title: 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 μM. We evaluated compound 2 as a diagnostic PET imaging agent. Compound 2 was radiolabeled with18F 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.
authors.affiliation: a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British Columbia , Canada.
authors.forename: Zhengxing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British Columbia , Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lau
authors.affiliation: a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British Columbia , Canada.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British Columbia , Canada.
authors.forename: Nadine
authors.initials: N
authors.lastname: Colpo
authors.affiliation: b Department of Neurofarba, Section of Pharmaceutical and Nutriceutical Sciences , Università Degli Studi Di Firenze , Florence , Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nocentini
authors.affiliation: b Department of Neurofarba, Section of Pharmaceutical and Nutriceutical Sciences , Università Degli Studi Di Firenze , Florence , Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British Columbia , Canada.|c Department of Functional Imaging , BC Cancer Agency , Vancouver , British Columbia , Canada.|d Department of Radiology , University of British Columbia , Vancouver , British Columbia , Canada.
authors.forename: François
authors.initials: F
authors.lastname: Bénard
authors.affiliation: a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British Columbia , Canada.|c Department of Functional Imaging , BC Cancer Agency , Vancouver , British Columbia , Canada.|d Department of Radiology , University of British Columbia , Vancouver , British Columbia , Canada.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
mesh_terms: D000818:Animals; D000071231:Carbonic Anhydrase IX / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005462:Fluorine Radioisotopes; D006801:Humans; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D013329:Structure-Activity Relationship
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D005462:Fluorine Radioisotopes; D000071231:Carbonic Anhydrase IX
keywords: Carbonic anhydrase IX; fluorine-18; molecular imaging; positron emission tomography