title: Design and synthesis of [(125)I]Pyricoxib: A novel (125)I-labeled cyclooxygenase-2 (COX-2) inhibitors.
abstract: Cyclooxygenase-2 (COX-2) is the key enzyme in the prostaglandin synthesis pathway which is involved in various pathophysiological conditions. The enzyme is membrane bound and located inside of the endoplasmic reticulum and nuclear membrane. Effective perfusion of inhibitors to the active site requires lipophilic drugs, which consequently display high unspecific background accumulation, for example, in fatty tissues. The objective of this work was the development of a small molecule radiolabeled with a long-lived iodine radioisotope to enable longer imaging times and better target-to-background ratios. A group of iodinated compounds (8-10) was synthesized and identified as selective COX-2 inhibitors (COX-2 IC50=0.85-13 μM). Molecular docking results provided the theoretical support for the experimental COX-2 inhibition data. Furthermore, a novel (125)I-containing trifluoro-pyrimidine compound ([(125)I]Pyricoxib) was prepared via radioiododestannylation reaction as potent and selective COX-2 inhibitor. Radiosynthesis of [(125)I]Pyricoxib was accomplished with innovative fluorous chemistry using fluorous chloroamine-T (F-CAT) as novel oxidizing agent in high radiochemical yields of 91 ± 4%.
authors.affiliation: Department of Oncology, University of Alberta, Canada.
authors.forename: Ole
authors.initials: O
authors.lastname: Tietz
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Dzandzi
authors.affiliation: Department of Oncology, University of Alberta, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Canada.
authors.forename: Atul
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Canada.
authors.forename: John F
authors.initials: JF
authors.lastname: Valliant
authors.affiliation: Department of Oncology, University of Alberta, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Canada. Electronic address: wuest@ualberta.ca.
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
mesh_terms: D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007457:Iodine Radioisotopes; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007457:Iodine Radioisotopes; D011743:Pyrimidines; D013450:Sulfones; C000611968:pyricoxib; D051546:Cyclooxygenase 2
keywords: Cyclooxygenase-2; Fluorous chemistry; Iodine-125