title: Synthesis and biological evaluation of [¹¹C]AZ12504948; a novel tracer for imaging of glucokinase in pancreas and liver.
abstract: BACKGROUND
  Glucokinase (GK) is potentially a target for imaging of islets of Langerhans. Here we report the radiosynthesis and preclinical evaluation of the GK activator, [(11)C]AZ12504948, for in vivo imaging of GK.
  
  
  METHODS
  [(11)C]AZ12504948 was synthesized by O-methylation of the precursor, AZ125555620, using carbon-11 methyl iodide ([(11)C]CH₃I). Preclinical evaluation was performed by autoradiography (ARG) of human tissues and PET/CT studies in pig and non-human primate.
  
  
  RESULTS
  [(11)C]AZ12504948 was produced in reproducible good radiochemical yield in 28-30 min. Radiochemical purity of the formulated product was >98% for up to 2 h with specific radioactivities 855 ± 209 GBq/μmol (n=8). The preclinical evaluation showed some specificity for GK in liver, but not in pancreas.
  
  
  CONCLUSIONS
  [(11)C]AZ12504948 images GK in liver, but the low specificity impedes the visualization of GK in pancreas. Improved target specificity is required for further progress using PET probes based on this class of GK activators.
authors: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research and Education, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Electronic address: mahabuba.jahan@ki.se.
authors: M
authors: M
authors: Jahan
authors: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research and Education, Karolinska University Hospital, SE-171 76 Stockholm, Sweden; AstraZeneca Translational Science Centre at Karolinska Institutet, SE-171 76, Stockholm, Sweden.
authors: P
authors: P
authors: Johnström
authors: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research and Education, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: S
authors: S
authors: Nag
authors: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research and Education, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: A
authors: A
authors: Takano
authors: Department of Immunology, Genetics and Pathology, Division of Immunology, Uppsala University, SE 751 87 Uppsala, Sweden.
authors: O
authors: O
authors: Korsgren
authors: AstraZeneca R&D, SE 431 50, Mölndal, Sweden.
authors: L
authors: L
authors: Johansson
authors: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research and Education, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: C
authors: C
authors: Halldin
authors: Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, SE 751 87 Uppsala, Sweden.
authors: O
authors: O
authors: Eriksson
mesh_terms: D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000737:chemistry; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000000981:diagnostic imaging / Q000201:enzymology*; D008252:Macaca fascicularis; D008297:Male; D057054:Molecular Imaging / Q000379:methods*; D010179:Pancreas / Q000000981:diagnostic imaging / Q000201:enzymology*; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D011854:Radiochemistry; D013552:Swine; D014057:Tomography, X-Ray Computed
chemical_list: C000604640:AZ12504948; D001384:Azetidines; D001549:Benzamides; D020536:Enzyme Activators; D011849:Radioactive Tracers; C082735:azetidine; D005941:Glucokinase
keywords: Beta cell imaging; Glucokinase activator (GKA); Islet imaging; Positron emission tomography (PET)