Design, Synthesis, and Evaluation of an (18)F-Labeled Radiotracer Based on Celecoxib-NBD for Positron Emission Tomography (PET) Imaging of Cyclooxygenase-2 (COX-2).
A series of novel fluorine-containing cyclooxygenase-2 (COX-2) inhibitors was designed and synthesized based on the previously reported fluorescent COX-2 imaging agent celecoxib-NBD (3; NBD=7-nitrobenzofurazan). In vitro COX-1/COX-2 inhibitory data show that N-(4-fluorobenzyl)-4-(5-p-tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide (5; IC50 =0.36 μM, SI>277) and N-fluoromethyl-4-(5-p-tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide (6; IC50 =0.24 μM, SI>416) are potent and selective COX-2 inhibitors. Compound 5 was selected for radiolabeling with the short-lived positron emitter fluorine-18 ((18) F) and evaluated as a positron emission tomography (PET) imaging agent. Radiotracer [(18) F]5 was analyzed in vitro and in vivo using human colorectal cancer model HCA-7. Although radiotracer uptake into COX-2-expressing HCA-7 cells was high, no evidence for COX-2-specific binding was found. Radiotracer uptake into HCA-7 tumors in vivo was low and similar to that of muscle, used as reference tissue.
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2 (Canada).|Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2E1 (Canada).
Jatinder
J
Kaur
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2 (Canada).
Ole
O
Tietz
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2 (Canada).|Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2E1 (Canada).
Atul
A
Bhardwaj
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2 (Canada).
Alison
A
Marshall
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2 (Canada).
Jenilee
J
Way
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2 (Canada).
Melinda
M
Wuest
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2 (Canada). wuest@ualberta.ca.|Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2E1 (Canada). wuest@ualberta.ca.
Frank
F
Wuest
D009327:4-Chloro-7-nitrobenzofurazan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000068579:Celecoxib / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D014018:Tissue Distribution; D000096926:Benzenesulfonamides
D009327:4-Chloro-7-nitrobenzofurazan; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D005462:Fluorine Radioisotopes; D011849:Radioactive Tracers; C000608760:N-(2-fluoroethyl)-4-(5-p-tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C000608759:N-(4-fluorobenzyl)-4-(5-p-tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide; C000608758:celecoxib-NBD
cancer; cyclooxygenases; drug design; positron emission tomography; radiochemistry