Meng Lingxin, Lin Rong, Zhang Jingru, Li Huifeng, Xia Dongsheng, Zhao Zuoquan, Zhuang Rongqiang, Huang Lumei, Zhang Xianzhong, Fang Jianyang, Miao Weibing, Guo Zhide
State Key Laboratory of Vaccines for Infectious Diseases, Center for Molecular Imaging and Translational Medicine, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China.
Department of Nuclear Medicine, the First Affiliated Hospital, Fujian Medical University, No. 20 Chazhong Road, Taijiang District, Fuzhou 350005, China.
J Med Chem. 2025 Mar 27;68(6):6576-6587. doi: 10.1021/acs.jmedchem.4c03133. Epub 2025 Mar 18.
Fibroblast activation protein (FAP) is a promising target for cancer theranostics, but most FAP-targeted radioprobes showed relatively insufficient tumor uptake and retention, which seriously hampered their further application. Inspired by the squirrel tail, this study developed a novel FAP-targeted molecule, FSND, which is modified with three Asp-peptide adapters to enable both Ga ([Ga]Ga-FSND) and F ([F]AlF-FSND) PET imaging. Compared to [Ga]Ga-FAPI-04, [Ga]Ga-FAPI-42, and [F]AlF-FAPI-42, [F]AlF-FSND and [Ga]Ga-FSND showed enhanced tumor uptake and prolonged residence in HT-1080-FAP and pancreatic tumor models, demonstrating the effectiveness of Asp-peptide adapters in pharmacomodulating FAP-targeted radioligands. The first-in-human pilot study revealed that [F]AlF- and [Ga]Ga-FSND exhibited comparable uptake in the primary lesion, higher-contrast images, and higher uptake in some metastases like in bone and brain, to 2-[F] FDG PET/CT imaging. As a proof of concept, these results offer a significant enhancement to the diversity of the FAP-targeted tracer arsenal.
成纤维细胞活化蛋白（FAP）是癌症诊疗的一个有前景的靶点，但大多数靶向FAP的放射性探针显示出相对不足的肿瘤摄取和滞留，这严重阻碍了它们的进一步应用。受松鼠尾巴的启发，本研究开发了一种新型靶向FAP的分子FSND，它用三个天冬氨酸肽接头进行修饰，以实现镓（[Ga]Ga-FSND）和氟（[F]AlF-FSND）的正电子发射断层显像（PET）成像。与[Ga]Ga-FAPI-04、[Ga]Ga-FAPI-42和[F]AlF-FAPI-42相比，[F]AlF-FSND和[Ga]Ga-FSND在HT-1080-FAP和胰腺肿瘤模型中显示出增强的肿瘤摄取和延长的滞留时间，证明了天冬氨酸肽接头在药物调节靶向FAP的放射性配体方面的有效性。首例人体初步研究表明，与2-[F]氟代脱氧葡萄糖（FDG）PET/CT成像相比，[F]AlF-和[Ga]Ga-FSND在原发灶摄取相当，图像对比度更高，在一些转移灶如骨和脑中摄取更高。作为概念验证，这些结果显著增加了靶向FAP的示踪剂库的多样性。
