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Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China's engagement with FAPI tracers, aiming to guide future research endeavors., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Extensive research has been conducted on radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) and p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH 2 (LM3) peptides for imaging of FAP and somatostatin receptor 2 (SSTR2)-positive tumors. In this study, we designed and synthesized a FAPI-LM3 heterobivalent molecule radiolabeled with 68 Ga and evaluated its effectiveness in both tumor xenografts and patients with nasopharyngeal carcinoma (NPC). Methods: The synthesis of FAPI-LM3 was based on the structures of FAPI-46 and LM3. After radiolabeling with 68 Ga, its dual-receptor-binding affinity was evaluated in vitro and in vivo. Preclinical studies, including small-animal PET and biodistribution evaluation, were conducted on HT-1080-FAP and HT-1080-SSTR2 tumor xenografts. The feasibility of 68 Ga-FAPI-LM3 PET/CT in a clinical setting was evaluated in patients with NPC, and the results were compared with those of 18 F-FDG. Results: 68 Ga-FAPI-LM3 showed high affinity for both FAP and SSTR2. The tumor uptake of 68 Ga-FAPI-LM3 was significantly higher than that of 68 Ga-FAPI-46 and 68 Ga-DOTA-LM3 in HT-1080-FAP-plus-HT-1080-SSTR2 tumor xenografts. In a clinical study involving 6 NPC patients, 68 Ga-FAPI-LM3 PET/CT showed significantly higher uptake than did 18 F-FDG in primary and metastatic lesions, leading to enhanced lesion detectability and tumor delineation. Conclusion: 68 Ga-FAPI-LM3 exhibited FAPI and SSTR2 dual-receptor-targeting properties both in vitro and in vivo, resulting in improved tumor uptake and retention compared with that observed with monomeric 68 Ga-FAPI and 68 Ga-DOTA-LM3. This study highlights the clinical feasibility of 68 Ga-FAPI-LM3 PET/CT for NPC imaging., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

This study aims to develop a novel 68 Ga-labeled tracer, which can covalently bind to albumin in vivo based on the maleimide-thiol strategy, and to evaluate its potential applications using positron emission tomography (PET). 68 Ga-labeled maleimide-monoamide-DOTA (denoted as [ 68 Ga]Ga-DM) was prepared conveniently with a high radiochemical yield (>90%) and radiochemical purity (>99%). Its molar activity was calculated as 249.60 ± 68.50 GBq/μmol, and the octanol-water partition coefficient (Log P ) was -3.15 ± 0.08 with good stabilities. In vitro experiments showed that [ 68 Ga]Ga-DM can bind to albumin efficiently and rapidly, with a binding fraction of over 70%. High uptake and excellent retention in blood were observed with a long half-life ( t 1/2Z ) of 190.15 ± 24.14 min, which makes it possible for blood pool PET imaging with high contrast. The transient micro-bleeding in the rat model was detected successfully with PET imaging. In addition, the uptakes of [ 68 Ga]Ga-DM in the inflammatory popliteal lymph nodes depend on the severity (5.90% ID/g and 2.32% ID/g vs 1.01% ID/g for healthy lymph nodes at 0.5 h post-injection) indicating its feasibility for lymphatic imaging. In conclusion, a novel 68 Ga-labeled tracer was prepared with high efficiency and yield in mild conditions. Based on the promising properties of bonding covalently to albumin, great stability, high blood contrast with a long half-life, and well environmental tolerance, [ 68 Ga]Ga-DM could be developed as a potential tracer for PET imaging of blood pool, bleeding, and vascular permeability alteration diseases in the clinic., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

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 < 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., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)