[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging
[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging
复制标题
DOI：
10.1007/s11307-020-01497-6
复制
发表时间：
2020-04-27
影响因子：
3.1
通讯作者：
Cornelissen, Bart
中科院分区：
文献类型：
--
作者：
Guibbal, Florian;Hopkins, Samantha L.;Cornelissen, Bart
聚（adp -核糖）聚合酶（PARP）抑制剂被广泛研究并用作抗癌药物，作为单一药物或与其他疗法联合使用。迄今为止开发的大多数放射性示踪剂都是根据强PARP1-3亲和力来选择的。因此，我们拟研究一种对PARP3亲和力较低的PARP抑制剂AZD2461，并探讨其在体内靶向PARP的潜力。方法利用精心设计的放射性标记前体的cu介导的f -18氟代波化，我们获得了PARP抑制剂AZD2461的f -18标记同位素。在体外评估[F-18]AZD2461在一系列胰腺细胞系（PSN-1、PANC-1、CFPAC-1和AsPC-1）中的细胞摄取，以评估PARP在异种移植小鼠体内的表达。用olaparib和AZD2461进行阻断实验。结果[F-18]AZD2461通过人工和自动程序有效地进行了放射性标记（9% +/- 3%和3% +/- 1%活性产生非衰变校正）。[F-18]AZD2461在体内表达parp1的肿瘤中被摄取，其中PSN-1细胞的摄取最高（7.34 +/- 1.16% ID/g）。体外阻断实验显示，奥拉帕尼降低[F-18]AZD2461结合的能力较弱，表明奥拉帕尼与AZD2461的选择性存在差异。综上所述，我们显示了筛选放射性标记PARP抑制剂作为PET显像剂的PARP选择性谱的重要性。
Background Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1-3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3, and to investigate its potential for PARP targeting in vivo. Methods Using the Cu-mediated F-18-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the F-18-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [F-18]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461. Results [F-18]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % +/- 3 % and 3 % +/- 1 % activity yields non-decay corrected). [F-18]AZD2461 was taken up in vivo in PARP1-expressing tumours, and the highest uptake was observed for PSN-1 cells (7.34 +/- 1.16 %ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [F-18]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461. Conclusion Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.