Design, synthesis and evaluation of 18F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging

Carbonic anhydrase IX (CA-IX) is a marker for tumor hypoxia, and its expression is negatively correlated with patient survival. CA-IX represents a potential target for eliminating hypoxic cancers. We synthesized fluorinated cationic sulfonamide inhibitors 1-3 designed to target CA-IX. The binding affinity for CA-IX ranged from 0.22 to 0.96 mu M. We evaluated compound 2 as a diagnostic PET imaging agent. Compound 2 was radiolabeled with F-18 in 10 +/- 4% decay-corrected radiochemical yield with 85.1 +/- 70.3 GBq/lmol specific activity and >98% radiochemical purity. F-18-labeled 2 was stable in mouse plasma at 37 degrees C after 1 h incubation. PET/CT imaging was conducted at 1 h post-injection in a human colorectal cancer xenograft model. F-18-labeled 2 cleared through hepatobiliary and renal pathways. Tumor uptake was approximately 0.41 +/- 0.06% ID/g, with a tumor-to-muscle ratio of 1.99 +/- 0.25. Subsequently, tumor xenografts were visualized with moderate contrast. This study demonstrates the use of a cationic motif for conferring isoform selectively for CA-IX imaging agents.