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Imaging of Urokinase-Type Plasminogen Activator Receptor Expression Using a ⁶⁴Cu-Labeled Linear Peptide Antagonist by microPET

Authors' Affiliations: ¹ Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California; ² Department of Surgery and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia; and ³ Finsen Laboratory, Copenhagen, Denmark

Requests for reprints: Xiaoyuan Chen, Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, P095, Stanford, CA 94305-5484. Phone: 650-725-0950; Fax: 650-736-7925; E-mail: shawchen{at}stanford.edu.

Purpose: Malignant tumors are capable of degrading the surrounding extracellular matrix, resulting in local invasion or metastasis. Urokinase-type plasminogen activator (uPA) and its cell surface receptor (uPAR) are central molecules in one of the major protease systems involved in extracellular matrix degradation. Noninvasive imaging of this receptor in vivo with radiolabeled peptides that specifically target uPAR may therefore be useful to decipher the potential invasiveness of malignant lesions.

Experimental Design: In this study, we developed a ⁶⁴Cu-labeled uPAR-binding peptide for positron emission tomography (PET) imaging. A linear, high-affinity uPAR-binding peptide antagonist AE105 was conjugated with 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA) and labeled with ⁶⁴Cu for microPET imaging of mice bearing U87MG human glioblastoma (uPAR positive) and MDA-MB-435 human breast cancer (uPAR negative).

Results: Surface plasmon resonance measurements show that AE105 with DOTA conjugated at the -amino group (DOTA-AE105) has high affinity toward uPAR. microPET imaging reveals a rapid and high accumulation of ⁶⁴Cu-DOTA-AE105 in uPAR-positive U87MG tumors (10.8 ± 1.5%ID/g at 4.5 hours, n = 3) but not in uPAR-negative MDA-MB-435 tumors (1.2 ± 0.6%ID/g at 4.5 hours, n = 3). Specificity of this peptide-based imaging of uPAR was validated by further control experiments. First, a nonbinding variant of AE105 carrying a single amino acid replacement (TrpGlu) does not target U87MG tumors in vivo. Second, targeting of U87MG tumors by ⁶⁴Cu-DOTA-AE105 is specifically inhibited by a nonlabeled antagonist.

Conclusion: The successful demonstration of the ability of a ⁶⁴Cu labeled uPAR-specific probe to visualize uPAR expression in vivo may allow clinical translation of this class of radiopharmaceuticals for uPAR-positive cancer detection and patient stratification for uPA/uPAR system-based cancer therapy.