A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain

The two tandem bromodomains of BET (bromodomain and extraterminal domain) proteins (BD1 and BD2) may play distinct and critical roles in neurological diseases. To better understand the underlying mechanisms of the BD1 bromodomain and facilitate brain permeable domain-selective inhibitor development, we describe here the development of the first BET BD1 positron emission tomography (PET) radioligand [C-11]1a. Compound la was tested to possess potent binding affinities and good selectivity (> 20-fold over BD2) for BD1 bromodomains of BRD2 (K-d = 25 nM), BRD3 (K-d = 24 nM), and BRD4 (K-d = 19 nM). Physicochemical characterization of la indicated the brain permeability and specific binding. [C-11]1a was radiosynthesized in a good radiochemical yield (RCY: 25-30%) and molar activity (258 GBq mu mol(-1)). The PET imaging studies of [C-11]1a in mice showed moderate brain uptake (with peak SUV = 0.7) and binding specificity. Furthermore, [C-11]1a demonstrated translational potential in the non-human primate (NHP) PET imaging study, which sets the stage for clinical translation.