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 [ 11 C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [ 11 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, [ 11 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 [ 11 C]BRD1158 human PET.
Competing Interests: The authors declare the following competing financial interest(s): Dr. Jacob Hooker discloses the following relationships: Massachusetts Institute of Technology Consultant; American Chemical Society (ACS), ACS Publications, ACS Chemical Neuroscience Editorial Role; Eikonizo Therapeutics Co-Founder, Advisor; Sensorium Therapeutics Co-Founder, Advisor; Psy Therapeutics Consultant; Delix Therapeutics Advisor; Fuzionaire Diagnostics Advisor; Arclight Therapeutics Advisor; Proximity Therapeutics Advisor; Human Health Advisor, Rocket Science Health Advisor; Atai Life Sciences Sponsored research, training grant/gift. Dr. Beth Stevens discloses the following relationships: Beth Stevens serves on the scientific advisory board of Annexon Biosciences and is a minor shareholder of this company.
(© 2024 The Authors. Published by American Chemical Society.)