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

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.