Comparison of rat dopamine D2 receptor occupancy for a series of antipsychotic drugs measured using radiolabeled or nonlabeled raclopride tracer

Life Sci. 2006 May 22;78(26):3007-12. doi: 10.1016/j.lfs.2005.11.031. Epub 2006 Jan 24.


Preclinical brain receptor occupancy measures have heretofore been conducted by quantifying the brain distribution of a radiolabeled tracer ligand using either scintillation spectroscopy or tomographic imaging. For smaller animals like rodents, the majority of studies employ tissue dissection and scintillation spectroscopy. These measurements can also be accomplished using liquid chromatography coupled to mass spectral detection to measure the brain distribution of tracer molecules, obviating the need for radioligands. In order to validate mass spectroscopy-based receptor occupancy methods, we examined dopamine D2 receptor dose-occupancy curves for a number of antipsychotic drugs in parallel experiments using either mass spectroscopy or radioligand-based approaches. Oral dose-occupancy curves were generated for 8 antipsychotic compounds in parallel experiments using either radiolabeled or unlabeled raclopride tracer. When curves generated by these two methods were compared and ED(50) values determined, remarkably similar data were obtained. Occupancy ED(50) values were (mg/kg): chlorpromazine, 5.1 and 2.7; clozapine, 41 and 40; haloperidol, 0.2 and 0.3; olanzapine, 2.1 and 2.2; risperidone, 0.1 and 0.4; spiperone, 0.5 and 0.4; thioridazine 9.2 and 9.5; and ziprasidone 1.4 and 2.1 (unlabeled and radiolabeled raclopride tracer, respectively). The observation that in vivo application of both techniques led to comparable data adds to the validation state of the mass spectroscopy-based approach to receptor occupancy assays.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / metabolism*
  • Cerebellum / drug effects
  • Cerebellum / metabolism
  • Chromatography, High Pressure Liquid
  • Chromatography, Liquid
  • Dopamine Antagonists* / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Male
  • Mass Spectrometry
  • Neostriatum / drug effects
  • Neostriatum / metabolism
  • Nerve Tissue Proteins / metabolism
  • Raclopride* / pharmacokinetics
  • Radiopharmaceuticals
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / metabolism*


  • Antipsychotic Agents
  • Dopamine Antagonists
  • Nerve Tissue Proteins
  • Radiopharmaceuticals
  • Receptors, Dopamine D2
  • Raclopride