一种正电子发射断层成像探针，选择性靶向 BD1 溴结构域和额外末端结构域。
A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain.
机构信息
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
出版信息
Chem Commun (Camb). 2022 Aug 25;58(69):9654-9657. doi: 10.1039/d2cc03785h.
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 [C]1a. Compound 1a was tested to possess potent binding affinities and good selectivity (>20-fold over BD2) for BD1 bromodomains of BRD2 ( = 25 nM), BRD3 ( = 24 nM), and BRD4 ( = 19 nM). Physicochemical characterization of 1a indicated the brain permeability and specific binding. [C]1a was radiosynthesized in a good radiochemical yield (RCY: 25-30%) and molar activity (258 GBq μmol). The PET imaging studies of [C]1a in mice showed moderate brain uptake (with peak SUV = 0.7) and binding specificity. Furthermore, [C]1a demonstrated translational potential in the non-human primate (NHP) PET imaging study, which sets the stage for clinical translation.
双串联溴结构域蛋白（BET）的两个溴结构域（BD1 和 BD2）可能在神经疾病中发挥独特而关键的作用。为了更好地了解 BD1 溴结构域的潜在机制，并促进脑穿透结构域选择性抑制剂的开发，我们在此描述了首个 BET BD1 正电子发射断层扫描（PET）放射性配体 [C]1a 的开发。研究表明，化合物 1a 对 BRD2（ = 25 nM）、BRD3（ = 24 nM）和 BRD4（ = 19 nM）的 BD1 溴结构域具有很强的结合亲和力和良好的选择性（比 BD2 高出 20 倍）。1a 的物理化学特性表明其具有脑渗透性和特异性结合。[C]1a 的放射合成产率（RCY：25-30%）和摩尔活性（258 GBq μmol）都很好。[C]1a 在小鼠的 PET 成像研究中显示出中等的脑摄取（峰值 SUV = 0.7）和结合特异性。此外，[C]1a 在非人类灵长类动物（NHP）的 PET 成像研究中表现出转化潜力，为临床转化奠定了基础。
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