Determination of the in vivo selectivity of a new κ-opioid receptor antagonist PET tracer 11C-LY2795050 in the rhesus monkey

J Nucl Med. 2013 Sep;54(9):1668-74. doi: 10.2967/jnumed.112.118877. Epub 2013 Aug 5.


(11)C-LY2795050 is a novel κ-selective antagonist PET tracer. The in vitro binding affinities (Ki) of LY2795050 at the κ-opioid (KOR) and μ-opioid (MOR) receptors are 0.72 and 25.8 nM, respectively. Thus, the in vitro KOR/MOR binding selectivity is about 36:1. Our goal in this study was to determine the in vivo selectivity of this new KOR antagonist tracer in the monkey.

Methods: To estimate the ED50 value (dose of a compound [or drug] that gives 50% occupancy of the target receptor) of LY2795050 at the MOR and KOR sites, 2 series of blocking experiments were performed in 3 rhesus monkeys using (11)C-LY2795050 and (11)C-carfentanil with coinjections of various doses of unlabeled LY2795050. Kinetic modeling was applied to calculate regional binding potential (BP(ND)), and 1- and 2-site binding curves were fitted to these data to measure (11)C-LY2795050 binding selectivity.

Results: The LY2795050 ED50 at MOR was 119 μg/kg based on a 1-site model for (11)C-carfentanil. The 1-site binding model was also deemed sufficient to describe the specific binding of (11)C-LY2795050 at KOR. The ED50 at KOR estimated from the 1-site model was 15.6 μg/kg. Thus, the ED50 ratio for MOR:KOR was 7.6.

Conclusion: The in vivo selectivity of (11)C-LY2795050 for KOR over MOR is 7.6. (11)C-LY2795050 has 4.7-fold-lower selectivity at KOR over MOR in vivo as compared with in vitro. Nevertheless, on the basis of our finding in vivo, 88% of the PET-observed specific binding of (11)C-LY2795050 under baseline conditions will be due to binding of the tracer at the KOR site in a region with similar prevalence of KOR and MOR. (11)C-LY2795050 is sufficiently selective for KOR over MOR in vivo to be considered an appropriate probe for studying the KOR with PET.

Keywords: PET; in vivo; selectivity; κ-opioid receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacokinetics*
  • Brain / diagnostic imaging*
  • Brain / metabolism*
  • Computer Simulation
  • Image Interpretation, Computer-Assisted / methods*
  • Macaca mulatta
  • Metabolic Clearance Rate
  • Models, Biological
  • Positron-Emission Tomography / methods*
  • Pyrrolidines / pharmacokinetics*
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacokinetics
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, kappa / metabolism*
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Tissue Distribution


  • 3-chloro-4-(4-((2-(3-pyridyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide
  • Benzamides
  • Pyrrolidines
  • Radiopharmaceuticals
  • Receptors, Opioid, kappa