학술논문
A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging
Document Type
Article
Author
Placzek, Michael S.; Wilton, Daniel K.; Weïwer, Michel; Manter, Mariah A.; Reid, Sarah E.; Meyer, Christopher J.; Campbell, Arthur J.; Bajrami, Besnik; Bigot, Antoine; Bricault, Sarah; Fayet, Agathe; Frouin, Arnaud; Gergits, Frederick; Gupta, Mehak; Jiang, Wei; Melanson, Michelle; Romano, Chiara D.; Riley, Misha M.; Wang, Jessica M.; Wey, Hsiao-Ying; Wagner, Florence F.; Stevens, Beth; Hooker, Jacob M.
Source
ACS Central Science; May 2024, Vol. 10 Issue: 5 p1105-1114, 10p
Subject
Language
ISSN
23747943; 23747951
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.