","position":12,"is_corresponding":false},{"id":1071633,"name":"Longbin Liu","orcid":"0000-0002-3051-0090","position":13,"is_corresponding":false},{"id":1071634,"name":"Jonathan Bard","orcid":"0000-0002-5097-1361","position":14,"is_corresponding":false},{"id":301295,"name":"Jodi L. McBride","orcid":"0000-0002-4816-7569","position":15,"is_corresponding":false},{"id":957509,"name":"Daniele Bertoglio","orcid":"0000-0003-4205-5432","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T01:10:40.496978Z","pmid":"37591545","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}