2. Academic Validation
  3. Design, Synthesis, and Evaluation of Thienodiazepine Derivatives as Positron Emission Tomography Imaging Probes for Bromodomain and Extra-Terminal Domain Family Proteins

Design, Synthesis, and Evaluation of Thienodiazepine Derivatives as Positron Emission Tomography Imaging Probes for Bromodomain and Extra-Terminal Domain Family Proteins

  • J Med Chem. 2021 Oct 14;64(19):14745-14756. doi: 10.1021/acs.jmedchem.1c01323.
Ping Bai 1,  Yu Lan 1,  Debasis Patnaik 2,  Hao Wang 1,  Yan Liu 1,  Zude Chen 1,  Gengyang Yuan 3,  Sepideh Afshar 3,  Robin Striar 1,  Julia S Zagaroli 1,  Darcy R Tocci 1,  Amelia G Langan 1,  Stephen J Haggarty 2,  Changning Wang 1
Affiliations

Affiliations

  • 1 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • 2 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States.
  • 3 Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
PMID: 34549949 DOI: 10.1021/acs.jmedchem.1c01323
Abstract

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.

Figures
Products