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

Abstract

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 μM. We evaluated compound 2 as a diagnostic PET imaging agent. Compound 2 was radiolabeled with ¹⁸F in 10 ± 4% decay-corrected radiochemical yield with 85.1 ± 70.3 GBq/μmol specific activity and >98% radiochemical purity. ¹⁸F-labeled 2 was stable in mouse plasma at 37 °C after 1 h incubation. PET/CT imaging was conducted at 1 h post-injection in a human colorectal cancer xenograft model. ¹⁸F-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.

Keywords:

• Carbonic anhydrase IX
• fluorine-18
• molecular imaging
• positron emission tomography

Acknowledgements

This work was supported by the Canadian Institutes of Health Research (FDN-148465) and the Leading Edge Endowment Fund. The authors would like to thank Wade English and Baljit Singh for their technical assistance.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by the Canadian Institutes of Health Research (FDN-148465) and the Leading Edge Endowment Fund.