Synthesis and biological evaluation of [¹¹C]AZ12504948; a novel tracer for imaging of glucokinase in pancreas and liver

M Jahan; P Johnström; S Nag; A Takano; O Korsgren; L Johansson; C Halldin; O Eriksson

doi:10.1016/j.nucmedbio.2014.12.003

Synthesis and biological evaluation of [¹¹C]AZ12504948; a novel tracer for imaging of glucokinase in pancreas and liver

Nucl Med Biol. 2015 Apr;42(4):387-94. doi: 10.1016/j.nucmedbio.2014.12.003. Epub 2014 Dec 6.

Authors

M Jahan¹, P Johnström², S Nag³, A Takano³, O Korsgren⁴, L Johansson⁵, C Halldin³, O Eriksson⁶

Affiliations

¹ 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.
² 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.
³ Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research and Education, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
⁴ Department of Immunology, Genetics and Pathology, Division of Immunology, Uppsala University, SE 751 87 Uppsala, Sweden.
⁵ AstraZeneca R&D, SE 431 50, Mölndal, Sweden.
⁶ Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, SE 751 87 Uppsala, Sweden.

PMID: 25633247
DOI: 10.1016/j.nucmedbio.2014.12.003

Abstract

Introduction: 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.

Result: [(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.

Conclusion: [(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.

Keywords: Beta cell imaging; Glucokinase activator (GKA); Islet imaging; Positron emission tomography (PET).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azetidines / chemical synthesis*
Azetidines / chemistry
Benzamides / chemical synthesis*
Benzamides / chemistry
Chemistry Techniques, Synthetic
Enzyme Activators / chemical synthesis*
Enzyme Activators / chemistry
Glucokinase / metabolism*
Humans
Liver / diagnostic imaging
Liver / enzymology*
Macaca fascicularis
Male
Molecular Imaging / methods*
Pancreas / diagnostic imaging
Pancreas / enzymology*
Positron-Emission Tomography
Radioactive Tracers
Radiochemistry
Swine
Tomography, X-Ray Computed

Substances

AZ12504948
Azetidines
Benzamides
Enzyme Activators
Radioactive Tracers
azetidine
Glucokinase