Design, Synthesis, and Evaluation of a Novel Positron Emission Tomography Tracer Targeting Fibroblast Activation Protein: From Bench to Bedside
FAPI-PET/CT has become a promising tool for cancer diagnosis. However, the pharmacokinetic properties of FAPI tracers need optimization. Here, we developed a novel FAPI tracer, [<sup>18</sup>F]AlF-NOTA-SP<sub>2</sub>A-FAPT, for cancer imaging. NOTA-SP<sub>2</sub>A-FAPT was successfully synthesized and radiolabeled with a high radiochemical purity. [<sup>18</sup>F]AlF-NOTA-SP<sub>2</sub>A-FAPT displayed satisfying stability, hydrophilicity, and affinity to FAP, as well as specific uptake in A549-FAP cells. Micro-PET/CT showed that [<sup>18</sup>F]AlF-NOTA-SP<sub>2</sub>A-FAPT is rapidly excreted through the renal system. [<sup>18</sup>F]AlF-NOTA-SP<sub>2</sub>A-FAPT exhibited high tumor uptake and excellent retention, showing better tumor delineation compared to [<sup>18</sup>F]FDG and [<sup>18</sup>F]AlF-NOTA-FAPI-42. Pilot clinical studies of [<sup>18</sup>F]AlF-NOTA-SP<sub>2</sub>A-FAPT and head-to-head comparison with [<sup>18</sup>F]FDG were performed on 13 cancer patients. Compared to [<sup>18</sup>F]FDG, [<sup>18</sup>F]AlF-NOTA-SP<sub>2</sub>A-FAPT had higher uptake in primary tumor and lymph node metastases as well as favorable distribution and good tumor retention. In conclusion, [<sup>18</sup>F]AlF-NOTA-SP<sub>2</sub>A-FAPT demonstrated high tumor accumulation, as well as improved pharmacokinetic properties. [<sup>18</sup>F]AlF-NOTA-SP<sub>2</sub>A-FAPT could emerge as a promising alternative to the currently established FAPI tracers.
Authors
- Zhanwen Zhang (ORCID: https://orcid.org/0000-0003-3877-5672)
- Fengping Gong (ORCID: https://orcid.org/0009-0004-8027-6820)
- K.-T. Chen
- Ganghua Tang (ORCID: https://orcid.org/0000-0002-2712-253X)
- Xiaojun Zhang (ORCID: https://orcid.org/0000-0002-0304-0003)
- Rongqin Zhang (ORCID: https://orcid.org/0000-0001-5573-2733)
- Yanchao Huang
- Jiawen Huang (ORCID: https://orcid.org/0000-0003-2439-4043)
Institutions
- Sun Yat-sen University (CN)
- Sixth Affiliated Hospital of Sun Yat-sen University (CN)
- Nanfang Hospital (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02961
- Citations
- 3
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province
- Guangzhou Municipal Science and Technology Project
- National Key Research and Development Program of China
- Basic and Applied Basic Research Foundation of Guangdong Province