[⁶⁸Ga]Ga-labeled FAPI Conjugated with Gly-Pro Sequence for PET Imaging of Malignant Tumors.

IF 3 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Molecular Imaging and Biology Pub Date : 2024-08-01 Epub Date: 2024-07-10 DOI:10.1007/s11307-024-01935-9

Yuxiang Shang, Guojin Zhang, Xinchao Yao, Chaoquan Lai, Fanghu Wang, Baozhen Zeng, Entao Liu, Hui Yuan, Zhen Cheng, Lei Jiang

{"title":"[68Ga]Ga-labeled FAPI Conjugated with Gly-Pro Sequence for PET Imaging of Malignant Tumors.","authors":"Yuxiang Shang, Guojin Zhang, Xinchao Yao, Chaoquan Lai, Fanghu Wang, Baozhen Zeng, Entao Liu, Hui Yuan, Zhen Cheng, Lei Jiang","doi":"10.1007/s11307-024-01935-9","DOIUrl":null,"url":null,"abstract":"Purpose: To improve tumor uptake and prolong tumor retention, a novel fibroblast activation protein (FAP) ligand based on a quinoline-based FAP inhibitor (FAPI) conjugated with the Gly-Pro sequence and 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) was radiolabeled with [68Ga]GaCl3 ([68Ga]Ga-DOTA-GPFAPI-04). Due to the tumor heterogeneity, this study aimed to further validate the preclinical value of [68Ga]Ga-DOTA-GPFAPI-04 PET imaging in tumor mice models with different FAP expression levels.Methods: [68Ga]Ga-DOTA-GPFAPI-04 was synthesized and its partition coefficient was measured. The stability of [68Ga]Ga-DOTA-GPFAPI-04 was tested in phosphate-buffered saline (PBS, pH 7.4) and fetal bovine serum (FBS). Small animal PET and semi-quantitative studies were conducted in Panc-1 and A549 xenograft tumor mice models compared with [68Ga]Ga-DOTA-FAPI-04. Immunofluorescent and immunohistochemical staining and western blot assay were performed to confirm FAP expression in xenograft tumors.Results: [68Ga]Ga-DOTA-GPFAPI-04 exhibited a radiochemical purity of > 99% and high stability in PBS and FBS. [68Ga]Ga-DOTA-GPFAPI-04 had higher hydrophilic property than [68Ga]Ga-DOTA-FAPI-04 (-4.09 ± 0.05 vs -3.45 ± 0.05). Small animal PET and semi-quantitative analysis revealed Panc-1 xenograft tumor displayed higher tumor uptake of [68Ga]Ga-DOTA-GPFAPI-04 and tumor-to-background ratios compared to A549 xenograft tumor, consistent with the results of immunofluorescence, immunohistochemistry, and western blot. Moreover, [68Ga]Ga-DOTA-GPFAPI-04 demonstrated higher tumor accumulation and longer tumor retention than [68Ga]Ga-DOTA-FAPI-04 in both Panc-1 and A549 xenograft tumors. Furthermore, the FAP-binding specificity of [68Ga]Ga-DOTA-GPFAPI-04 was confirmed in vivo by co-injection of unlabeled GPFAPI-04.Conclusion: [68Ga]Ga-DOTA-GPFAPI-04 showed more favorable in vivo tumor imaging and longer tumor retention compared to [68Ga]Ga-DOTA-FAPI-04, which has high potential to be a promising PET probe for detecting FAP-positive tumors.","PeriodicalId":18760,"journal":{"name":"Molecular Imaging and Biology","volume":" ","pages":"729-737"},"PeriodicalIF":3.0000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Imaging and Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11307-024-01935-9","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/10 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: To improve tumor uptake and prolong tumor retention, a novel fibroblast activation protein (FAP) ligand based on a quinoline-based FAP inhibitor (FAPI) conjugated with the Gly-Pro sequence and 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) was radiolabeled with [⁶⁸Ga]GaCl₃ ([⁶⁸Ga]Ga-DOTA-GPFAPI-04). Due to the tumor heterogeneity, this study aimed to further validate the preclinical value of [⁶⁸Ga]Ga-DOTA-GPFAPI-04 PET imaging in tumor mice models with different FAP expression levels.

