title: Synthesis of three 18F-labelled cyclooxygenase-2 (COX-2) inhibitors based on a pyrimidine scaffold.
abstract: Cyclooxygenase (COX) is the key enzyme within the complex conversion of arachidonic acid into prostaglandins (PGs). Inhibitors of this enzyme represent a particularly promising class of compounds for chemoprevention and cancer therapy. The experimental data on the involvement of COX isoform COX-2 in tumour development and progression, as well as the observed overexpression of COX-2 in a variety of human cancers provide the rationale for targeting COX-2 for molecular imaging and therapy of cancer. A series of trifluoromethyl-substituted pyrimidines was prepared as a novel class of selective COX-2 inhibitors, based on the lead structure 1a. All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Molecular docking studies using the catalytic site of COX-1 and COX-2, respectively, provided complementary theoretical support for the obtained experimental biological structure–activity relationship data of three highly potent and selective fluorobenzyl-containing COX-2 inhibitors. Selected fluorobenzyl-substituted pyrimidine derivatives were further developed as (18)F-labelled radiotracers ([(18)F]1a, [(18)F]2a, [(18)F]3a). Radiotracers [(18)F]1a and [(18)F]2a were radiolabelled using 4-[(18)F]fluorobenzylamine ([(18)F]FBA) as a building block. Radiotracer [(18)F]3a was radiofluorinated directly using a nucleophilic aromatic substitution reaction with no-carrier-added (n.c.a.) [(18)F]fluoride on an iodylaryl compound as a labelling precursor.
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Canada. wuest@ualberta.ca.
authors.forename: Ole
authors.initials: O
authors.lastname: Tietz
authors.forename: Sai Kiran
authors.initials: SK
authors.lastname: Sharma
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.forename: Jenilee
authors.initials: J
authors.lastname: Way
authors.forename: Alison
authors.initials: A
authors.lastname: Marshall
authors.forename: Melinda
authors.initials: M
authors.lastname: Wuest
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
mesh_terms: D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D012756:Sheep; D013329:Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D005462:Fluorine Radioisotopes; D011743:Pyrimidines; D011994:Recombinant Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C030986:pyrimidine