Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, 200032, China.
Eur J Nucl Med Mol Imaging. 2023 Jul;50(9):2606-2620. doi: 10.1007/s00259-023-06249-6. Epub 2023 May 5.
Imaging the PARP expression using F probes has been approved in clinical trials. Nevertheless, hepatobiliary clearance of both F probes hindered their application in monitoring abdominal lesions. Our novel Ga-labelled probes aim for fewer abdominal signals while ensuring PARP targeting by optimizing the pharmacokinetic properties of radioactive probes.
Three radioactive probes targeted PARP were designed, synthesized, and evaluated based on the PARP inhibitor Olaparib. These Ga-labelled radiotracers were assessed in vitro and in vivo.
Precursors that did not lose binding affinity for PARP were designed, synthesized, and then labelled with Ga in high radiochemical purity (> 97%). The Ga-labelled radiotracers were stable. Due to the increased expression of PARP-1 in SK-OV-3 cells, the uptake of the three radiotracers by SK-OV-3 cells was significantly greater than that by A549 cells. PET/CT imaging of the SK-OV-3 models indicated that the tumor uptake of Ga-DOTA-Olaparib (0.5 h: 2.83 ± 0.55%ID/g; 1 h: 2.37 ± 0.64%ID/g) was significantly higher than that of the other Ga-labelled radiotracers. There was a significant difference in the T/M (tumor-to-muscle) ratios between the unblocked and blocked groups as calculated from the PET/CT images (4.07 ± 1.01 vs. 1.79 ± 0.45, P = 0.0238 < 0.05). Tumor autoradiography revealed high accumulation in tumor tissues, further confirming the above data. PARP-1 expression in the tumor was confirmed by immunochemistry.
As the first Ga-labelled PARP inhibitor, Ga-DOTA-Olaparib displayed high stability and quick PARP imaging in a tumor model. This compound is thus a promising imaging agent that can be used in a personalized PARP inhibitor treatment regimen.
使用 F 探针对 PARP 表达进行成像已在临床试验中得到认可。然而，两种 F 探针的肝胆清除率都阻碍了它们在监测腹部病变中的应用。我们的新型 Ga 标记探针旨在减少腹部信号，同时通过优化放射性探针的药代动力学特性来确保 PARP 靶向。
根据 PARP 抑制剂奥拉帕利，设计、合成了三种靶向 PARP 的放射性探针，并进行了评估。这些 Ga 标记的放射性示踪剂在体外和体内进行了评估。
设计、合成了不丧失与 PARP 结合亲和力的前体，然后用 Ga 以高放射化学纯度（>97%）进行标记。Ga 标记的放射性示踪剂稳定。由于 SK-OV-3 细胞中 PARP-1 的表达增加，三种放射性示踪剂被 SK-OV-3 细胞摄取的量明显高于 A549 细胞。SK-OV-3 模型的 PET/CT 成像表明，Ga-DOTA-Olaparib（0.5 h：2.83±0.55%ID/g；1 h：2.37±0.64%ID/g）的肿瘤摄取量明显高于其他 Ga 标记的放射性示踪剂。从 PET/CT 图像计算得出，未阻断组和阻断组的 T/M（肿瘤与肌肉）比值有显著差异（4.07±1.01 与 1.79±0.45，P=0.0238<0.05）。肿瘤放射自显影显示肿瘤组织中高浓度积聚，进一步证实了上述数据。免疫组织化学证实了肿瘤中 PARP-1 的表达。
作为第一个 Ga 标记的 PARP 抑制剂，Ga-DOTA-Olaparib 在肿瘤模型中显示出高稳定性和快速的 PARP 成像。因此，该化合物是一种很有前途的成像剂，可用于个性化 PARP 抑制剂治疗方案。
