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In Vivo [I-123]CNS-1261 Binding to D-Serine-Activated and MK801-Blocked NMDA Receptors: A Storage Phosphor Imaging Study in Rats

Author(s): R. J. J. Knol, K. de Bruin, B. L. F. van Eck-Smit, S. Pimlott, D. J. Wyper, J. Booij

Abstract:
Disturbances of activity of the glutamatergic neurotransmitter system in the brain are present in many neuropsychiatric disorders. The N-methyl-D-aspartate (NMDA) receptor is the most abundant receptor of the glutamatergic system. In the neurodegenerative events of Alzheimer's disease, excessive activation of NMDA receptors may contribute to neuronal death. Inhibition of NMDA receptor activation may have neuroprotective effects and (semi)quantitative imaging of the activated system may help in the selection of patients for such inhibition therapies. In this study we evaluated [I-123]CNS-1261 binding in the rat brain. This radiotracer binds in vivo to the MK801 binding site of activated NMDA receptors. To determine the optimal time point for ex vivo assessments after bolus injection [I-123]CNS-1261 binding in rats, we performed a time course biodistribution study using dissection techniques. [I-123]CNS-1261 binding was also studied in the rat brain using autoradiography by means of storage phosphor imaging, with prior facilitation of NMDA receptor activation by injection of the potent coagonist D-serine and after blocking of the NMDA receptor binding site by MK801 injection in D-serine pretreated rats. Measurements of [I-123]CNS-1261 uptake matched the distribution of similar tracers for the MK801 binding site of the NMDA receptor and revealed an optimal time point of 2 h post injection for the assessment of tracer distribution in the rat brain. The blocking experiments indicated specific binding of [I-123]CNS-1261 to NMDA receptors but also a considerable amount of nonspecific binding. Facilitation of NMDA receptor activation by D-serine did not result in an enhancement of binding of the radiotracer in the NMDA receptor-rich rat hippocampus compared to the untreated group, as measured by autoradiography. In conclusion, our study has shown that [I-123]CNS-1261 binding is influenced by NMDA receptor availability. However, high nonspecific binding limits quantification and small changes in receptor availability are unlikely to be detected. Synapse 63:557-564, 2009. (C) 2009 Wiley-Liss, Inc.

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ISBN: 0887-4476
Publication Year: 2009
Periodical: Synapse
Periodical Number: 7
Volume: 63
Pages: 557-564
Author Address: