Journal
JOURNAL OF NUCLEAR MEDICINE
Volume 59, Issue 9, Pages 1423-1429Publisher
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.118.210435
Keywords
PET; radiopharmaceuticals; FAP; activated fibroblasts; small molecule; tumor
Funding
- Federal Ministry of Education and Research [13N 13341]
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INBS-05]
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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. Methods: 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 with Ga-68-labeled FAPI. Results: 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 radiotracer F-18-FDG in a patient with locally advanced lung adenocarcinoma revealed that the new FAP ligand was clearly superior. Conclusion: Radiolabeled FAPIs allow fast imaging with very high contrast in tumors having a high stromal content and may therefore serve as pan-tumor agents. Coupling of these molecules to DOTA or other chelators allows labeling not only with Ga-68 but also with therapeutic isotopes such as Lu-177 or Y-90.
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