氟18标记的半乳糖衍生物[18F] FPGal的放射合成和生物学评估，用于对肝脏脱唾液酸糖蛋白受体进行成像。,Bioorganic & Medicinal Chemistry Letters

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氟18标记的半乳糖衍生物[18F] FPGal的放射合成和生物学评估，用于对肝脏脱唾液酸糖蛋白受体进行成像。
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-04-13 , DOI: 10.1016/j.bmcl.2020.127187
Penghui Sun ₁ , Yun Zhu ₂ , Yanjiang Han ₁ , Kongzhen Hu ₁ , Shun Huang ₁ , Meng Wang ₁ , Hubing Wu ₁ , Ganghua Tang ₁

Affiliation

脱唾液酸糖蛋白受体（ASGPR）在肝细胞表面大量表达，可识别并内吞具有半乳糖基和N-乙酰基半乳糖胺基团的糖蛋白。鉴于其肝脏分布，正电子显像剂可以靶向去唾液酸糖蛋白受体，以使用PET显像研究肝功能。在这项研究中，正电子显像剂[18F] FPGal被设计为特异性靶向肝去唾液酸糖蛋白受体，并在体外和体内模型中评估了其有效性。[18F] FPGal的放射合成需要50分钟，从[18F]氟化物得到的[18F] FPGal的总放射化学产率为10％（校正的放射化学产率）。HepG2细胞中[18F] FPGal对ASGPR的Kd为1.99±0.05 mM。在与HepG2细胞孵育30分钟内观察到的摄取值为0.55％，可能会被200 mM d（+）-半乳糖（<0.1％）阻断。体内生物分布分析表明，正常小鼠中[18F] FPGal在30分钟时的肝蓄积为4.47±0.96％ID / g，而肝纤维化小鼠为1.33±0.07％ID / g（P <0.01）。在30分钟时通过PET / CT图像确认了肝纤维化小鼠模型中摄取的减少。与正常小鼠相比，通过动态数据收集1 h评估肝纤维化小鼠的标准摄取值（SUV）显着降低。因此，[18F] FPGal是一种可行的PET探针，可提供有关ASGPR相关肝病的见解。在30分钟时通过PET / CT图像确认了肝纤维化小鼠模型中摄取的减少。与正常小鼠相比，通过动态数据收集1 h评估肝纤维化小鼠的标准摄取值（SUV）显着降低。因此，[18F] FPGal是一种可行的PET探针，可提供有关ASGPR相关肝病的见解。在30分钟时通过PET / CT图像确认了肝纤维化小鼠模型中摄取的减少。与正常小鼠相比，通过动态数据收集1 h评估肝纤维化小鼠的标准摄取值（SUV）显着降低。因此，[18F] FPGal是一种可行的PET探针，可提供有关ASGPR相关肝病的见解。

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Radiosynthesis and biological evaluation of an fluorine-18 labeled galactose derivative [18F]FPGal for imaging the hepatic asialoglycoprotein receptor.

The asialoglycoprotein receptor (ASGPR) is abundantly expressed on the surface of hepatocytes where it recognizes and endocytoses glycoproteins with galactosyl and N-acetylgalactosamine groups. Given its hepatic distribution, the asialoglycoprotein receptor can be targeted by positron imaging agents to study liver function using PET imaging. In this study, the positron imaging agent [18F]FPGal was designed to specifically target hepatic asialoglycoprotein receptor and its effectiveness was assessed in in vitro and in vivo models. The radiosynthesis of [18F]FPGal required 50 min with total radiochemical yields of [18F]FPGal from [18F]fluoride as 10% (corrected radiochemical yield). The Kd of [18F]FPGal to ASGPR in HepG2 cells was 1.99 ± 0.05 mM. Uptake values of 0.55% were observed within 30 min of incubation with HepG2 cells, which could be blocked by 200 mM d(+)-galactose (<0.1%). In vivo biodistribution analysis showed that the liver accumulation of [18F]FPGal at 30 min was 4.47 ± 0.96% ID/g in normal mice compared to 1.33 ± 0.07% ID/g in hepatic fibrotic mice (P < 0.01). Reduced uptake in the hepatic fibrosis mouse models was confirmed through PET/CT images at 30 min. Compared to normal mice, the standard uptake value (SUV) in the hepatic fibrosis mice was significantly lower when assessed through dynamic data collection for 1 h. Therefore, [18F]FPGal is a feasible PET probe that provide insight into ASGPR related liver disease.

更新日期：2020-04-13

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