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. Epub 2021 Sep 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / chemistry*
  • Azepines / pharmacokinetics
  • Drug Design*
  • Mice
  • Molecular Docking Simulation
  • Molecular Probes / chemistry*
  • Molecular Probes / pharmacokinetics
  • Positron-Emission Tomography / methods*
  • Protein Domains*
  • Transcription Factors / metabolism

Substances

  • Azepines
  • Molecular Probes
  • Transcription Factors
  • thienodiazepine substance