Discovery of a Positron Emission Tomography Radiotracer Selectively Targeting the BD1 Bromodomains of BET Proteins

In this paper, we report the design, synthesis, and biological evaluation of the first selective bromodomain and extra-terminal domain (BET) BD 1 bromodomains of the PET radiotracer [F-18]PB006. The standard compound PB006 showed high affinity and good selectivity toward BRD4 BD1 (K-d = 100 nM and 29-fold selectively for BD1 over BD2) in an in vitro binding assay. PET imaging experiments in rodents were performed to evaluate the bioactivity of [F-18]PB006 in vivo. A biodistribution study of [F-18]PB006 in mice revealed high radiotracer uptake in peripheral tissues, such as liver and kidney, and moderate radiotracer uptake in the brain. Further blocking studies demonstrated the significant radioactivity decreasing (20-30% reduction compared with baseline) by pretreating unlabeled PB006 and JQ1, suggesting the high binding selectivity and specificity of [F-18]PB006. Our study indicated that [F-18]PB006 is a potent PET probe selectively targeting BET BD 1, and further structural optimization of the radiotracer is still required to improve brain uptake to support neuroepigenetic imaging.