The recent development of quinoline-based PET tracers that act as fibroblast-activation-protein inhibitors (FAPIs) demonstrated promising preclinical and clinical results. FAP is overexpressed by cancer-associated fibroblasts of several tumor entities. Here, we quantify the tumor uptake on 68 Ga-FAPI PET/CT of various primary and metastatic tumors to identify the most promising indications for future application. Methods: 68 Ga-FAPI PET/CT scans were requested by various referring physicians according to individual clinical indications that were considered insufficiently covered by 18 F-FDG PET/CT or other imaging modalities. All PET/CT was performed 1 h after injection of 122-312 MBq of 68 Ga-FAPI-04. We retrospectively identified 80 patients with histopathologically proven primary tumors or metastases or radiologically unequivocal metastatic lesions of histologically proven primary tumors. Tumor uptake was quantified by SUV max and SUV mean (60% isocontour). Results: Eighty patients with 28 different tumor entities (54 primary tumors and 229 metastases) were evaluated. The highest average SUV max (.12) was found in sarcoma, esophageal, breast, cholangiocarcinoma, and lung cancer. The lowest 68 Ga-FAPI uptake (average SUV max , 6) was observed in pheochromocytoma, renal cell, differentiated thyroid, adenoid cystic, and gastric cancer. The average SUV max of hepatocellular, colorectal, head-neck, ovarian, pancreatic, and prostate cancer was intermediate . SUV varied across and within all tumor entities. Because of low background in muscle and blood pool (SUV max , 2), the tumor-to-background contrast ratios were more than 3-fold in the intermediate and more than 6fold in the high-intensity uptake group. Conclusion: Several highly prevalent cancers presented with remarkably high uptake and image contrast on 68 Ga-FAPI PET/CT. The high and rather selective tumor uptake may open up new applications for noninvasive tumor characterization, staging examinations, or radioligand therapy. ://jnm.snmjournals.org/content/60/6/801 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts and is involved in a variety of tumor-promoting activities such as matrix remodeling, angiogenesis, chemotherapy resistance, and immunosuppression. Because FAP shows low expression in most normal organs, it presents an interesting target for imaging and endoradiotherapy. In this investigation, FAP inhibitors (FAPIs) were modified and optimized for use as theranostic tracers. FAPIs based on a quinoline structure were synthesized and characterized with respect to binding, internalization, and efflux in cells expressing human and murine FAP as well as CD26. Preclinical pharmacokinetics were determined in tumor-bearing animals with biodistribution experiments and small-animal PET. Finally, a proof-of-concept approach toward imaging and therapy was chosen for 2 patients with metastasized breast cancer. Of 15 synthesized FAPIs, FAPI-04 was identified as the most promising tracer for clinical application. Compared with the previously published ligand, FAPI-02, FAPI-04 showed excellent stability in human serum, higher affinity for FAP as opposed to CD26, and slower excretion in vitro. In vivo, a higher SUV was reached in tumor-bearing animals, leading to larger areas under the curve as calculated from biodistribution experiments. Finally, PET/CT scans with Ga-FAPI-04 in 2 patients with metastasized breast cancer revealed high tracer uptake in metastases and a reduction in pain symptoms after therapy with a considerably low dose ofY-FAPI-04. FAPI-04 represents a promising tracer for both diagnostic imaging and, possibly, targeted therapy of malignant tumors with a high content of activated fibroblasts, such as breast cancer.