Discrepancies in Kappa Opioid Agonist Binding Revealed through PET Imaging

ACS Chem Neurosci. 2019 Jan 16;10(1):384-395. doi: 10.1021/acschemneuro.8b00293. Epub 2018 Oct 17.


Kappa opioid receptor (KOR) modulation has been pursued in many conceptual frameworks for the treatment of human pain, depression, and anxiety. As such, several imaging tools have been developed to characterize the density of KORs in the human brain and its occupancy by exogenous drug-like compounds. While exploring the pharmacology of KOR tool compounds using positron emission tomography (PET), we observed discrepancies in the apparent competition binding as measured by changes in binding potential (BPND, binding potential with respect to non-displaceable uptake). This prompted us to systematically look at the relationships between baseline BPND maps for three common KOR PET radioligands, the antagonists [11C]LY2795050 and [11C]LY2459989, and the agonist [11C]GR103545. We then measured changes in BPND using kappa antagonists (naloxone, naltrexone, LY2795050, JDTic, nor-BNI), and found BPND was affected similarly between [11C]GR103545 and [11C]LY2459989. Longitudinal PET studies with nor-BNI and JDTic were also examined, and we observed a persistent decrease in [11C]GR103545 BPND up to 25 days after drug administration for both nor-BNI and JDTic. Kappa agonists were also administered, and butorphan and GR89696 (racemic GR103545) impacted binding to comparable levels between the two radiotracers. Of greatest significance, kappa agonists salvinorin A and U-50488 caused dramatic reductions in [11C]GR103545 BPND but did not change [11C]LY2459989 binding. This discrepancy was further examined in dose-response studies with each radiotracer as well as in vitro binding experiments.

Keywords: PET; [11C]GR103545; [11C]LY2459989; kappa agonist; kappa antagonist; kappa opioid receptor.

Publication types

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

MeSH terms

  • Analgesics, Opioid / metabolism*
  • Animals
  • Benzamides / metabolism*
  • Benzamides / pharmacology
  • Binding, Competitive / drug effects
  • Binding, Competitive / physiology
  • Carbon Radioisotopes / metabolism*
  • Carbon Radioisotopes / pharmacology
  • Dose-Response Relationship, Drug
  • Male
  • Positron-Emission Tomography / methods*
  • Pyrrolidines / metabolism*
  • Pyrrolidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, kappa / agonists*
  • Receptors, Opioid, kappa / metabolism*


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