Wang Yanli, Wang Yongle, Xu Yulong, Tocci Darcy, Wang Changning
Department of Radiology Massachusetts General Hospital, Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts 02129, United States.
School of Pharmacy, Minzu University of China, Beijing 100081, China.
ACS Omega. 2024 Aug 12;9(34):36177-36184. doi: 10.1021/acsomega.4c01495. eCollection 2024 Aug 27.
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, [C]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 [C]I-58 for PET imaging of the BD2 bromodomain is evaluated. Initial PET study findings in mice indicate that [C]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 [C]I-58 to the BD2 bromodomain. These results establish [C]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.
位于溴结构域与额外末端（BET）家族蛋白中的成对溴结构域（BD1和BD2）在基因转录调控和表达中发挥特定功能。用抑制剂靶向特定溴结构域有望在减少副作用的情况下实现治疗益处。然而，对与该疾病相关的这一靶点的理解仍很有限。正电子发射断层扫描（PET）成像作为一种强大的工具，为探索BD2溴结构域提供了一条有价值的途径。本研究引入了一种用于PET靶向BET BD2结构域的新型放射性配体[C]I-58。详细介绍了化合物I-58的合成及其C11标记的放射性合成过程，并评估了[C]I-58用于BD2溴结构域PET成像的适用性。在小鼠身上进行的初步PET研究结果表明，[C]I-58在外周器官和组织中具有合适的生物分布。此外，体外放射自显影研究和阻断实验提供了有力证据，支持[C]I-58与BD2溴结构域的特异性结合。这些结果确立了[C]I-58作为用于BD2溴结构域PET成像的一种有前景的工具。本研究不仅有可能为开发精确靶向BD2溴结构域的PET放射性配体铺平道路，而且还增进了对与BD溴结构域相关的生物学机制的更深入理解。
