Lv Gaochao, Zhang Nan, Zhu Junyi, Hu Xin, Wang Qianhui, Qiu Bingqing, Liu Qingzhu, Qiu Ling, Lin Jianguo
NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, China.
Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
Eur J Nucl Med Mol Imaging. 2025 Apr 23. doi: 10.1007/s00259-025-07290-3.
Small molecule-based radiotracers offer several potential advantages in positron emission tomography (PET) imaging, and are therefore a promising approach for non-invasively and accurately monitoring of programmed death ligand 1 (PD-L1) expression in vivo. In this study, two small-molecule radiotracers were developed to assess PD-L1 expression and dynamics during treatments.
[F]LG-2 and [F]LG-3 were designed based on a phenoxymethyl-biphenyl scaffold with a tris-(hydroxymethyl)-aminomethane terminal group. The radiolabeling was achieved by a two-step method through the "click" chemistry. Cellular uptake assays in different tumor cells were performed to determine the specificity of the two tracers to PD-L1. The ability of [F]LG-2 and [F]LG-3 to detect PD-L1 expression in vivo as well as to monitor PD-L1 dynamics during chemotherapy and immunotherapy was investigated via PET imaging.
The radiolabeling of [F]LG-2 and [F]LG-3 was achieved with overall radiochemical yield of 15 ± 3% for [F]LG-2 and 18 ± 5% for [F]LG-3. In vitro cell uptake studies in tumor cells with varying PD-L1 levels demonstrated the specific binding of these tracers to PD-L1. PET imaging in mice bearing B16-F10 tumors displayed comparable tumor uptake of 6.45 ± 0.38%ID/mL for [F]LG-2 and 5.64 ± 0.02%ID/mL for [F]LG-3, while [F]LG-3 showed nearly a 50% reduction in uptake in the liver and intestines compared to [F]LG-2. PET signals of [F]LG-3 in A375-hPD-L1, A375-hPD-L1/A375 and A375 tumor-bearing mice demonstrated a strong and linear correlation with PD-L1 expression levels. The dynamic of PD-L1 status in tumors after cisplatin and PD-L1 inhibitor treatments were accurately evaluated with [F]LG-3 PET imaging.
The small-molecule radiotracer [F]LG-3 is a promising candidate for evaluating PD-L1 expression and monitoring the dynamic of PD-L1 status during the treatment process.
基于小分子的放射性示踪剂在正电子发射断层扫描（PET）成像中具有若干潜在优势，因此是一种用于在体内非侵入性且准确监测程序性死亡配体1（PD-L1）表达的有前景的方法。在本研究中，开发了两种小分子放射性示踪剂以评估治疗期间的PD-L1表达和动态变化。
[F]LG-2和[F]LG-3基于具有三（羟甲基）氨基甲烷端基的苯氧基甲基联苯支架设计。通过两步法利用“点击”化学实现放射性标记。在不同肿瘤细胞中进行细胞摄取试验以确定这两种示踪剂对PD-L1的特异性。通过PET成像研究[F]LG-2和[F]LG-3在体内检测PD-L1表达以及监测化疗和免疫治疗期间PD-L1动态变化的能力。
[F]LG-2和[F]LG-3的放射性标记得以实现，[F]LG-2的总放射化学产率为15±3%，[F]LG-3为18±5%。在具有不同PD-L1水平的肿瘤细胞中进行的体外细胞摄取研究证明了这些示踪剂与PD-L1的特异性结合。在携带B16-F10肿瘤的小鼠中进行的PET成像显示，[F]LG-2的肿瘤摄取为6.45±0.38%ID/mL，[F]LG-3为5.64±0.02%ID/mL，二者相当，而与[F]LG-2相比，[F]LG-3在肝脏和肠道中的摄取减少了近50%。[F]LG-3在A375-hPD-L1、A375-hPD-L1/A375和携带A375肿瘤的小鼠中的PET信号与PD-L1表达水平呈现出强线性相关性。通过[F]LG-3 PET成像准确评估了顺铂和PD-L1抑制剂治疗后肿瘤中PD-L1状态的动态变化。
小分子放射性示踪剂[F]LG-3是评估PD-L1表达以及监测治疗过程中PD-L1状态动态变化的有前景的候选物。
