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Imaging Autotaxin In Vivo with 18F-Labeled Positron Emission Tomography Ligands
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2021-10-18 , DOI: 10.1021/acs.jmedchem.1c00913
Xiaoyun Deng 1, 2 , Fernando Salgado-Polo 3 , Tuo Shao 1 , Zhiwei Xiao 1 , Richard Van 4 , Jiahui Chen 1 , Jian Rong 1 , Ahmed Haider 1 , Yihan Shao 4 , Lee Josephson 1 , Anastassis Perrakis 3 , Steven H Liang 1
Affiliation  

Autotaxin (ATX) is a secreted phosphodiesterase that has been implicated in a remarkably wide array of pathologies, especially in fibrosis and cancer. While ATX inhibitors have entered the clinical arena, a validated probe for positron emission tomography (PET) is currently lacking. With the aim to develop a suitable ATX-targeted PET radioligand, we have synthesized a focused library of fluorinated imidazo[1,2-a]pyridine derivatives, determined their inhibition constants, and confirmed their binding mode by crystallographic analysis. Based on their promising in vitro properties, compounds 9c, 9f, 9h, and 9j were radiofluorinated. Also, a deuterated analog of [18F]9j, designated as [18F]ATX-1905 ([18F]20), was designed and proved to be highly stable against in vivo radiodefluorination compared with [18F]9c, [18F]9f, [18F]9h, and [18F]9j. These results along with in vitro and in vivo studies toward ATX in a mouse model of LPS-induced liver injury suggest that [18F]ATX-1905 is a suitable PET probe for the non-invasive quantification of ATX.

中文翻译:

使用 18F 标记的正电子发射断层扫描配体对自体运动因子进行体内成像

自分泌运动因子 (ATX) 是一种分泌型磷酸二酯酶,与多种病理学有关,尤其是纤维化和癌症。虽然 ATX 抑制剂已进入临床领域,但目前缺乏一种经过验证的正电子发射断层扫描 (PET) 探针。为了开发合适的 ATX 靶向 PET 放射性配体,我们合成了一个聚焦的氟化咪唑并[1,2- a ]吡啶衍生物库,确定了它们的抑制常数,并通过晶体学分析确认了它们的结合模式。基于它们有希望的体外特性,化合物9c9f9h9j被放射性氟化。此外,[ 18F] 9j,命名为[ 18 F]ATX-1905 ([ 18 F] 20 ),与[ 18 F] 9c , [ 18 F] 9f , [ 18 F ]相比,设计并证明对体内放射性脱氟具有高度稳定性] 9h和 [ 18 F] 9j。这些结果以及LPS 诱导的肝损伤小鼠模型中对 ATX 的体外体内研究表明,[ 18 F]ATX-1905 是一种适用于 ATX 非侵入性定量的 PET 探针。
更新日期:2021-10-28
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