A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain.
A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain.
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DOI：
10.1039/d2cc03785h
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发表时间：
2022-08-25
影响因子：
4.9
通讯作者：
Wang, Changning
中科院分区：
文献类型：
--
作者：
Bai, Ping;Yan, Liu;Bagdasarian, Frederick A.;Wilks, Moses Q.;Wey, Hsiao-Ying;Wang, Changning
BET的两个串联的溴结构域（bromodomain和extra-terminal domain）蛋白（BD 1和BD 2）可能在神经系统疾病中发挥独特且关键的作用。为了更好地理解BD 1布罗莫结构域的潜在机制并促进脑可渗透结构域选择性抑制剂的开发，我们在此描述了第一个BET BD 1正电子发射断层扫描（PET）放射性配体[11 C]1a的开发。化合物1a经测试对BRD 2（Kd = 25 nM）、BRD 3（Kd = 24 nM）和BRD 4（Kd = 19 nM）的BD 1溴结构域具有有效的结合亲和力和良好的选择性（超过BD 2>20倍）。理化性质表明1a具有脑渗透性和特异性结合。[11 C]1a以良好的放射化学产率（RCY：25-30%）和摩尔活性（258 GBq μmol−1）放射合成。小鼠中[11 C]1a的PET成像研究显示出中等脑摄取（峰值SUV = 0.7）和结合特异性。此外，[11 C]1a在非人灵长类动物（NHP）PET成像研究中证明了翻译潜力，这为临床翻译奠定了基础。
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 [11C]1a. Compound 1a was tested to possess potent binding affinities and good selectivity (>20-fold over BD2) for BD1 bromodomains of BRD2 (Kd = 25 nM), BRD3 (Kd = 24 nM), and BRD4 (Kd = 19 nM). Physicochemical characterization of 1a indicated the brain permeability and specific binding. [11C]1a was radiosynthesized in a good radiochemical yield (RCY: 25–30%) and molar activity (258 GBq μmol−1). The PET imaging studies of [11C]1a in mice showed moderate brain uptake (with peak SUV = 0.7) and binding specificity. Furthermore, [11C]1a demonstrated translational potential in the non-human primate (NHP) PET imaging study, which sets the stage for clinical translation.
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影响因子：
37.3
作者：
Donati B;Lorenzini E;Ciarrocchi A
通讯作者：
Ciarrocchi A
DOI：
10.1126/science.aaz8455
发表时间：
2020-04-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gilan O;Rioja I;Knezevic K;Bell MJ;Yeung MM;Harker NR;Lam EYN;Chung CW;Bamborough P;Petretich M;Urh M;Atkinson SJ;Bassil AK;Roberts EJ;Vassiliadis D;Burr ML;Preston AGS;Wellaway C;Werner T;Gray JR;Michon AM;Gobbetti T;Kumar V;Soden PE;Haynes A;Vappiani J;Tough DF;Taylor S;Dawson SJ;Bantscheff M;Lindon M;Drewes G;Demont EH;Daniels DL;Grandi P;Prinjha RK;Dawson MA
通讯作者：
Dawson MA
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
13.8
作者：
Pike VW
通讯作者：
Pike VW
影响因子：
4.2
作者：
Bai, Ping;Lu, Xiaoxia;Wang, Changning
通讯作者：
Wang, Changning