Design, synthesis and evaluation of¹⁸F-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 lM. We evaluated compound 2 as a diagnostic PET imaging agent. Compound 2 was radiolabeled with 18 F in 10 ± 4% decay-corrected radiochemical yield with 85.1 ± 70.3 GBq/lmol specific activity and >98% radiochemical purity.18 F-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.18 F-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. ARTICLE HISTORY

Mucin 5B, carbonic anhydrase 9 and claudin 18 are potential theranostic markers of gallbladder carcinoma

“…24 Interestingly, different molecules have been developed to visualize hypoxic areas by the use of in-vivo imaging of CA9. [25][26][27][28] Here, we have demonstrated that CA9 is normally expressed at high and even levels in normal gallbladder epithelium, and was conserved at high levels in half of the GBC cases. Therefore, CA9 represents a promising candidate for theranostic strategies in GBC.…”

“…CA9 catalyses the reversible hydration of carbon dioxide; therefore, it has been studied as a potential target for cancer, as it is enriched in hypoxic niches of neoplastic tissues . Interestingly, different molecules have been developed to visualize hypoxic areas by the use of in‐vivo imaging of CA9 . Here, we have demonstrated that CA9 is normally expressed at high and even levels in normal gallbladder epithelium, and was conserved at high levels in half of the GBC cases.…”

Synthesis and evaluation of an 18F‐labeled trifluoroborate derivative of 2‐nitroimidazole for imaging tumor hypoxia with positron emission tomography

“…Extremely low uptake at 0.03 ± 0.01%ID/g was observed in brain. Such low brain uptake level is normally observed by using cell‐impermeable radiotracers such as peptides and charged molecules, indicating the incapability of 18 F‐AmBF 3 ‐Bu‐2NI to freely cross blood‐brain barrier.…”

“…Biodistribution and PET/CT imaging studies were conducted following previously published procedures . These studies were conducted in accordance with the guidelines established by the Canadian Council on Animal Care and approved by the Animal Ethics Committee of the University of British Columbia.…”

Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

“…The initial ligands of the sulfonamide and coumarin type, incorporating 99m Tc or 18 F, although possessing good affinity for CA IX, did not show a strong accumulation in the hypoxic tumor, probably due to pharmacokinetic reasons . However, second generation such ligands, incorporating polycyclic moieties that may complex trivalent metal ions, as Ga(III), In(III) (derivatives 56–58 in Figure incorporating 68 Ga, a positron emitting isotope), were highly effective for the imaging of CA IX positive colorectal and RCC tumors . Thus, there is probably a future for CA IX inhibitors as diagnostic agents too.…”