Development and Evaluation of [¹¹C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging

The paired bromodomains (BD1 and BD2), located in the bromodomain and extra-terminal (BET) family proteins, perform specific functions in gene transcriptional control and expression. Targeting specific bromodomains with inhibitors holds promise for achieving therapeutic benefits with reduced side effects. However, the comprehension of this target related to the disease is still restricted. Positron emission tomography (PET) imaging is a powerful tool that provides a valuable avenue for exploring the BD2 bromodomain. This investigation introduces a novel radioligand, [¹¹C]I-58, for PET targeting the BET BD2 domain. The synthesis of compound I-58, along with its radiosynthetic process for C11 labeling, is detailed, and the suitability of [¹¹C]I-58 for PET imaging of the BD2 bromodomain is evaluated. Initial PET study findings in mice indicate that [¹¹C]I-58 exhibits suitable biodistribution in peripheral organs and tissues. Additionally, in vitro autoradiography studies and blocking experiments provide compelling evidence supporting the specific binding of [¹¹C]I-58 to the BD2 bromodomain. These results establish [¹¹C]I-58 as a promising instrument for the PET imaging of the BD2 bromodomain. This research not only holds the potential to pave the path for developing PET radioligands precisely targeting the BD2 bromodomain but also adds to a more profound comprehension of the biological mechanisms linked to the BD bromodomain.