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

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, <b>3a</b> and <b>6a</b>, as potent BET inhibitors. Further <i>in vivo</i> pharmacokinetic studies and analysis of <i>in vitro</i> metabolic stability of <b>6a</b> revealed excellent brain penetration and reasonable metabolic stability. Compounds <b>3a</b> and <b>6a</b> 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]<b>3a</b> and [¹⁸F]<b>6a</b> have good brain uptake (with maximum SUV = 1.7 and 2, respectively) and binding specificity in mice brains. These results show that [¹⁸F]<b>6a</b> 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]<b>6a</b> are still needed in order to create optimal PET imaging probes of BET family members.