title: Development of indazolylpyrimidine derivatives as high-affine EphB4 receptor ligands and potential PET radiotracers.
abstract: Due to their essential role in the pathogenesis of cancer, members of the Eph (erythropoietin-producing hepatoma cell line-A2) receptor tyrosine kinase family represent promising candidates for molecular imaging. Thus, the development and preparation of novel radiotracers for the noninvasive imaging of the EphB4 receptor via positron emission tomography (PET) is described. First in silico investigations with the indazolylpyrimidine lead compound which is known to be highly affine to EphB4 were executed to identify favorable labeling positions for an introduction of fluorine-18 to retain the affinity. Based on this, reference compounds as well as precursors were developed and labeled with carbon-11 and fluorine-18, respectively. For this purpose, a protecting group strategy essentially had to be generated to prevent unwanted methylation and to enable the introduction of fluorine-18. Further, a convenient radiolabeling strategy using [(11)C]methyl iodide was established which afforded the isotopically labeled radiotracer in 30-35% RCY (d.c.) which is identical with the original inhibitor molecule. A spiro ammonium precursor was prepared for radiolabeling with fluorine-18. Unfortunately, the labeling did not lead to the desired (18)F-radiotracer under the chosen conditions.
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Bautzner Landstraße 400, D-01328 Dresden, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ebert
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Bautzner Landstraße 400, D-01328 Dresden, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Wiemer
authors.affiliation: Universidad de Talca, Centro de Bioinformática y Simulación Molecular, 2 Norte 685, Casilla 721, Talca, Chile.
authors.forename: Julio
authors.initials: J
authors.lastname: Caballero
authors.affiliation: Universität Rostock, Institut für Chemie, Anorganische Festkörperchemie, Albert-Einstein-Straße 3a, D-18057 Rostock, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Köckerling
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Bautzner Landstraße 400, D-01328 Dresden, Germany; TU Dresden, Fachbereich Chemie und Lebensmittelchemie, D-01062 Dresden, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Bautzner Landstraße 400, D-01328 Dresden, Germany; TU Dresden, Fachbereich Chemie und Lebensmittelchemie, D-01062 Dresden, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Bautzner Landstraße 400, D-01328 Dresden, Germany; TU Dresden, Fachbereich Chemie und Lebensmittelchemie, D-01062 Dresden, Germany. Electronic address: c.mamat@hzdr.de.
authors.forename: Constantin
authors.initials: C
authors.lastname: Mamat
mesh_terms: D005462:Fluorine Radioisotopes / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000737:chemistry*; D036224:Receptor, EphB4
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D036224:Receptor, EphB4
keywords: Carbon-11; Eph receptor; Fluorine-18; In silico studies; Radiolabeling; Spiro precursor