A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain

• Published in: Chemical communications (Cambridge, England) Vol. 58; no. 69; pp. 9654 - 9657
• Main Authors: Bai, Ping, Yan, Liu, Bagdasarian, Frederick A, Wilks, Moses Q, Wey, Hsiao-Ying, Wang, Changning
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 25.08.2022; Royal Society of Chemistry
• Subjects: Animals; Binding; Brain; Cell Cycle Proteins; Chemistry; Chemistry, Multidisciplinary; Emission analysis; Medical imaging; Mice; Neurological diseases; Nuclear Proteins - metabolism; Physical Sciences; Positron emission; Positron-Emission Tomography; Protein Domains; Radiochemistry; Science & Technology; Selectivity; Tomography; Transcription Factors - chemistry; DISCOVERY
• ISSN: 1359-7345; 1364-548X
• DOI: 10.1039/d2cc03785h

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. Development of a novel brain-permeable PET probe for BET BD1 bromodomain imaging.