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

Background: Antipsychotic drugs modulate N-methyl-D-aspartate (NMDA) receptor function in animals. The novel single photon emission tomography (SPET) radiotracer [I-123]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 [I-123]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 [I-123]CNS-1261 SPET scanning. Total volume of distribution of [I-123]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 [I-123]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 [I-123]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 [I-123]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.