title: Formation of fluorine-18 labeled diaryl ureas--labeled VEGFR-2/PDGFR dual inhibitors as molecular imaging agents for angiogenesis.
abstract: Urea subunits are common components of various pharmaceuticals' core structure. Since in most cases the design and development of PET biomarkers is based on approved or potential drugs, there is a growing need for a general labeling methodology of urea-containing pharmacophores. As a part of research in the field of molecular imaging of angiogenic processes, we synthesized several highly potent VEGFR-2/PDGFR dual inhibitors as potential PET biomarkers. The structure of these inhibitors is based on the N-phenyl-N'-{4-(4-quinolyloxy)phenyl}urea skeleton. A representative inhibitor was successfully labeled with fluorine-18 by a three-step process. Initially, a two-step radiosynthesis of 4-[(18)F]fluoro-aniline from 1,4-dinitrobenzene (60min, EOB decay corrected yield: 63%) was performed. At the third and final step, the 4-[(18)F]fluoro-aniline synthon reacted for 30min at room temperature with 4-(2-fluoro-4-isocyanato-phenoxy)-6,7-dimethoxy-quinoline to give complete conversion of the labeled synthon to 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(4-[(18)F]fluoro-phenyl)-urea. The desired labeled product was obtained after total radiosynthesis time of 3h including HPLC purification with 46+/-1% EOB decay corrected radiochemical yield, 99% radiochemical purity, 99% chemical purity, and a specific activity of 400+/-37GBq/mmol (n=5).
authors.affiliation: Department of Medical Biophysics and Nuclear Medicine, Hadassah Hebrew University Hospital, Jerusalem 91120, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Ilovich
authors.forename: O
authors.initials: O
authors.lastname: Jacobson
authors.forename: Y
authors.initials: Y
authors.lastname: Aviv
authors.forename: A
authors.initials: A
authors.lastname: Litchi
authors.forename: R
authors.initials: R
authors.lastname: Chisin
authors.forename: E
authors.initials: E
authors.lastname: Mishani
mesh_terms: D002219:Carbamates / Q000737:chemistry; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D017953:Isocyanates / Q000737:chemistry; D007553:Isotope Labeling; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000175:diagnosis / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014508:Urea / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002219:Carbamates; D005462:Fluorine Radioisotopes; D007093:Imidazoles; D017953:Isocyanates; D047428:Protein Kinase Inhibitors; C029899:imidazole; D014508:Urea; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2