Use of a peptide derived from foot-and-mouth disease virus for the Noninvasive Imaging of human cancer:: Generation and evaluation of 4-[18F]fluorobenzoyl A20FMDV2 for in vivo imaging of integrin αvβ6 expression with positron emission tomography

Expression of the epithelial- specific integrin alpha(v)beta(6)is low or undetectable in most adult tissues but may be increased during wound healing and inflammation and is up-regulated dramatically by many different carcinomas, making alpha(v)beta(6) a promising target for the in vivo detection of cancer using noninvasive imaging. In addition, alpha(v)beta(6) is recognized as promoting invasion and correlates with aggressive behavior of human cancers and thus agents that recognize alpha(v)beta(6) specifically in vivo will be an essential tool for the future management Of alpha(v)beta(6)-Positive cancers. Recently, we identified the peptide NAVPNLRGDLQVLAQKVART (A20FMDV2), derived from foot-and-mouth disease virus, as a potent inhibitor of alpha(v)beta(6). Using flow cytometry and ELISA, we show that this peptide is highly selective, inhibiting alpha(v)beta(6)-ligand binding with a IC50 of 3 nmol/L, an activity 1,000-fold more selective for alpha(v)beta(6) than for other RGD-directed integrins alpha(v)beta(3), alpha(v)beta 5 and alpha(5)beta(1)). A20FMDV2 was radiolabeled on solid-phase using 4- [F-18] fluorobenzoic acid, injected into mice bearing both alpha(v)beta(6)-negative and alpha(v)beta(6) positive (DX3puro/DX3puro beta 6 cell lines) xenografts and imaged using a small animal positron emission tomography (PET) scanner. Rapid uptake (< 30 min) and selective retention (> 5 h) of radioactivity in the alpha(v)beta(6)-Positive versus the alpha(v)beta(6) negative tumor, together with fast renal elimination of nonspecifically bound activity, resulted in specific imaging of the alpha(v)beta(6)-positive neoplasm. These data suggest that PET imaging of alpha(v)beta(6)-POsitive tumors is feasible and will provide an important new tool for early detection and improved management of many types of cancers.