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Background: Accurate clinical staging is crucial to managing gastrointestinal cancer, but fluorine 18 (18 F) fluorodeoxyglucose (FDG) PET/CT has limitations. Targeting fibroblast-activation protein is a newer diagnostic approach for the visualization of tumor stroma, and gallium 68 (68 Ga)-labeled fibroblast-activation protein inhibitors (FAPIs), hereafter 68 Ga-FAPIs, present a promising alternative to 18 F-FDG. Purpose: To compare the diagnostic efficacy of 68 Ga-FAPI PET/CT in primary and metastatic lesions of gastrointestinal malignancies with that of 18 F-FDG PET/CT. Materials and Methods: Images from patients with gastric, duodenal, and colorectal cancers who underwent contemporaneous 18 F-FDG and 68 Ga-FAPI PET/CT between October 2019 through June 2020 were retrospectively analyzed. 18 F-FDG and 68 Ga-FAPI uptakes were compared by using the Wilcoxon signed-rank test. The McNemar test was used to compare the diagnostic performance between the two techniques. Results: Thirty-five patients (median age, 64 years [interquartile range, 53-68 years]; 18 men) were evaluated. In treatment-naive patients (n = 19), 68 Ga-FAPI PET/CT led to upstaging of the clinical TNM stage in four (21%) patients compared with 18 F-FDG PET/CT. Tracer uptake was higher with 68 Ga-FAPI PET/CT than with 18 F-FDG PET/CT in primary lesions (gastric cancer: 12.7 vs 3.7, respectively, P = .003; colorectal cancer: 15.9 vs 7.9, P = .03), involved lymph nodes (6.7 vs 2.4, P , .001), and bone and visceral metastases (liver metastases: 9.7 vs 5.2, P , .001; peritoneal metastases: 8.4 vs 3.6, P , .001; bone metastases: 4.3 vs 2.2, P , .001; lung metastases: 4.4 vs 1.9, P = .01). In addition, the sensitivity of 68 Ga-FAPI PET/CT was higher than that of 18 F-FDG PET/CT in the detection of primary tumors (100% [19 of 19] vs 53% [10 of 19], respectively; P = .004), lymph nodes (79% [22 of 28] vs 54% [15 of 28], P , .001), and bone and visceral metastases (89% [31 of 35] vs 57% [20 of 35], P , .001). Conclusion: Gallium 68 fibroblast-activation protein inhibitor PET/CT was superior to fluorine 18 fluorodeoxyglucose PET/CT in the detection of primary and metastatic lesions in gastric, duodenal, and colorectal cancers, with higher tracer uptake in most primary and metastatic lesions. Published under a CC BY 4.0 license.

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Molecular imaging for non-invasive assessment of angiogenesisis is of great interest for clinicians because of the wide-spread application of anti-angiogenic cancer therapeutics. Besides, many other interventions that involve the change of blood vessel/tumor microenvironment would also benefit from such imaging strategies. Of the imaging techniques that target angiogenesis, radiolabeled Arg-Gly-Asp (RGD) peptides have been a major focus because of their high affinity and selectivity for integrin αvβ3--one of the most extensively examined target of angiogenesis. Since the level of integrin αvβ3 expression has been established as a surrogate marker of angiogenic activity, imaging αvβ3 expression can potentially be used as an early indicator of effectiveness of antiangiogenic therapy at the molecular level. In this review, we summarize RGD-based PET tracers that have already been used in clinical trials and intercompared them in terms of radiosynthesis, dosimetry, pharmacokinetics and clinical applications. A perspective of their future use in the clinic is also provided.

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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 FAP inhibitor (FAPI)-04 and FAPI-46, have shown promising results in tumor diagnosis. However, these molecules have relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a 68 Ga-labeled FAPI dimer (denoted as 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 based on the quinoline-based FAPI variants (FAPI-46), and its binding properties were assayed in CAFs.Preclinical pharmacokinetics was determined in FAP-positive patient-derived xenografts (PDXs) using small-animal PET and biodistribution experiments. The effective dosimetry of 68 Ga-DOTA-2P(FAPI)2 was evaluated in three healthy volunteers, and PET/ CT imaging of 68 Ga-FAPI-46 and 68 Ga-DOTA-2P(FAPI)2 was performed in three 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 two-fold stronger than that of 4 68 Ga-FAPI-46 in PDXs, while the 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, PET/CT scans in three cancer patients revealed higher intratumoral uptake of 68 Ga-DOTA-2P(FAPI)2 than that of 68 Ga-FAPI-46 in all tumor lesions (maximum standardized uptake value: 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 to 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.