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Al 18F标记的新型环肽探针Al 18F－FAP－NOX在肿瘤靶向分子影像中的研究
张梓奇
刘少玉
钟嘉伟
赵睿玥
熊爽
周美娟
符乙敏
钟惠贞
王欣璐
作者及单位信息
·
DOI： 10.3760/cma.j.cn321828-20240515-00170
Research of Al 18F-labeled novel cyclic peptide probe Al 18F-FAP-NOX in tumor-targeted molecular imaging
Zhang Ziqi
Liu Shaoyu
Zhong Jiawei
Zhao Ruiyue
Xiong Shuang
Zhou Meijuan
Fu Yimin
Zhong Huizhen
Wang Xinlu
Authors Info & Affiliations
Zhang Ziqi
Department of Nuclear Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Liu Shaoyu
Department of Nuclear Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Zhong Jiawei
Department of Nuclear Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Zhao Ruiyue
Department of Nuclear Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Xiong Shuang
Department of Nuclear Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Zhou Meijuan
Department of Nuclear Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Fu Yimin
Department of Nuclear Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Zhong Huizhen
Department of Nuclear Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Wang Xinlu
Department of Nuclear Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
·
DOI： 10.3760/cma.j.cn321828-20240515-00170
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摘要

目的制备新型成纤维细胞激活蛋白(FAP)环肽显像剂Al 18F－FAP－NOX，评价其体内外性质，探究其用于FAP表达阳性的肿瘤PET/CT显像的可行性。

方法进行Al 18F－FAP－NOX手动标记合成。利用放射性高效液相色谱测定Al 18F－FAP－NOX的体外稳定性，并测定脂水分配系数log P、行体外细胞摄取实验、293T－FAP荷瘤裸鼠microPET/CT显像与生物分布，初步评估Al 18F－FAP－NOX在小鼠体内药代动力学性质和生物学效能。对1例肺癌患者(男，65岁)行Al 18F－FAP－NOX PET/CT显像。

结果成功合成Al 18F－FAP－NOX，产率为(26.28±2.31)%(未经衰减校正， n＝4)，放化纯大于95%。体外实验显示，Al 18F－FAP－NOX具有良好的稳定性和亲水性(log P＝－3.02±0.08， n＝5)。在细胞实验中，HT1080－FAP细胞摄取Al 18F－FAP－NOX于15 min到达平台期[(7.31±0.53)每百万细胞百分注射剂量率(%ID/mio cells)]，表现出较高的细胞摄取，且摄取能被1，4，7，10－四氮杂环十二烷－1，4，7，10－四乙酸(DOTA)－FAP－2286明显抑制。293T－FAP荷瘤裸鼠microPET/CT显像发现，Al 18F－FAP－NOX在FAP表达阳性的肿瘤组织中摄取增高[60 min：(12.47±1.66)每克组织百分注射剂量率(%ID/g)]，而在FAP表达阴性的肿瘤中摄取未见增高。生物学分布结果与荷瘤裸鼠microPET/CT显像结果相似。人体试验显像示肺癌病灶Al 18F－FAP－NOX摄取增高，SUV max约5.5。

结论新型环肽探针Al 18F－FAP－NOX具有良好的稳定性和亲水性，动物实验及人体试验均显示其对肿瘤病灶具有靶向性，是一种有应用前景的新型环肽PET显像剂。

肽类，环;同位素标记;氟放射性同位素;正电子发射断层显像术;体层摄影术，X线计算机;肿瘤细胞，培养的;小鼠，裸
ABSTRACT

ObjectiveTo develop a novel fibroblast activation protein (FAP) cyclic peptide imaging agent, Al 18F-FAP-NOX, evaluate its in vitro and in vivo properties, and explore its feasibility of PET/CT imaging in tumors with FAP positive expression.

MethodsAl 18F-FAP-NOX was manually synthesized. The in vitro stability of Al 18F-FAP-NOX was determined using radio high performance liquid chromatography (HPLC). The lipid water partition coefficient log P, in vitro cell uptake experiments, microPET/CT imaging and biodistribution in 293T-FAP tumor-bearing mice were conducted to preliminarily evaluate the pharmacokinetics and biological efficacy of Al 18F-FAP-NOX. Afterwards, a patient (male, 65 years old) with lung cancer underwent Al 18F-FAP-NOX PET/CT imaging.

