Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, 4221-116 Xiang'an South Rd., Xiamen, 361102, China.
Eur J Nucl Med Mol Imaging. 2022 Nov;49(13):4312-4324. doi: 10.1007/s00259-022-05876-9. Epub 2022 Jul 14.
PD-L1 PET imaging allows for the whole body measuring its expression across primary and metastatic tumors and visualizing its spatiotemporal dynamics before, during, and after treatment. In this study, we reported a novel F-labeled D-peptide antagonist, F-NOTA-NF12, for PET imaging of PD-L1 status in preclinical and first-in-human studies.
Manual and automatic radiosynthesis of F-NOTA-NF12 was performed. Cell uptake and binding assays were completed in MC38, H1975, and A549 cell lines. The capacity for imaging of PD-L1 status, biodistribution, and pharmacokinetics were investigated in preclinical models. The PD-L1 status was verified by western blotting, immunohistochemistry/fluorescence, and flow cytometry. The safety, radiation dosimetry, biodistribution, and PD-L1 imaging potential were evaluated in healthy volunteers and patients.
The radiosynthesis of F-NOTA-NF12 was achieved via manual and automatic methods with radiochemical yields of 41.7 ± 10.2 % and 70.6 ± 4.2 %, respectively. In vitro binding assays demonstrated high specificity and affinity with an IC of 78.35 nM and K of 85.08 nM. The MC38 and H1975 tumors were clearly visualized with the optimized tumor-to-muscle ratios of 5.36 ± 1.17 and 7.13 ± 1.78 at 60 min after injection. Gemcitabine- and selumetinib-induced modulation of PD-L1 dynamics was monitored by F-NOTA-NF12. The tumor uptake correlated well with their PD-L1 expression. F-NOTA-NF12 exhibited renal excretion and rapid clearance from blood and other non-specific organs, contributing to high contrast imaging in the clinical time frame. In NSCLC and esophageal cancer patients, the specificity of F-NOTA-NF12 for PD-L1 imaging was confirmed. The F-NOTA-NF12 PET/CT and F-FDG PET/CT had equivalent findings in patients with high PD-L1 expression.
F-NOTA-NF12 was developed successfully as a PD-L1-specific tracer with promising results in preclinical and first-in-human trials, which support the further validation of F-NOTA-NF12 for PET imaging of PD-L1 status in clinical settings.
PD-L1 PET 成像可用于全身测量原发性和转移性肿瘤的表达，并在治疗前后可视化其时空动力学。在本研究中，我们报告了一种新型 F 标记的 D-肽拮抗剂 F-NOTA-NF12，用于 PD-L1 状态的 PET 成像的临床前和首次人体研究。
手动和自动合成 F-NOTA-NF12。在 MC38、H1975 和 A549 细胞系中完成细胞摄取和结合实验。在临床前模型中研究了 PD-L1 状态、生物分布和药代动力学的成像能力。通过 Western blot、免疫组化/荧光和流式细胞术验证 PD-L1 状态。在健康志愿者和患者中评估了安全性、辐射剂量学、生物分布和 PD-L1 成像潜力。
通过手动和自动方法实现了 F-NOTA-NF12 的放射合成，放射化学产率分别为 41.7±10.2%和 70.6±4.2%。体外结合实验表明具有高特异性和亲和力，IC 为 78.35 nM，K 为 85.08 nM。在注射后 60 分钟，MC38 和 H1975 肿瘤的肿瘤与肌肉比分别为 5.36±1.17 和 7.13±1.78，清晰可见。通过 F-NOTA-NF12 监测吉西他滨和 Selumetinib 诱导的 PD-L1 动力学调节。肿瘤摄取与 PD-L1 表达密切相关。F-NOTA-NF12 表现出肾排泄和从血液和其他非特异性器官的快速清除，有助于在临床时间范围内获得高对比度成像。在 NSCLC 和食管癌患者中，F-NOTA-NF12 对 PD-L1 成像的特异性得到了证实。在 PD-L1 高表达的患者中，F-NOTA-NF12 PET/CT 和 F-FDG PET/CT 的发现相当。
成功开发了 F-NOTA-NF12 作为 PD-L1 特异性示踪剂，在临床前和首次人体试验中取得了有希望的结果，这支持了 F-NOTA-NF12 在临床环境中用于 PD-L1 状态的 PET 成像的进一步验证。
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