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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 68 Ga-labeled FAPI dimer, 68 Ga-DOTA-2P(FAPI) 2 , to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs. Methods:  68 Ga-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 68 Ga-DOTA-2P(FAPI) 2 was evaluated in 3 healthy volunteers, and PET/CT imaging of 68 Ga-FAPI-46 and 68 Ga-DOTA-2P(FAPI) 2 was performed on 3 cancer patients. Results:  68 Ga-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 68 Ga-DOTA-2P(FAPI) 2 was approximately 2-fold stronger than that of 68 Ga-FAPI-46 in patient-derived xenografts, whereas healthy organs showed low tracer uptake and fast body clearance. The effective dose of 68 Ga-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 68 Ga-DOTA-2P(FAPI) 2 than of 68 Ga-FAPI-46 in all tumor lesions (SUV max , 8.1-39.0 vs. 1.7-24.0, respectively; P &lt; 0.001). Conclusion:  68 Ga-DOTA-2P(FAPI) 2 has increased tumor uptake and retention properties compared with 68 Ga-FAPI-46, and it could be a promising tracer for both diagnostic imaging and targeted therapy of malignant tumors with positive expression of FAP.

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

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