Synthesis, Preclinical Evaluation, and a Pilot Clinical PET Imaging Study of 68Ga-Labeled FAPI Dimer

  • J Nucl Med. 2022 Jun;63(6):862-868. doi: 10.2967/jnumed.121.263016.
Liang Zhao  1  2 ,  Bo Niu  3 ,  Jianyang Fang  4 ,  Yizhen Pang  1 ,  Siyang Li  3 ,  Chengrong Xie  5 ,  Long Sun  1 ,  Xianzhong Zhang  4 ,  Zhide Guo  6 ,  Qin Lin  2 ,  Haojun Chen  7
Affiliations
  • 1. Department of Nuclear Medicine and Minnan PET Center, The First Affiliated Hospital of Xiamen University, Xiamen, China.
  • 2. Department of Radiation Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, China.
  • 3. School of Medicine, Xiamen University, Xiamen, China.
  • 4. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China; and.
  • 5. Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, China.
  • 6. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China; and [email protected] [email protected].
  • 7. Department of Nuclear Medicine and Minnan PET Center, The First Affiliated Hospital of Xiamen University, Xiamen, China; [email protected] [email protected].
PMID: 34556528 DOI: 10.2967/jnumed.121.263016
Abstract

Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs. FAP-targeted molecular imaging agents, including the FAP inhibitors (FAPIs) 04 and 46, have shown promising results in tumor diagnosis. However, these molecules have a relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a 68Ga-labeled FAPI dimer, 68Ga-DOTA-2P(FAPI)2, to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs. Methods:68Ga-DOTA-2P(FAPI)2 was synthesized on the basis of the quinoline-based FAPI variant (FAPI-46), and its binding properties were assayed in CAFs. Preclinical pharmacokinetics were determined in FAP-positive patient-derived xenografts using small-animal PET and biodistribution experiments. The effective dosimetry of 68Ga-DOTA-2P(FAPI)2 was evaluated in 3 healthy volunteers, and PET/CT imaging of 68Ga-FAPI-46 and 68Ga-DOTA-2P(FAPI)2 was performed on 3 Cancer patients. Results:68Ga-DOTA-2P(FAPI)2 was stable in phosphate-buffered saline and fetal bovine serum for 4 h. The FAPI dimer showed high affinity and specificity for FAP in vitro and in vivo. The tumor uptake of 68Ga-DOTA-2P(FAPI)2 was approximately 2-fold stronger than that of 68Ga-FAPI-46 in patient-derived xenografts, whereas healthy organs showed low tracer uptake and fast body clearance. The effective dose of 68Ga-DOTA-2P(FAPI)2 was 1.19E-02 mSv/MBq, calculated using OLINDA. Finally, the PET/CT scans of the 3 Cancer patients revealed higher intratumoral uptake of 68Ga-DOTA-2P(FAPI)2 than of 68Ga-FAPI-46 in all tumor lesions (SUVmax, 8.1-39.0 vs. 1.7-24.0, respectively; P < 0.001). Conclusion:68Ga-DOTA-2P(FAPI)2 has increased tumor uptake and retention properties compared with 68Ga-FAPI-46, and it could be a promising tracer for both diagnostic imaging and targeted therapy of malignant tumors with positive expression of FAP.

Keywords
FAPI dimer; PET imaging; cancer-associated fibroblasts; fibroblast activation protein; patient-derived xenografts.
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