Preclinical study and first-in-human imaging of [18F]FAP-2286, and comparison with 2-[18F]FDG PET/CT in various cancer patients
Preclinical study and first-in-human imaging of [18F]FAP-2286, and comparison with 2-[18F]FDG PET/CT in various cancer patients
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DOI：
10.1007/s00259-024-06626-9
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发表时间：
2024-02-08
影响因子：
9.1
通讯作者：
Zhang，Zhanwen
中科院分区：
文献类型：
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作者：
Liu，Lifang;Zhong，Jiawei;Zhang，Zhanwen
成纤维细胞活化蛋白（Fibroblast-activatedprotein，FAP）在许多实体瘤的癌相关成纤维细胞（cancer-associatedfibroblasts，CAFs）中高表达，而在正常组织中低表达或缺失。本研究旨在开发一种新的FAP特异性示踪剂，即[18F]FAP-2286，并将其与临床前研究中成熟的药物如[18F]FAPI-42和[68 Ga]Ga-FAP-2286以及中试临床研究中的2-[18F]FDG进行比较。随后的研究包括使用HT-1080 hFAP细胞系的细胞摄取、竞争性结合亲和力、内化和外排测定。在HEK-293 ThFAP、A549 hFAP、HT-1080 hFAP荷瘤小鼠以及HEK-293 T、A549和HT-1080对照组中进行PET成像和生物分布研究。结果[18F] FAP-2286的放射性标记产率为30.53 ± 5.20%，放射化学纯度大于97%。在细胞测定中，[18F]FAP-2286显示出特异性摄取、高内化分数和低细胞外排。在微型PET成像和癌症患者上观察到快速肿瘤摄取和令人满意的肿瘤保留。结论[18 F] FAP-2286在荷瘤小鼠和肿瘤患者体内均表现出良好的上级显像质量，靶点摄取迅速，靶点保留率高。它可能成为早期或延迟相成像和2-[18F]FDG非亲癌PET扫描的有希望的候选者。
PurposeFibroblast-activated protein (FAP) is highly expressed in cancer-associated fibroblasts (CAFs) of many solid cancers, but low or absent in normal tissues. Our study aimed to develop a novel FAP-specific tracer, namely [18F]FAP-2286, and evaluated its performance in comparison with well-established agents such as [18F]FAPI-42 and [68Ga]Ga-FAP-2286 in preclinical research, as well as 2-[18F]FDG in pilot clinical study.Methods[18F]FAP-2286 was manually synthesized in accordance with Good Manufacturing Practice (GMP). Subsequent investigations encompassed cell uptake, competitive binding affinity, internalization and efflux assays using HT-1080hFAP cell lines. PET imaging and biodistribution studies were conducted in HEK-293ThFAP, A549hFAP, HT-1080hFAP tumor-bearing mice as well as HEK-293T, A549 and HT-1080 control groups. Furthermore, clinical evaluation of [18F]FAP-2286 was performed in fifteen patients with various cancers compared to 2-[18F]FDG PET.ResultsThe radiolabeling yield of [18F]FAP-2286 was 30.53 ± 5.20%, with a radiochemical purity exceeding 97%. In cell assays, [18F]FAP-2286 showed specific uptake, high internalization fraction and low cellular efflux. Rapid tumor uptake and satisfactory tumor retention was observed on micro-PET imaging and cancer patients. Meanwhile, the clinical research demonstrated that [18F]FAP-2286 may represent an alternative for low glucose-metabolism malignant tumors PET imaging such as gastric cancers.Conclusion[18F]FAP-2286 showed superior imaging quality including rapid and high target uptake and satisfactory retention in both tumor-bearing mice and cancer patients. It may emerge as a promising candidate for early or delayed phase imaging and 2-[18F]FDG non-avid cancers PET scan.