当前位置：
X-MOL 学术
›
Bioconjugate Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Caspase-3 Substrates for Noninvasive Pharmacodynamic Imaging of Apoptosis by PET/CT
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-08-31 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00514 Brian J. Engel , Seth T. Gammon , Rajan Chaudhari , Zhen Lu , Federica Pisaneschi , Hailing Yang , Argentina Ornelas , Victoria Yan , Lindsay Kelderhouse , Amer M. Najjar , William P. Tong , Shuxing Zhang 1 , David Piwnica-Worms , Robert C. Bast , Steven W. Millward
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-08-31 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00514 Brian J. Engel , Seth T. Gammon , Rajan Chaudhari , Zhen Lu , Federica Pisaneschi , Hailing Yang , Argentina Ornelas , Victoria Yan , Lindsay Kelderhouse , Amer M. Najjar , William P. Tong , Shuxing Zhang 1 , David Piwnica-Worms , Robert C. Bast , Steven W. Millward
Affiliation
|
Quantitative imaging of apoptosis in vivo could enable real-time monitoring of acute cell death pathologies such as traumatic brain injury, as well as the efficacy and safety of cancer therapy. Here, we describe the development and validation of F-18-labeled caspase-3 substrates for PET/CT imaging of apoptosis. Preliminary studies identified the O-benzylthreonine-containing substrate 2MP-TbD-AFC as a highly caspase 3-selective and cell-permeable fluorescent reporter. This lead compound was converted into the radiotracer [18F]-TBD, which was obtained at 10% decay-corrected yields with molar activities up to 149 GBq/μmol on an automated radiosynthesis platform. [18F]-TBD accumulated in ovarian cancer cells in a caspase- and cisplatin-dependent fashion. PET imaging of a Jo2-induced hepatotoxicity model showed a significant increase in [18F]-TBD signal in the livers of Jo2-treated mice compared to controls, driven through a reduction in hepatobiliary clearance. A chemical control tracer that could not be cleaved by caspase 3 showed no change in liver accumulation after induction of hepatocyte apoptosis. Our data demonstrate that [18F]-TBD provides an immediate pharmacodynamic readout of liver apoptosis in mice by dynamic PET/CT and suggest that [18F]-TBD could be used to interrogate apoptosis in other disease states.
中文翻译：
Caspase-3底物用于PET / CT对细胞凋亡的无创药效成像
体内细胞凋亡的定量成像可以实时监测急性细胞死亡病理（例如脑外伤）以及癌症治疗的有效性和安全性。在这里，我们描述了用于PET / CT凋亡成像的F-18标记的caspase-3底物的开发和验证。初步研究确定了含有O-苄基苏氨酸的底物2MP-TbD-AFC是一种高度胱天蛋白酶3选择性和细胞渗透性的荧光报告分子。将该先导化合物转化为放射性示踪剂[ 18 F] -TBD，在自动放射性合成平台上以10％衰减校正的收率获得了该化合物，摩尔活性高达149 GBq /μmol。[ 18F] -TBD以caspase和顺铂依赖性方式累积在卵巢癌细胞中。与对照组相比，Jo2诱导的肝毒性模型的PET成像显示，与对照组相比，Jo2治疗的小鼠肝脏中[ 18 F] -TBD信号显着增加，这是由肝胆清除率降低引起的。不能被胱天蛋白酶3切割的化学对照示踪剂显示诱导肝细胞凋亡后肝脏蓄积没有变化。我们的数据表明[ 18 F] -TBD通过动态PET / CT提供了小鼠肝细胞凋亡的即时药效学读数，并表明[ 18 F] -TBD可用于询问其他疾病状态下的细胞凋亡。
更新日期：2018-08-31
中文翻译：
Caspase-3底物用于PET / CT对细胞凋亡的无创药效成像
体内细胞凋亡的定量成像可以实时监测急性细胞死亡病理（例如脑外伤）以及癌症治疗的有效性和安全性。在这里，我们描述了用于PET / CT凋亡成像的F-18标记的caspase-3底物的开发和验证。初步研究确定了含有O-苄基苏氨酸的底物2MP-TbD-AFC是一种高度胱天蛋白酶3选择性和细胞渗透性的荧光报告分子。将该先导化合物转化为放射性示踪剂[ 18 F] -TBD，在自动放射性合成平台上以10％衰减校正的收率获得了该化合物，摩尔活性高达149 GBq /μmol。[ 18F] -TBD以caspase和顺铂依赖性方式累积在卵巢癌细胞中。与对照组相比，Jo2诱导的肝毒性模型的PET成像显示，与对照组相比，Jo2治疗的小鼠肝脏中[ 18 F] -TBD信号显着增加，这是由肝胆清除率降低引起的。不能被胱天蛋白酶3切割的化学对照示踪剂显示诱导肝细胞凋亡后肝脏蓄积没有变化。我们的数据表明[ 18 F] -TBD通过动态PET / CT提供了小鼠肝细胞凋亡的即时药效学读数，并表明[ 18 F] -TBD可用于询问其他疾病状态下的细胞凋亡。
京公网安备 11010802027423号