One-step radiosynthesis and initial evaluation of a small molecule PET tracer for PD-L1 imaging
One-step radiosynthesis and initial evaluation of a small molecule PET tracer for PD-L1 imaging
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DOI：
10.1016/j.bmcl.2020.127572
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发表时间：
2020-12-15
影响因子：
2.7
通讯作者：
Lin, Jianguo
中科院分区：
文献类型：
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作者：
Miao, Yinxing;Lv, Gaochao;Lin, Jianguo
程序性细胞死亡蛋白-配体1（PD-L1）是免疫治疗中的重要生物标志物，其表达水平在指导抗PD-L1治疗中起关键作用。据报告，PD-L1可通过使用更先进的放射性示踪剂进行无创成像进行定量。在我们的研究中，设计了一种新型[F-18]氟化物标记的小分子抑制剂[F-18]LN，用于PD-L1转染（A375-hPD-L1）和未转染（A375）黑色素瘤荷瘤小鼠的正电子发射断层扫描（PET）成像。LN显示出对PD-L1的特异性（IC 50 = 50.39 +/- 2.65 nM），通过竞争性组合和细胞流式细胞术（FACS）分析证实。放射性示踪剂[F-18]LN通过F-18-F-19同位素交换从前体LN获得。经放射性合成，[F-18]LN的放化纯度（RCP）大于95%，摩尔放射性为36.34 ± 5.73GBq/μ mol。通过特异性结合测定，[F-18]LN显示出与PD-L1的中等亲和力（K-d = 65.27 +/- 3.47 nM）。在A375-hPD-L1细胞中的摄取比A375细胞高1.3倍。PET显像显示[F-18]LN可进入PD-L1表达的肿瘤部位，并可显示肿瘤的轮廓。阳性组肿瘤摄取（1.96 ± 0.27%ID/g）在15 min时达到最大值，是阴性组（0.89 ± 0.31%ID/g）和阻断组（1.07 ± 0.26%ID/g）的2.2倍。同时，生物分布可以轻微区分阳性和阴性。结果表明，进一步优化[F-18] LN将成为评估PD-L1表达的有效工具。
Programmed cell death protein-ligand 1 (PD-L1) is a crucial biomarker in immunotherapy and its expression level plays a key role in the guidance of anti-PD-L1 therapy. It had been reported that PD-L1 was quantified by noninvasive imaging with more developed radiotracers. In our study, a novel [F-18]fluoride labeled small molecule inhibitor, [F-18]LN was designed for positron emission tomography (PET) imaging in both PD-L1 transfected (A375-hPD-L1) and non-transfected (A375) melanoma-bearing mice. LN showed the specificity (IC50 = 50.39 +/- 2.65 nM) to PD-L1 confirmed by competitive combination and cell flow cytometry (FACS) analysis. The radiotracer [F-18]LN was obtained via F-18-F-19 isotope exchange from precursor LN. After radio synthesis, [F-18]LN was achieved with a high radiochemical purity (RCP) above 95% and got a favorable molar activity of 36.34 +/- 5.73 GBq/mu mol. [F-18]LN displayed the moderate affinity (K-d = 65.27 +/- 3.47 nM) to PD-L1 by specific binding assay. And it showed 1.3-fold higher uptake in A375-hPD-L1 cells than that in A375 cells. PET imaging revealed that [F-18]LN could enter into PD-L1 expressing tumor site and visualize the outline of tumor. And tumor uptake (1.96 +/- 0.27 %ID/g) reached the maximum at 15 min in the positive group, showed 2.2-fold higher than the negative (0.89 +/- 0.31 %ID/g) or the blocked (1.07 +/- 0.26 %ID/g) groups. Meanwhile, biodistribution could slightly distinguish the positive from the negative. The results indicated [F-18] LN would become an efficient tool for evaluating PD-L1 expression with further optimization.