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Targeted In vivo Imaging of Integrin _vβ₆ with an Improved Radiotracer and Its Relevance in a Pancreatic Tumor Model

¹ Department of Biomedical Engineering and ² Center for Molecular and Genomic Imaging, University of California Davis, Davis, California; ³ Department of Psychology, University of California Santa Barbara, Santa Barbara, California; ⁴ Division of Surgical Oncology, University of California Davis Medical Center, Sacramento, California; and ⁵ Tumour Biology Centre, Barts and The London Medical School, London, United Kingdom

Requests for reprints: Julie L. Sutcliffe, Department of Biomedical Engineering, Genomics and Biomedical, Sciences Facility, 451 Health Sciences Drive, University of California Davis, Davis, CA 95616. Phone: 530-754-7107; Fax: 530-754-5739; E-mail: jlsutcliffe{at}ucdavis.edu.

Key Words: integrin (v)β(6) • PEGylation • peptide radiotracer

The cell surface receptor _vβ₆ is epithelial specific, and its expression is tightly regulated; it is low or undetectable in adult tissues but has been shown to be increased in many different cancers, including pancreatic, cervical, lung, and colon cancers. Studies have described _vβ₆ as a prognostic biomarker linked to poor survival. We have recently shown the feasibility of imaging _vβ₆ in vivo by positron emission tomography (PET) using the peptide [¹⁸F]FBA-A20FMDV2. Here, we describe improved _vβ₆ imaging agents and test their efficacy in a mouse model with endogenous _vβ₆ expression. The modified compounds maintained high affinity for _vβ₆ and >1,000-fold selectivity over related integrins (by ELISA) and showed significantly improved _vβ₆-dependent binding in cell-based assays (>60% binding versus <10% for [¹⁸F]FBA-A20FMDV2). In vivo studies using either a melanoma cell line (transduced _vβ₆ expression) or the BxPC-3 human pancreatic carcinoma cell line (endogenous _vβ₆ expression) revealed that the modified compounds showed significantly improved tumor retention. This, along with good clearance of nonspecifically bound activity, particularly for the new radiotracer [¹⁸F]FBA-PEG₂₈-A20FMDV2, resulted in improved PET imaging. Tumor/pancreas and tumor/blood biodistribution ratios of >23:1 and >47:1, respectively, were achieved at 4 hours. Significantly, [¹⁸F]FBA-PEG₂₈-A20FMDV2 was superior to 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) in imaging the BxPC-3 tumors. Pancreatic ductal adenocarcinoma is highly metastatic and current preoperative evaluation of resectability using noninvasive imaging has limited success, with most patients having metastases at time of surgery. The fact that these tumors express _vβ₆ suggests that this probe has significant potential for the in vivo detection of this malignancy, thus having important implications for patient care and therapy. [Cancer Res 2009;69(14):5843–50]

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