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

The two tandem bromodomains of BET (bromodomain and extra-terminal 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 [¹¹C]1a. Compound 1a 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 1a indicated the brain permeability and specific binding. [¹¹C]1a was radiosynthesized in a good radiochemical yield (RCY: 25-30%) and molar activity (258 GBq μmol^-1). The PET imaging studies of [¹¹C]1a in mice showed moderate brain uptake (with peak SUV = 0.7) and binding specificity. Furthermore, [¹¹C]1a demonstrated translational potential in the non-human primate (NHP) PET imaging study, which sets the stage for clinical translation.