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A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging.
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.
Afiliação
  • Placzek MS; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Wilton DK; Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • Weïwer M; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • Manter MA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Reid SE; Lurie Center for Autism, 1 Maguire Road, Lexington, Massachusetts 02421, United States.
  • Meyer CJ; Massachusetts General Hospital, 55 Fruit St., Boston, Massachusetts 02114, United States.
  • Campbell AJ; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Bajrami B; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • Bigot A; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • Bricault S; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • Fayet A; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • Frouin A; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Gergits F; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • Gupta M; Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • Jiang W; Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • Melanson M; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • Romano CD; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • Riley MM; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • Wang JM; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • Wey HY; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Wagner FF; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Stevens B; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Hooker JM; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
ACS Cent Sci ; 10(5): 1105-1114, 2024 May 22.
Article em En | MEDLINE | ID: mdl-38799654
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.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: ACS Cent Sci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: ACS Cent Sci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos