Fibroblast activation protein targeting radiopharmaceuticals: From drug design to clinical translation.

Yuxuan WU; Xingkai WANG; Xiaona SUN; Xin GAO; Siqi ZHANG; Jieting SHEN; Hao TIAN; Xueyao CHEN; Hongyi HUANG; Shuo JIANG; Boyang ZHANG; Yingzi ZHANG; Minzi LU; Hailong ZHANG; Zhicheng SUN; Ruping LIU; Hong ZHANG; Ming-Rong ZHANG; Kuan HU; Rui WANG

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Fibroblast activation protein targeting radiopharmaceuticals: From drug design to clinical translation.

Author: Yuxuan WU ¹ ; Xingkai WANG ¹ ; Xiaona SUN ¹ ; Xin GAO ¹ ; Siqi ZHANG ¹ ; Jieting SHEN ¹ ; Hao TIAN ¹ ; Xueyao CHEN ¹ ; Hongyi HUANG ¹ ; Shuo JIANG ¹ ; Boyang ZHANG ¹ ; Yingzi ZHANG ² ; Minzi LU ¹ ; Hailong ZHANG ³ ; Zhicheng SUN ⁴ ; Ruping LIU ⁴ ; Hong ZHANG ⁵ ; Ming-Rong ZHANG ⁶ ; Kuan HU ¹ ; Rui WANG ¹
Author Information

1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
2. Department of Orthopaedics, the Second Affiliated Hospital of Soochow University, Suzhou 215031, China.
3. Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China.
4. School of Printing and Packaging Engineering, Beijing Institute of Graphic Communication, Beijing 102600, China.
5. Department of Nuclear Medicine and Positron Emission Tomography Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310058, China.
6. Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
Publication Type:Review
Keywords: Bench-to-bedside; Cancer-associated fibroblasts; Fibroblast activation protein; Radionuclide therapy; Radiopharmaceutical; Radiotheranostics; Small molecule inhibitors; Tumor microenvironment
From: Acta Pharmaceutica Sinica B 2025;15(9):4511-4542
CountryChina
Language:English
Abstract: The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth, migration, and treatment response, thereby influencing tumor progression and therapeutic outcomes. Owing to the proliferation and metastasis of tumors, fibroblast activation protein (FAP) is typically highly expressed in the tumor stroma, whereas it is nearly absent in adult normal tissues and benign lesions, making it an attractive target for precision medicine. Radiolabeled agents targeting FAP have the potential for targeted cancer diagnosis and therapy. This comprehensive review aims to describe the evolution of FAPI-based radiopharmaceuticals and their structural optimization. Within its scope, this review summarizes the advances in the use of radiolabeled small molecule inhibitors for tumor imaging and therapy as well as the modification strategies for FAPIs, combined with insights from structure-activity relationships and clinical studies, providing a valuable perspective for radiopharmaceutical clinical development and application.