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 ¹⁸F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the ¹⁸F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [¹⁸F]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

[¹⁸F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % ± 3 % and 3 % ± 1 % activity yields non-decay corrected). [¹⁸F]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 [¹⁸F]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.

中文翻译：

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[18F]AZD2461，对 DNA 损伤反应 PET 成像 PARP 结合谱差异的见解。

 背景

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基于 PARP1-3 的强亲和力而选择的。在此，我们建议研究 AZD2461（一种对 PARP3 具有较低亲和力的 PARP 抑制剂），并研究其体内PARP 靶向的潜力。

 方法

利用精心设计的放射性标记前体的 Cu 介导的¹⁸ F-氟脱硼，我们获得了 PARP 抑制剂 AZD2461 的¹⁸ F 标记同位素体。在一系列胰腺细胞系（PSN-1、PANC-1、CFPAC-1 和 AsPC-1）中评估 [ ¹⁸ F]AZD2461 的体外细胞摄取，以评估异种移植小鼠体内的 PARP 表达。使用奥拉帕尼和 AZD2461 进行阻断实验。

 结果

[ ¹⁸ F]AZD2461通过手动和自动程序进行有效放射性标记（9 % ± 3 % 和 3 % ± 1 % 活性产生非衰变校正）。 [ ¹⁸ F]AZD2461在体内表达 PARP1 的肿瘤中被摄取，PSN-1 细胞的摄取量最高 (7.34 ± 1.16 %ID/g)。体外阻断实验显示奥拉帕尼减少[ ¹⁸ F]AZD2461结合的能力较低，表明奥拉帕尼和AZD2461之间的选择性存在差异。

 结论

总之，我们展示了筛选用作 PET 显像剂的放射性标记 PARP 抑制剂的 PARP 选择性特征的重要性。