18F-labeled tracers targeting fibroblast activation protein

Abstract

Background Cancer-associated fibroblasts are found in the stroma of epithelial tumors. They are characterized by overexpression of the fibroblast activation protein (FAP), a serine protease which was already proven as attractive target for chelator-based theranostics. Unfortunately, the value of gallium-68 labeled tracers is limited by their batch size and the short nuclide half-life. To overcome this drawback, radiolabeling with aluminum fluoride complexes and 6-fluoronicotinamide derivatives of the longer-lived nuclide fluorine-18 was established. The novel compounds were tested for their FAP-specific binding affinity. Uptake and binding competition were studied in vitro using FAP expressing HT-1080 cells. HEK cells transfected with the closely related dipeptidyl peptidase-4 (HEK-CD26) were used as negative control. Small animal positron emission tomography imaging and biodistribution experiments were performed in HT-1080-FAP xenografted nude mice. [18F]AlF-FAPI-74 was selected for PET/CT imaging in a non-small cell lung cancer (NSCLC) patient. Results In vitro, 18F-labeled FAPI-derivatives demonstrated high affinity (EC50 = < 1 nm to 4.2 nm) and binding of up to 80% to the FAP-expressing HT1080 cells while no binding to HEK-CD26 cells was observed. While small animal PET imaging revealed unfavorable biliary excretion of most of the 18F-labeled compounds, the NOTA bearing compounds [18F]AlF-FAPI-74 and -75 achieved good tumor-to-background ratios, as a result of their preferred renal excretion. These two compounds showed the highest tumor accumulation in PET imaging. The organ distribution values of [18F]AlF-FAPI-74 were in accordance with the small animal PET imaging results. Due to its less complex synthesis, fast clearance and low background values, [18F]AlF-FAPI-74 was chosen for clinical imaging. PET/CT of a patient with metastasized non-small cell lung cancer (NSCLC), enabled visualization of the primary tumor and its metastases at the hepatic portal and in several bones. This was accompanied by a rapid clearance from the blood pool and low background in healthy organs. Conclusion [18F]AlF-labeled FAPI derivatives represent powerful tracers for PET. Owing to an excellent performance in PET imaging, FAPI-74 can be regarded as a promising precursor for [18F]AlF-based FAP-imaging.

FAPI-PET/CT in Cancer Imaging: A Potential Novel Molecule of the Century

“…Others have attempted to label multiple FAPIs with [ 18 F] AlF and found that 18 F-FAPI-74 gave the most favorable results in an in vitro study, and they performed a visualization study in a patient with metastatic non–small cell lung cancer and obtained conclusions similar to those of Giesel et al. ( 20 , 39 ).…”

Molecular imaging in oncology: Current impact and future directions

“…Given the intrinsic advantages of 18 F‐labeled compounds, investigators have begun labeling FAPI‐based radiotracers with radiofluorine, including the use of 18 F‐aluminium fluoride in place of 68 Ga in the chelator moieties of existing compounds 96 . A subset of such radiotracers has been found to have favorable pharmacokinetics with high tumor‐to‐background ratios 97 …”

“…Specifically, we detail techniques in optical and near‐infrared (NIR) imaging, magnetic resonance imaging (MRI), and nuclear medicine techniques, including single‐photon emission computed tomography (SPECT) and positron emission tomography (PET) (Table 1). 4‐119 We also provide specific examples from translational science and cancer clinical care of the utilization of molecular imaging, with a particular focus on the use of these methods to guide and improve patient management. Finally, we delineate the challenges faced by the field and the potential benefits of overcoming them.…”

Radioligands Targeting Fibroblast Activation Protein (FAP)

“…While [ 18 F]AlF-FAPI-42, the NOTA-derivative of FAPI-04, showed hepatobiliary excretion, Lindner et al succeeded with FAPI-74, the analog precursor lacking the difluoro substitution at the pyrrolidine ring. For the corresponding radiotracers [ 18 F]AlF-FAPI-74 and 68 Ga-FAPI-74, Giesel et al demonstrated an equal performance compared to 68 Ga-FAPI-04 PET/CT in clinical applications [ 22 , 23 ]. Independently, Jiang et al reported preclinical results and a first-in-man study of [ 18 F]AlF-labeled NOTA-FAPI-04 (FAPI-42) [ 24 ].…”

“…With the anticipation of these uncertainties, the development of the FAPI-tracers focused more on tumor retention and pharmacokinetics than the absolute uptake or IC 50 values. Another aim was to exclude hepatobiliary excretion and, especially, to reduce the exposure of non-target tissues, such as bone marrow or salivary glands [ 17 , 18 , 23 , 25 ].…”