Methods: [⁶⁸Ga]Ga-DOTA-GPFAPI-04 was synthesized and its partition coefficient was measured. The stability of [⁶⁸Ga]Ga-DOTA-GPFAPI-04 was tested in phosphate-buffered saline (PBS, pH 7.4) and fetal bovine serum (FBS). Small animal PET and semi-quantitative studies were conducted in Panc-1 and A549 xenograft tumor mice models compared with [⁶⁸Ga]Ga-DOTA-FAPI-04. Immunofluorescent and immunohistochemical staining and western blot assay were performed to confirm FAP expression in xenograft tumors.

Results: [⁶⁸Ga]Ga-DOTA-GPFAPI-04 exhibited a radiochemical purity of > 99% and high stability in PBS and FBS. [⁶⁸Ga]Ga-DOTA-GPFAPI-04 had higher hydrophilic property than [⁶⁸Ga]Ga-DOTA-FAPI-04 (-4.09 ± 0.05 vs -3.45 ± 0.05). Small animal PET and semi-quantitative analysis revealed Panc-1 xenograft tumor displayed higher tumor uptake of [⁶⁸Ga]Ga-DOTA-GPFAPI-04 and tumor-to-background ratios compared to A549 xenograft tumor, consistent with the results of immunofluorescence, immunohistochemistry, and western blot. Moreover, [⁶⁸Ga]Ga-DOTA-GPFAPI-04 demonstrated higher tumor accumulation and longer tumor retention than [⁶⁸Ga]Ga-DOTA-FAPI-04 in both Panc-1 and A549 xenograft tumors. Furthermore, the FAP-binding specificity of [⁶⁸Ga]Ga-DOTA-GPFAPI-04 was confirmed in vivo by co-injection of unlabeled GPFAPI-04.

Conclusion: [⁶⁸Ga]Ga-DOTA-GPFAPI-04 showed more favorable in vivo tumor imaging and longer tumor retention compared to [⁶⁸Ga]Ga-DOTA-FAPI-04, which has high potential to be a promising PET probe for detecting FAP-positive tumors.

Abstract Image

查看原文本刊更多论文

与 Gly-Pro 序列共轭的[68Ga]Ga 标记 FAPI 用于恶性肿瘤 PET 成像。

目的：为了提高肿瘤摄取率和延长肿瘤保留时间，一种新型成纤维细胞活化蛋白（FAP）配体被[68Ga]GaCl3放射性标记（[68Ga]Ga-DOTA-GPFAPI-04），该配体基于一种喹啉基FAP抑制剂（FAPI），与Gly-Pro序列和1,4,7,10-四氮杂环十二烷-N,N',N″,N‴-四乙酸（DOTA）共轭。方法：合成[68Ga]Ga-DOTA-GPFAPI-04并测定其分配系数。测试了[68Ga]Ga-DOTA-GPFAPI-04在磷酸盐缓冲盐水（PBS，pH 7.4）和胎牛血清（FBS）中的稳定性。与[68Ga]Ga-DOTA-FAPI-04 相比，在 Panc-1 和 A549 异种移植肿瘤小鼠模型中进行了小动物 PET 和半定量研究。免疫荧光和免疫组化染色以及 Western 印迹检测证实了 FAP 在异种移植瘤中的表达：结果：[68Ga]Ga-DOTA-GPFAPI-04的放射化学纯度大于99%，在PBS和FBS中具有很高的稳定性。[68Ga]Ga-DOTA-GPFAPI-04的亲水性高于[68Ga]Ga-DOTA-FAPI-04（-4.09 ± 0.05 vs -3.45 ± 0.05）。小动物正电子发射计算机断层显像和半定量分析显示，与A549异种移植瘤相比，Panc-1异种移植瘤对[68Ga]Ga-DOTA-GPFAPI-04的摄取率和肿瘤-背景比更高，这与免疫荧光、免疫组化和Western blot的结果一致。此外，与[68Ga]Ga-DOTA-FAPI-04相比，[68Ga]Ga-DOTA-GPFAPI-04在Panc-1和A549异种移植瘤中的肿瘤蓄积率更高，肿瘤保留时间更长。此外，[68Ga]Ga-DOTA-GPFAPI-04与未标记的GPFAPI-04在体内的结合特异性也得到了证实：结论：与[68Ga]Ga-DOTA-FAPI-04相比，[68Ga]Ga-DOTA-GPFAPI-04显示出更良好的体内肿瘤成像效果和更长的肿瘤保留时间，极有可能成为检测FAP阳性肿瘤的PET探针。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.