Discovery of a Positron Emission Tomography Radiotracer Selectively Targeting the BD1 Bromodomains of BET Proteins
Discovery of a Positron Emission Tomography Radiotracer Selectively Targeting the BD1 Bromodomains of BET Proteins
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DOI：
10.1021/acsmedchemlett.0c00650
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发表时间：
2021-01-08
影响因子：
4.2
通讯作者：
Wang, Changning
中科院分区：
文献类型：
--
作者：
Bai, Ping;Lu, Xiaoxia;Wang, Changning
本文报道了PET放射性示踪剂[F-18] PB 006的第一个选择性溴结构域和末端外结构域（BET）BD 1溴结构域的设计、合成和生物学评价。在体外结合测定中，标准化合物PB 006显示出对BRD 4 BD 1的高亲和力和良好的选择性（Kd = 100 nM，BD 1的选择性是BD 2的29倍）。在啮齿动物中进行PET成像实验以评价[F-18] PB 006的体内生物活性。[F-18] PB 006在小鼠中的生物分布研究显示，外周组织（如肝脏和肾脏）中的放射性示踪剂摄取较高，大脑中的放射性示踪剂摄取中等。进一步的阻断研究表明，通过预处理未标记的PB 006和JQ 1，放射性显著降低（与基线相比降低20-30%），表明[F-18] PB 006具有高结合选择性和特异性。我们的研究表明，[F-18] PB 006是一种选择性靶向BET BD 1的有效PET探针，并且仍需要进一步优化放射性示踪剂的结构以改善脑摄取以支持神经表观遗传成像。
In this paper, we report the design, synthesis, and biological evaluation of the first selective bromodomain and extra-terminal domain (BET) BD 1 bromodomains of the PET radiotracer [F-18]PB006. The standard compound PB006 showed high affinity and good selectivity toward BRD4 BD1 (K-d = 100 nM and 29-fold selectively for BD1 over BD2) in an in vitro binding assay. PET imaging experiments in rodents were performed to evaluate the bioactivity of [F-18]PB006 in vivo. A biodistribution study of [F-18]PB006 in mice revealed high radiotracer uptake in peripheral tissues, such as liver and kidney, and moderate radiotracer uptake in the brain. Further blocking studies demonstrated the significant radioactivity decreasing (20-30% reduction compared with baseline) by pretreating unlabeled PB006 and JQ1, suggesting the high binding selectivity and specificity of [F-18]PB006. Our study indicated that [F-18]PB006 is a potent PET probe selectively targeting BET BD 1, and further structural optimization of the radiotracer is still required to improve brain uptake to support neuroepigenetic imaging.