Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein

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. 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.

Determination of neutron capture cross sections of 232 Th at 14.1 MeV and 14.8 MeV using the neutron activation method

“…It can be seen from Table 2, our measured results are in good agreement with the literature data [19] but much lower than [20]. For purpose of comparison, the 232 Th(n,γ) 231 Th reaction cross sections from the present work and the similar experimental data from the literatures [21][22][23][24][25][26][27] were plotted in Fig. 1 together with the evaluated data [4][5][6] as well as the theoretical values from computer code TALYS1.6…”

68Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer

“…Differentiation between residual/recurrent disease and postchemoradiation fibrosis was reported to be a diagnostic challenge for 18 F-FDG (21). It should be mentioned that unspecific fibrosis may also cause issues for 68 Ga-FAPI PET; however, because of the inherent difference in normal activated fibroblasts and cancerassociated fibroblasts (4,5), this possibility still needs to be proven. Intermediate to high 68 Ga-FAPI uptake was also observed in prostate cancer.…”

“…Synthesis and labeling of 68 Ga-FAPI-04 have already been described previously (4,5). Following the regulations of the German Pharmaceuticals Act x13(2b), the indication for the exam and labeling of the FAPI tracers was done under the direct responsibility of the applying physician.…”

“…Many cancer-associated fibroblasts differ from normal fibroblasts by their relative specific expression of fibroblast activation protein (FAP). Therefore, FAP-specific inhibitors were first developed as anticancer drugs and then were consecutively advanced into tumor-targeting radiopharmaceuticals (4,5).…”

Fibroblast-Activating Protein: Targeting the Roots of the Tumor Microenvironment

“…In 2 seminal papers in this issue of The Journal of Nuclear Medicine, Haberkorn's group now moves a big step ahead in targeting FAP for clinical use (14,15). Based on a strategy to inhibit FAP enzyme activity by using 4,4-difluoroproline as described previously (16), they developed a series of quinoline-based radiopharmaceuticals for diagnostic and therapeutic use.…”