Despite irreversible binding, PET tracer [11C]-SA5845 is suitable for imaging of drug competition at sigma receptors-the cases of ketamine and haloperidol

Neurochem Int. 2008 Jul;53(1-2):45-50. doi: 10.1016/j.neuint.2008.04.010. Epub 2008 May 13.

Abstract

Many psychotropic compounds bind to sigma receptors and several new sigma ligands are in development for psychiatric indications such as anxiety, attention deficit hyperactivity disorder, depression and psychosis. Of special interest for drug development are tomographic methods that can quantify the binding of promising sigma ligands in a regional manner. Here we present the development of such a method and the first evaluation of sigma ligand [11C]-SA5845 in a primate. Extensive pharmacokinetic modeling was done on tissue curves and a heart lumen curve. The effects of pretreatment and challenge with haloperidol were studied as well as those of pretreatment with +/- -ketamine. The tracer had a plasma half-life of 77+/-1.7min and was rapidly taken up by all brain areas. The binding pattern was consistent with binding to sigma receptors and compartment modeling showed there was considerable specific binding that was irreversible. We therefore calculated the net influx rate, Ki, with the Gjedde-Patlak linearization, as a measure of free receptors. As expected, Ki was very sensitive to the presence of competing ligands - -ketamine and/or haloperidol. Summarizing, the tracer is well suited for visualizing sigma receptors in the brain and moreover, the presented method is able to quantify, on a regional basis, specific binding of unlabeled ligands to sigma receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Anesthesia
  • Anesthetics, Dissociative / metabolism
  • Animals
  • Antipsychotic Agents / metabolism*
  • Binding, Competitive / drug effects
  • Brain / diagnostic imaging
  • Excitatory Amino Acid Antagonists / metabolism*
  • Half-Life
  • Haloperidol / metabolism*
  • Ketamine / metabolism*
  • Ligands
  • Macaca mulatta
  • Male
  • Models, Statistical
  • Piperazines* / pharmacokinetics
  • Positron-Emission Tomography
  • Radiopharmaceuticals* / pharmacokinetics
  • Receptors, sigma / metabolism*
  • Whole-Body Counting

Substances

  • Anesthetics, Dissociative
  • Antipsychotic Agents
  • Excitatory Amino Acid Antagonists
  • Ligands
  • Piperazines
  • Radiopharmaceuticals
  • Receptors, sigma
  • SA5845
  • Ketamine
  • Haloperidol