Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with ⁶⁴Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion

Abstract

Expression levels of the urokinase-type plasminogen activator receptor (uPAR) represent an established biomarker for poor prognosis in a variety of human cancers. The objective of the present study was to explore whether noninvasive PET can be used to perform a quantitative assessment of expression levels of uPAR across different human cancer xenograft models in mice and to illustrate the clinical potential of uPAR PET in future settings for individualized therapy. Methods: To accomplish our objective, a linear, high-affinity uPAR peptide antagonist, AE105, was conjugated with DOTA and labeled with 64 Cu ( 64 Cu-DOTA-AE105). Small-animal PET was performed in 3 human cancer xenograft mice models, expressing different levels of human uPAR, and the tumor uptake was correlated with the uPAR expression level determined by uPAR enzyme-linked immunosorbent assay. The tumor uptake pattern of this tracer was furthermore compared with 18 F-FDG uptake, and finally the correlation between sensitivity toward 5-fluorouracil therapy and uPAR expression level was investigated. Results: The uPARtargeting PET tracer was produced in high purity and with high specific radioactivity. A significant correlation between tumor uptake of 64 Cu-DOTA-AE105 and uPAR expression was found (R 2 5 0.73; P , 0.0001) across 3 cancer xenografts, thus providing a strong argument for specificity. A significantly different uptake pattern of 64 Cu-DOTA-AE105, compared with that of 18 F-FDG, was observed, thus emphasizing the additional information that can be obtained on tumor biology using 64 Cu-DOTA-AE105 PET. Furthermore, a significant correlation between baseline uPAR expression and sensitivity toward 5-fluorouracil was revealed, thus illustrating the possible potentials of uPAR PET in a clinical setting. Conclusion: Our results clearly demonstrate that the peptide-based PET tracer 64 Cu-DOTA-AE105 enables the noninvasive quantification of uPAR expression in tumors in vivo, thus emphasizing its potential use in a clinical setting to detect invasive cancer foci and for individualized cancer therapy.

Safety, Dosimetry, and Tumor Detection Ability of 68Ga-NOTA-AE105: First-in-Human Study of a Novel Radioligand for uPAR PET Imaging

“…Accordingly, we have for several years focused on development of radioligands based on the high-affinity peptide antagonist AE105 for PET imaging of uPAR expression (12)(13)(14)(15)(16)(17). We recently published results from a promising first-in-human study with 64 Cu-DOTA-AE105 showing high uptake in both primary tumor lesions and lymph node metastases paralleled with high uPAR expression in excised tumor tissue, thereby providing evidence for uPAR PET imaging in cancer patients (4).…”

Imaging of human pancreatic cancer xenografts by single-photon emission computed tomography with 99mTc-Hynic-PEG-AE105

“…Previous studies investigated the use of a high-affinity 9-mer peptide antagonist of the uPA-uPAR (AE105) for positron emission tomography (PET) imaging of uPAR expression, and showed that copper-64 ( 64 Cu)-labeled DOTA-AE105 exhibited specific and high-affinity binding to uPAR in vitro and in vivo (16)(17)(18). However, the clinical application of this protocol is restricted due to the limited availability of 64 Cu and the high cost of PET imaging.…”

uPAR as a Glioma Imaging Target

“…More recently, the Kjaer group performed a series of important steps to modify and characterize radioactive uPAR ligands. They developed and examined the radioactive uPAR ligands 68 Ga-DOTA-AE105-NH 2 (14), 68 Ga-NODAGA-AE105-NH 2 (14), 18 F-AlF-NOTA-AE105 (15), 64 Cu-CB-TE2A-PA-AE105 (16), and 64 Cu-DOTA-AE105 (17). In this issue of The Journal of Nuclear Medicine, Persson et al from the Kjaer group present evidence of the usefulness of two new uPAR PET tracers, 64 Cu-NOTA-AE105 and 68 Ga-NOTA-AE105, in glioblastoma imaging (18).…”