Impact of schizophrenia and chronic antipsychotic treatment on [123I]CNS-1261 binding to N-methyl-D-aspartate receptors in vivo

Biol Psychiatry. 2005 Jul 1;58(1):41-6. doi: 10.1016/j.biopsych.2005.03.016.

Abstract

Background: Antipsychotic drugs modulate N-methyl-D-aspartate (NMDA) receptor function in animals. The novel single photon emission tomography (SPET) radiotracer [123I]CNS-1261 binds to the PCP/MK-801 intrachannel site of the NMDA receptor, allowing the noninvasive estimation of NMDA receptor activity in living humans. We used [123I]CNS-1261 to determine whether binding to the NMDA receptor intrachannel PCP/MK-801 site is affected by schizophrenia or by treatment with typical antipsychotics and clozapine in vivo.

Methods: Three groups of schizophrenia patients were recruited-drug free (n = 5), typical antipsychotic treated (n = 7), and clozapine treated (n = 9)-as well as a control group of healthy normal volunteers (n = 13). All underwent [123I]CNS-1261 SPET scanning. Total volume of distribution of [123I]CNS-1261 was determined within predefined user-independent regions of interest after alignment of all images to a common template.

Results: There was no apparent difference in total volume of distribution of [123I]CNS-1261 in drug-free patients relative to healthy control subjects. A nonsignificant reduction in total volume of distribution was observed in typical antipsychotic treated patients. A significant decline in total volume of distribution of [123I]CNS-1261 was observed in all examined brain regions in the clozapine-treated patient group relative to healthy control subjects (p < .005).

Conclusions: Clozapine treatment resulted in a global reduction in [123I]CNS-1261 binding to the NMDA receptor intrachannel PCP/MK-801 site in vivo. This supports an effect of the drug on glutamatergic systems that could be exploited for future antipsychotic drug discovery.

Publication types

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

MeSH terms

  • Adult
  • Antipsychotic Agents / pharmacology*
  • Antipsychotic Agents / therapeutic use
  • Clozapine / pharmacology
  • Clozapine / therapeutic use
  • Dose-Response Relationship, Drug
  • Female
  • Guanidines* / metabolism
  • Humans
  • Iodine Radioisotopes* / metabolism
  • Male
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Schizophrenia / diagnostic imaging*
  • Schizophrenia / drug therapy*
  • Schizophrenia / physiopathology
  • Tomography, Emission-Computed, Single-Photon

Substances

  • Antipsychotic Agents
  • CNS 1261
  • Guanidines
  • Iodine Radioisotopes
  • Receptors, N-Methyl-D-Aspartate
  • Clozapine