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.

Fibroblast activation protein (FAP) is overexpressed in cancer associated fibroblasts of several tumor entities. Recent development of quinoline based positron-emission-tomography (PET)-tracers that act as FAP-Inhibitors (FAPI) demonstrated promising results preclinically and already also in few clinical cases. Consecutively this novel tracer is now applied in our hospital to amend the diagnostics of cancer patients facing limitations of standard exams. Here we analyze the tissue biodistribution and preliminary dosimetry of two members of this new class of PET-radiopharmaceuticals. A preliminary dosimetry estimate for FAPI-02 and FAPI-04 was based on two patients examined at 0.2h, 1h and 3h after tracer injection using the QDOSE dosimetry software suit. Further PET/CT scans of tumor patients were acquired 1 h after injection of either FAPI-02 ( = 25) or FAPI-04 ( = 25); for 6 patients an intra-individual related FDG-scan (also acquired 1h p.i.) was available. For the normal tissue of 16 organs, a 2 cm Spheric-VOI was placed in the parenchyma, for tumor lesions a threshold segmented VOI was used to quantify SUVmean/max. Very similar to literature values forF-FDG, Ga-DOTATATE orGa-PSMA-11, an exam with 200 MBq Ga-FAPI-2/4 corresponds to an equivalent dose of approx. 3-4 mSv. After a fast clearance via the kidneys the normal organs showed a low tracer uptake with only minimal changes between 10 min and 3 h p.i.. In FAPI-02 the tumor uptake from 1h to 3h p.i. decreased by 75%, whereas the tumor retention was prolonged with FAPI-04 (25% washout). Regarding tumor-to-background ratios, at 1h p.i. both FAPI-tracers performed equally. In comparison to FDG the tumor uptake was almost equal (average SUV-FDG 7.41; SUV-FAPI-2 7.37; n.s.); the background uptake in brain (11.01 vs 0.32), liver (2.77 vs 1.69) and oral/pharyngeal mucosa (4.88 vs 2.57) was significantly lower with FAPI; other organs were not relevantly different between FDG and FAPI. FAPI-PET/CT is a new diagnostic method in imaging cancer patients. In contrast to FDG no diet/fasting in preparation of the exam is necessary and image acquisition can potentially be started few minutes after tracer application. Tumor-to-background contrast ratios were equal or even improved in comparison to FDG.

The tumor stroma, which accounts for a large part of the tumor mass, represents an attractive target for the delivery of diagnostic and therapeutic compounds. Here, the focus is notably on a subpopulation of stromal cells, known as cancer-associated fibroblasts, which are present in more than 90% of epithelial carcinomas, including pancreatic, colon, and breast cancer. Cancer-associated fibroblasts feature high expression of fibroblast activation protein (FAP), which is not detectable in adult normal tissue but is associated with a poor prognosis in cancer patients. We developed an iodinated and a DOTA-coupled radiotracer based on a FAP-specific enzyme inhibitor (FAPI) and evaluated them in vitro using uptake, competition, and efflux studies as well as confocal microscopy of a fluorescence-labeled variant. Furthermore, we performed imaging and biodistribution studies on tumor-bearing animals. Finally, proof of concept was realized by imaging patients withGa-labeled FAPI. Both FAPIs showed high specificity, affinity, and rapid internalization into FAP-expressing cells in vitro and in vivo. Biodistribution studies on tumor-bearing mice and on the first cancer patients demonstrated high intratumoral uptake of the tracer and fast body clearance, resulting in high-contrast images and negligible exposure of healthy tissue to radiation. A comparison with the commonly used radiotracerF-FDG in a patient with locally advanced lung adenocarcinoma revealed that the new FAP ligand was clearly superior. Radiolabeled FAPIs allow fast imaging with very high contrast in tumors having a high stromal content and may therefore serve as pantumor agents. Coupling of these molecules to DOTA or other chelators allows labeling not only withGa but also with therapeutic isotopes such as Lu orY.

