A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain. Issue 69 (9th August 2022)

• Record Type: Journal Article
• Authors: Bai, Ping; Yan, Liu; Bagdasarian, Frederick A.; Wilks, Moses Q.; Wey, Hsiao-Ying; Wang, Changning
• Is Part Of: Chemical communications. Volume 58:Issue 69(2022)
• Page Start: 9654
• Page End: 9657
• Publication Date: 2022-08-09
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1039/d2cc03785h
• Languages: English
• ISSNs: 1359-7345

Abstract

Abstract : Development of a novel brain-permeable PET probe for BET BD1 bromodomain imaging. Abstract : The two tandem bromodomains of BET (bromodomain and extra-terminal domain) proteins (BD1 and BD2) may play distinct and critical roles in neurological diseases. To better understand the underlying mechanisms of the BD1 bromodomain and facilitate brain permeable domain-selective inhibitor development, we describe here the development of the first BET BD1 positron emission tomography (PET) radioligand [ 11 C]1a . Compound 1a was tested to possess potent binding affinities and good selectivity (>20-fold over BD2) for BD1 bromodomains of BRD2 ( K d = 25 nM), BRD3 ( K d = 24 nM), and BRD4 ( K d = 19 nM). Physicochemical characterization of 1a indicated the brain permeability and specific binding. [ 11 C]1a was radiosynthesized in a good radiochemical yield (RCY: 25–30%) and molar activity (258 GBq μmol −1 ). The PET imaging studies of [ 11 C]1a in mice showed moderate brain uptake (with peak SUV = 0.7) and binding specificity. Furthermore, [ 11 C]1a demonstrated translational potential in the non-human primate (NHP) PET imaging study, which sets the stage for clinical translation.