Michael S. Placzek, Daniel K. Wilton, Michel Weïwer, Mariah A. Manter, Sarah E. Reid, Christopher J. Meyer, Arthur J. Campbell, Besnik Bajrami, Antoine Bigot, Sarah Bricault, Agathe Fayet, Arnaud Frouin, Frederick Gergits, Mehak Gupta, Wei Jiang, Michelle Melanson, Chiara D. Romano, Misha M. Riley, Jessica M. Wang, Hsiao-Ying Wey, Florence F. Wagner, Beth Stevens and Jacob M. Hooker*,
{"title":"A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging","authors":"Michael S. Placzek, Daniel K. Wilton, Michel Weïwer, Mariah A. Manter, Sarah E. Reid, Christopher J. Meyer, Arthur J. Campbell, Besnik Bajrami, Antoine Bigot, Sarah Bricault, Agathe Fayet, Arnaud Frouin, Frederick Gergits, Mehak Gupta, Wei Jiang, Michelle Melanson, Chiara D. Romano, Misha M. Riley, Jessica M. Wang, Hsiao-Ying Wey, Florence F. Wagner, Beth Stevens and Jacob M. Hooker*, ","doi":"10.1021/acscentsci.3c01564","DOIUrl":null,"url":null,"abstract":"<p >Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [<sup>11</sup>C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [<sup>11</sup>C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [<sup>11</sup>C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington’s disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [<sup>11</sup>C]BRD1158 human PET.</p><p >A COX-2 specific radiotracer for positron emission tomography imaging, [<sup>11</sup>C]BRD1158, was developed and evaluated in rodent models. [<sup>11</sup>C]BRD1158 demonstrated rapid binding and functional reversibility and shows promise for human translation. Additionally, evidence for the involvement of COX-2 in Huntington’s disease is presented, highlighting the relevance of [<sup>11</sup>C]BRD1158 to clinical and research applications in neurodegeneration.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":null,"pages":null},"PeriodicalIF":12.7000,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.3c01564","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Central Science","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acscentsci.3c01564","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [11C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [11C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [11C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington’s disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [11C]BRD1158 human PET.
A COX-2 specific radiotracer for positron emission tomography imaging, [11C]BRD1158, was developed and evaluated in rodent models. [11C]BRD1158 demonstrated rapid binding and functional reversibility and shows promise for human translation. Additionally, evidence for the involvement of COX-2 in Huntington’s disease is presented, highlighting the relevance of [11C]BRD1158 to clinical and research applications in neurodegeneration.
期刊介绍:
ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.