Targeted In vivo Imaging of Integrin AvB6 with an Improved Radiotracer and Its Relevance in a Pancreatic Tumor Model

The cell surface receptor AvB6 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 AvB6 as a prognostic biomarker linked to poor survival. We have recently shown the feasibility of imaging AvB6 in vivo by positron emission tomography (PET) using the peptide [F]FBA-A20FMDV2. Here, we describe improved AvB6 imaging agents and test their efficacy in a mouse model with endogenous AvB6 expression. The modified compounds maintained high affinity for AvB6 and >1,000-fold selectivity over related integrins (by ELISA) and showed significantly improved AvB6-dependent binding in cell-based assays (>60% binding versus <10% for [F]FBA-A20FMDV2). In vivo studies using either a melanoma cell line (transduced AvB6 expression) or the BxPC-3 human pancreatic carcinoma cell line (endogenous AvB6 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 [F]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, [F]FBA-PEG28-A20FMDV2 was superior to 2-[F]fluoro-2-deoxy-D-glucose ([F]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 AvB6 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):OF1–7]