ResultsAl 18F-FAP-NOX was successfully synthesized with a yield of (26.28±2.31)% without attenuation correction ( n=4), and the radiochemical purity was more than 95%. Al 18F-FAP-NOX exhibited good stability and hydrophilicity (log P=-3.02±0.08, n=5). In cell assays, the uptake of Al 18F-FAP-NOX in HT1080-FAP cells reached the plateau phase at 15 min ((7.31±0.53) percentage activity of injection dose per million cells (%ID/mio cells)), exhibiting high cellular uptake. The uptake of Al 18F-FAP-NOX could be significantly inhibited by 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-FAP-2286. The microPET/CT results of 293T-FAP tumor-bearing mice in vivo showed that Al 18F-FAP-NOX was highly uptaken in FAP-positive tumor tissues (60 min: (12.47±1.66) percentage activity of injection dose per gram of tissue (%ID/g)), while the uptake was very low in FAP-negative tumors. The biodistribution results were similar to the microPET/CT imaging results of tumor-bearing mice. The human clinical imaging showed an abnormal increase in Al 18F-FAP-NOX uptake (SUV max 5.5) of the lung cancer lesions.

ConclusionsA novel cyclic peptide radiopharmaceutical, Al 18F-FAP-NOX, demonstrates good stability and hydrophilicity. It can be quickly distributed to tumor tissue in vivo. The human clinical PET/CT imaging shows certain diagnostic ability of Al 18F-FAP-NOX for lung cancer lesions. It is a promising cyclic peptide agent for PET imaging.

Peptides, cyclic;Isotope labeling;Fluorine radioisotopes;Positron-emission tomography;Tomography, X-ray computed;Tumor cells, cultured;Mice, nude
Wang Xinlu, Email: mocdef.3ab61ul17
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引用本文

张梓奇,刘少玉,钟嘉伟,等. Al 18F标记的新型环肽探针Al 18F－FAP－NOX在肿瘤靶向分子影像中的研究 [J]. 中华核医学与分子影像杂志,2025,45(02)：82-87.

DOI:10.3760/cma.j.cn321828-20240515-00170

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成纤维细胞激活蛋白(fibroblast activation protein, FAP)特异性高表达于肿瘤组织中的癌相关成纤维细胞 [ 1 , 2 , 3 , 4 ]。FAP抑制剂(FAP inhibitor, FAPI)能与FAP特异性结合，有利于早期发现FAP表达阳性的病灶 [ 5 ]。
近年来，基于FAPI开发了大量放射性分子探针 [ 6 , 7 , 8 , 9 ]，包括大分子FAPI和小分子FAPI，特别是新型小分子环肽FAPI——FAP－2286。 68Ga－FAP－2286能够与FAP特异性结合，在恶性肿瘤淋巴结转移的病灶中摄取高于 18F－FDG，且较小分子线性肽FAPI在肿瘤中滞留时间更长 [ 10 , 11 , 12 ]。然而，与 68Ga－FAPI－46相比，其肝脏摄取较高，药代动力学性质尚待优化 [ 10 ]。同时， 18F(半衰期约109.8 min，96.7% β ＋)与 68Ga(半衰期约68 min，88.9% β ＋)相比，具有较长的半衰期、更短的正电子范围和更高的正电子产率，可以获得空间分辨率更好和对比度更高的诊断图像 [ 13 ]。另外，使用回旋加速器可以大量生产 18F标记的放射性药物，满足临床诊断需求。
因此，本研究设计合成了一种基于FAP－2286的新型 18F标记放射性环肽显像剂Al 18F－FAP－NOX，探索其体内外性质并进行临床PET/CT患者显像，综合评估其作为肿瘤靶向显像剂的可行性。
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备注信息
A
王欣璐，Email: mocdef.3ab61ul17
B

张梓奇：研究实施、论文撰写、统计学分析；刘少玉、王欣璐：研究指导、论文修改、经费支持；钟嘉伟、熊爽：研究实施、论文撰写；赵睿玥：统计学分析；周美娟、符乙敏、钟惠贞：患者管理

C
所有作者声明无利益冲突
D
国家自然科学基金 (82001879)
国家工业与信息化部科研基金 (CEIEC－2022－ZM02－0219)
广州市科技计划项目 (2024A03J1080)
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