A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066 - estimating occupancy in the absence of a reference region

Neuroimage. 2013 Nov 15;82:160-9. doi: 10.1016/j.neuroimage.2013.05.006. Epub 2013 May 11.


AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [(11)C]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived from each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret.

Keywords: Nonlinear mixed effects modelling; Positron emission tomography; Receptor occupancy; [(11)C]-ABP688; mGluR5 receptor.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Analgesics / pharmacokinetics*
  • Anti-Anxiety Agents / pharmacokinetics*
  • Brain / diagnostic imaging*
  • Brain / drug effects*
  • Carbon Radioisotopes
  • Healthy Volunteers
  • Humans
  • Isoxazoles / pharmacokinetics*
  • Male
  • Middle Aged
  • Oximes
  • Positron-Emission Tomography
  • Pyridines
  • Radiopharmaceuticals
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
  • Triazoles / pharmacokinetics*
  • Young Adult


  • 3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime
  • AZD2066
  • Analgesics
  • Anti-Anxiety Agents
  • Carbon Radioisotopes
  • GRM5 protein, human
  • Isoxazoles
  • Oximes
  • Pyridines
  • Radiopharmaceuticals
  • Receptor, Metabotropic Glutamate 5
  • Triazoles