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 α_vβ⁶ expression with positron emission tomography

Expression of the epithelial-specific integrin α_vβ 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 α_vβ₆ a promising target for the in vivo detection of cancer using noninvasive imaging. In addition, α_vβ₆ is recognized as promoting invasion and correlates with aggressive behavior of human cancers and thus agents that recognize α_vβ₆ specifically in vivo will be an essential tool for the future management of α _vβ₆-positive cancers. Recently, we identified the peptide NAVPNLRGDLQV-LAQKVART (A20FMDV2), derived from foot-and-mouth disease virus, as a potent inhibitor of α_vβ₆. Using flow cytometry and ELISA, we show that this peptide is highly selective, inhibiting α_vβ₆-ligand binding with a IC ₅₀ of 3 nmol/L, an activity 1,000-fold more selective for α_vβ₆ than for other RGD-directed integrins (α_vβ₃, α_vβ₅, and α₅β₁). A20FMDV2 was radiolabeled on solid-phase using 4-[¹⁸F]fluorobenzoic acid, injected into mice bearing both α_vβ₆-negative and α_vβ₆-positive (DX3puro/DX3puroβ6 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 α_vβ₆-positive versus the α_vβ₆-negative tumor, together with fast renal elimination of nonspecifically bound activity, resulted in specific imaging of the α_vβ₆-positive neoplasm. These data suggest that PET imaging of α_vβ₆-positive tumors is feasible and will provide an important new tool for early detection and improved management of many types of cancers.