@article {Persson272, author = {Morten Persson and Mette K. Nedergaard and Malene Brandt-Larsen and Dorthe Skovgaard and Jesper T. J{\o}rgensen and Signe R. Michaelsen and Jacob Madsen and Ulrik Lassen and Hans S. Poulsen and Andreas Kjaer}, title = {Urokinase-Type Plasminogen Activator Receptor as a Potential PET Biomarker in Glioblastoma}, volume = {57}, number = {2}, pages = {272--278}, year = {2016}, doi = {10.2967/jnumed.115.161703}, publisher = {Society of Nuclear Medicine}, abstract = {Glioblastoma is one of the most malignant types of human cancer, and the prognosis is poor. The development and validation of novel molecular imaging biomarkers has the potential to improve tumor detection, grading, risk stratification, and treatment monitoring of gliomas. The aim of this study was to explore the potential of PET imaging of the urokinase-type plasminogen activator receptor (uPAR) in glioblastoma. Methods: The uPAR messenger RNA expression of tumors from 19 glioblastoma patients was analyzed, and a cell culture derived from one of these patients was used to establish an orthotopic xenograft model of glioblastoma. Tumor growth was monitored using bioluminescence imaging. Five to six weeks after inoculation, all mice were scanned with small-animal PET/CT using two new uPAR PET ligands (64Cu-NOTA-AE105 and 68Ga-NOTA-AE105) and, for comparison, O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET). One MRI scan was obtained for each mouse to confirm tumor location. The uPAR specificity of 64Cu-NOTA-AE105 was confirmed by alignment of hematoxylin- and eosin-stained and uPAR immunohistochemistry{\textendash}stained slides of the brain with the activity distribution as determined using autoradiography. Results: uPAR expression was found in all 19 glioblastoma patient tumors, and high expression of uPAR correlated with decreased overall survival (P = 0.04). Radiolabeling of NOTA-AE105 with 64Cu and 68Ga was straightforward, resulting in a specific activity of approximately 20 GBq/μmol and a radiochemical purity of more than 98\% for 64Cu-NOTA-AE105 and more than 97\% for 68Ga-NOTA-AE105. High image contrast resulting in clear tumor delineation was found for both 68Ga-NOTA-AE105 and 64Cu-NOTA-AE105. Absolute uptake in tumor was higher for 18F-FET (3.5 {\textpm} 0.8 percentage injected dose [\%ID]/g) than for 64Cu-NOTA-AE105 (1.2 {\textpm} 0.4 \%ID/g) or 68Ga-NOTA-AE105 (0.4 {\textpm} 0.1 \%ID/g). A similar pattern was observed in background brain tissue, where uptake was 1.9 {\textpm} 0.1 \%ID/g for 18F-fluorothymidine, compared with 0.05 {\textpm} 0.01 \%ID/g for 68Ga-NOTA-AE105 and 0.11 {\textpm} 0.02 \%ID/g for 64Cu-NOTA-AE105. The result was a significantly higher tumor-to-background ratio for both 68Ga-NOTA-AE105 (7.6 {\textpm} 2.1, P \< 0.05) and 64Cu-NOTA-AE105 (10.6 {\textpm} 2.3, P \< 0.01) than for 18F-FET PET (1.8 {\textpm} 0.3). Autoradiography of brain slides confirmed that the accumulation of 64Cu-NOTA-AE105 corresponded well with uPAR-positive cancer cells. Conclusion: On the basis of our translational study, uPAR PET may be a highly promising imaging biomarker for glioblastoma. Further clinical exploration of uPAR PET in glioblastoma is therefore justified.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/57/2/272}, eprint = {https://jnm.snmjournals.org/content/57/2/272.full.pdf}, journal = {Journal of Nuclear Medicine} }