Development and\nEvaluation of [<sup>11</sup>C]I-58:\nA Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic\nImaging

The paired bromodomains (BD1 and BD2), located in the\nbromodomain\nand extra-terminal (BET) family proteins, perform specific functions\nin gene transcriptional control and expression. Targeting specific\nbromodomains with inhibitors holds promise for achieving therapeutic\nbenefits with reduced side effects. However, the comprehension of\nthis target related to the disease is still restricted. Positron emission\ntomography (PET) imaging is a powerful tool that provides a valuable\navenue for exploring the BD2 bromodomain. This investigation introduces\na novel radioligand, [<sup>11</sup>C]I-58, for PET targeting the BET\nBD2 domain. The synthesis of compound I-58, along with its radiosynthetic\nprocess for C11 labeling, is detailed, and the suitability of [<sup>11</sup>C]I-58 for PET imaging of the BD2 bromodomain is evaluated.\nInitial PET study findings in mice indicate that [<sup>11</sup>C]I-58\nexhibits suitable biodistribution in peripheral organs and tissues.\nAdditionally, in vitro autoradiography studies and blocking experiments\nprovide compelling evidence supporting the specific binding of [<sup>11</sup>C]I-58 to the BD2 bromodomain. These results establish [<sup>11</sup>C]I-58 as a promising instrument for the PET imaging of the\nBD2 bromodomain. This research not only holds the potential to pave\nthe path for developing PET radioligands precisely targeting the BD2\nbromodomain but also adds to a more profound comprehension of the\nbiological mechanisms linked to the BD bromodomain.