Design, Synthesis, and Evaluation of Thienodiazepine Derivatives as Positron Emission Tomography Imaging Probes for Bromodomain and Extra-Terminal Domain Family Proteins
| Autor: | Gengyang Yuan, Darcy R. Tocci, Changning Wang, Stephen J. Haggarty, Zude Chen, Yan Liu, Hao Wang, Amelia G. Langan, Julia S. Zagaroli, Ping Bai, Robin Striar, Yu Lan, Sepideh Afshar, Debasis Patnaik |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.diagnostic_test
Chemistry Azepines In vitro Bromodomain Molecular Docking Simulation Mice chemistry.chemical_compound Protein Domains Design synthesis Positron emission tomography In vivo Drug Design Molecular Probes Positron-Emission Tomography Thienodiazepine Drug Discovery medicine Biophysics Animals Molecular Medicine Domain family Binding selectivity Transcription Factors |
| Zdroj: | Journal of Medicinal Chemistry. 64:14745-14756 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c01323 |
| Popis: | To better understand the role of bromodomain and extra-terminal domain (BET) proteins in epigenetic mechanisms, we developed a series of thienodiazepine-based derivatives and identified two compounds, 3a and 6a, as potent BET inhibitors. Further in vivo pharmacokinetic studies and analysis of in vitro metabolic stability of 6a revealed excellent brain penetration and reasonable metabolic stability. Compounds 3a and 6a were radiolabeled with fluorine-18 in two steps and utilized in positron emission tomography (PET) imaging studies in mice. Preliminary PET imaging results demonstrated that [18F]3a and [18F]6a have good brain uptake (with maximum SUV = 1.7 and 2, respectively) and binding specificity in mice brains. These results show that [18F]6a is a potential PET radiotracer that could be applied to imaging BET proteins in the brain. Further optimization and improvement of the metabolic stability of [18F]6a are still needed in order to create optimal PET imaging probes of BET family members. |
| Databáze: | OpenAIRE |
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