Abstract
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. Since FAP shows low expression in most normal organs it presents an interesting target for imaging and endoradiotherapy. In this paper, FAP inhibitors were modified and optimized for their use as theranostic tracers. Methods: FAP inhibitors (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 positron emission tomography (PET). Finally, a proof of concept approach of imaging and therapy was chosen in two patients with metastasized breast cancer. Results: Of 11 synthesized FAPIs FAPI-04 was identified as the most promising tracer for clinical application. Compared to the previously published ligand FAPI-02, FAPI-04 showed an excellent stability in human serum, a higher affinity for FAP as opposed to dipeptidyl peptidase 4 and a slower excretion in vitro. In vivo, a higher SUV was reached in tumor-bearing animals leading to higher area under curve values calculated from biodistribution experiments. Finally, PET/CT scans with 68Ga-FAPI-04 in two patients with metastasized breast cancer revealed high tracer uptake in metastases and a reduction of pain symptoms after therapy with a considerable low dose of 90Y-FAPI-04. Conclusion: FAPI-04 represents a promising tracer for both diagnostic imaging and possibly targeted therapy of malignant tumors with a high content of activated fibroblast such as breast cancer.
- Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.