title: Palladium mediated ¹¹C-cyanation and characterization in the non-human primate brain of the novel mGluR5 radioligand [¹¹C]AZD9272.
abstract: BACKGROUND
  The aims of the present positron emission tomography (PET) study were to set up a system for (11)C-cyanation labeling of the selective mGluR5-antagonist [(11)C]AZD9272 and to perform the first in vivo characterization of [(11)C]AZD9272 binding in cynomolgus monkeys.
  
  
  METHODS
  [(11)C]AZD9272 was labeled using palladium mediated (11)C-cyanation. Altogether seven PET measurements were performed in three cynomolgus monkeys including baseline and co-injection experiments with unlabelled AZD9272 (0.04 and 0.4 mg/kg). Radiometabolites in plasma were measured using HPLC.
  
  
  RESULTS
  [(11)C]AZD9272 was prepared in over 50% incorporation yield from hydrogen [(11)C]cyanide in a total synthesis time of 45-50 min. The radiochemical purity of the radioligand in its final formulation was high (>99%) and the mean specific radioactivity was 47 GBq/ μmol (1278 Ci/mmol, n=7) calculated at end of bombardment (EOB). In the baseline measurements 10% of the total injected radioactivity was present in monkey brain at five minutes after i.v. injection. The radioactivity concentration was high in the caudate, cingulate gyrus and thalamus whereas it was moderate in the temporal cortex and lower for the cerebellum. After co-injection with cold AZD9272 the binding of [(11)C]AZD9272 was reduced in a dose-dependent fashion. Analysis of radiometabolites showed relatively slow metabolism and resulted only in hydrophilic radiometabolites.
  
  
  CONCLUSIONS
  A fast and efficient method was developed to label AZD9272 with (11)C. PET-examination in Cynomolgus monkeys showed that [(11)C]AZD9272 entered the brain to a high extent, that binding was saturable and that the regional radioactivity pattern was in accordance with the known distribution of mGluR5. The results support further examination of [(11)C]AZD9272 binding in human subjects.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden. j.d.andersson@ki.se
authors.forename: Jan D
authors.initials: JD
authors.lastname: Andersson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seneca
authors.forename: Phong
authors.initials: P
authors.lastname: Truong
authors.forename: David
authors.initials: D
authors.lastname: Wensbo
authors.forename: Patrick
authors.initials: P
authors.lastname: Raboisson
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D005240:Feasibility Studies; D007267:Injections; D008024:Ligands; D008252:Macaca fascicularis; D009570:Nitriles / Q000737:chemistry*; D010069:Oxadiazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010165:Palladium / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011854:Radiochemistry; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C575965:AZD9272; D002250:Carbon Radioisotopes; D008024:Ligands; D009570:Nitriles; D010069:Oxadiazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D010165:Palladium