Cancer-associated fibroblasts constitute a vital subpopulation of the tumor stroma and are present in more than 90% of epithelial carcinomas. The overexpression of the serine protease fibroblast activation protein (FAP) allows a selective targeting of a variety of tumors by inhibitor-based radiopharmaceuticals (FAPIs). Of these compounds, FAPI-04 has been recently introduced as a theranostic radiotracer and demonstrated high uptake into different FAP-positive tumors in cancer patients. To enable the delivery of higher doses, thereby improving the outcome of a therapeutic application, several FAPI variants were designed to further increase tumor uptake and retention of these tracers. Methods: Novel quinoline-based radiotracers were synthesized by organic chemistry and evaluated in radioligand binding assays using FAP-expressing HT-1080 cells. Depending on their in vitro performance, small-animal PET imaging and biodistribution studies were performed on HT-1080-FAP tumor–bearing mice. The most promising compounds were used for clinical PET imaging in 8 cancer patients. Results: Compared with FAPI-04, 11 of 15 FAPI derivatives showed improved FAP binding in vitro. Of these, 7 compounds demonstrated increased tumor uptake in tumor-bearing mice. Moreover, tumor–to–normal-organ ratios were improved for most of the compounds, resulting in images with higher contrast. Notably two of the radiotracers, FAPI-21 and -46, displayed substantially improved ratios of tumor to blood, liver, muscle, and intestinal uptake. A first diagnostic application in cancer patients revealed high intratumoral uptake of both radiotracers already 10 min after administration but a higher uptake in oral mucosa, salivary glands, and thyroid for FAPI-21. Conclusion: Chemical modification of the FAPI framework enabled enhanced FAP binding and improved pharmacokinetics in most of the derivatives, resulting in high-contrast images. Moreover, higher doses of radioactivity can be delivered while minimizing damage to healthy tissue, which may improve therapeutic outcome.

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Ga-FAPI-2/4/46 have already been proposed as promising PET-tracers. However, the short half-life of 68 Ga (T1/2 68 min) creates problems with manufacture and delivery. 18 F (T1/2 110 min) labeling would result in a more practical large scale production and a cold-kit formulation would improve the spontaneous availability. The NOTA-chelator ligand FAPI-74 can be labeled with both 18 F-AlF (Aluminum-Fluoride) and 68 Ga. Here we describe the in-vivo evaluation of 18 F-FAPI-74 and a proof-of-mechanism of 68 Ga-FAPI-74 labeled at ambient temperature. Methods: In ten patients with lung cancer PET-scans were acquired at 10 min, 1h and 3h after administration of 259±26 MBq 18 F-FAPI-74. Physiological biodistribution and tumor uptake were semi-quantitatively evaluated based on SUV at each time-point. Absorbed doses were evaluated using OLINDA/EXM 1.1 and QDOSE dosimetry software with the dose calculator IDAC-Dose 2.1. Identical methods were used to evaluate one exam after injection of 263 MBq 68 Ga-FAPI-74. Results: The highest contrast was achieved 1 h p.i. in primary tumors, lymph node and distant metastases with SUVmax >10, respectively. The effective dose per 100 MBq administered activity of 18 F-FAPI-74 was 1.4±0.2 mSv and for 68 Ga-FAPI-74 it was 1.6 mSv. Thus, the radiation burden of a diagnostic 18 F-FAPI-74 PET-scan is even lower than that of PET-scans with 18 F-FDG and other 18 F-tracers; 68 Ga-FAPI-74 is comparable to other 68 Ga-ligands. FAPI-PET/CT supported target volume definition for guiding radiotherapy. Conclusion: High contrast and low radiation burden of FAPI-74 PET/CT favors multiple clinical applications. Centralized large-scale production of 18 F-FAPI-74 or decentralized cold-kit labeling of 68 Ga-FAPI-74 allows flexible routine use.

Background and Purpose-Computed tomographic perfusion represents an interesting physiological imaging modality to select patients for reperfusion therapy in acute ischemic stroke. The purpose of our study was to determine the accuracy of different commercial perfusion CT software packages (Philips (A), Siemens (B), and RAPID (C)) to predict the final infarct volume (FIV) after mechanical thrombectomy. Methods-Single-institutional computed tomographic perfusion data from 147 mechanically recanalized acute ischemic stroke patients were postprocessed. Ischemic core and FIV were compared about thrombolysis in cerebral infarction (TICI) score and time interval to reperfusion. FIV was measured at follow-up imaging between days 1 and 8 after stroke. Results-In 118 successfully recanalized patients (TICI 2b/3), a moderately to strongly positive correlation was observed between ischemic core and FIV. The highest accuracy and best correlation are shown in early and fully recanalized patients (Pearson r for A=0.42, B=0.64, and C=0.83; P<0.001). Bland-Altman plots and boxplots demonstrate smaller ranges in package C than in A and B. Significant differences were found between the packages about over-and underestimation of the ischemic core. Package A, compared with B and C, estimated more than twice as many patients with a malignant stroke profile (P<0.001). Package C best predicted hypoperfusion volume in nonsuccessfully recanalized patients. Conclusions-Our study demonstrates best accuracy and approximation between the results of a fully automated software (RAPID) and FIV, especially in early and fully recanalized patients. Furthermore, this software package overestimated the FIV to a significantly lower degree and estimated a malignant mismatch profile less often than other software.