In vivo evaluation of [11C]N-(2-chloro-5-thiomethylphenyl)-N'-(3-methoxy-phenyl)-N'-methylguanidine ([11C]GMOM) as a potential PET radiotracer for the PCP/NMDA receptor.

The development of imaging methods to measure changes in NMDA ion channel activation would provide a powerful means to probe the mechanisms of drugs and device based treatments (e.g., ECT) thought to alter glutamate neurotransmission. To provide a potential NMDA/PCP receptor PET tracer, we synthesized the radioligand [11C]GMOM (ki = 5.2 +/-0.3 nM; log P = 2.34) and evaluated this ligand in vivo in awake male rats and isoflurane anesthetized baboons. In rats, the regional brain uptake of [11C]GMOM ranged from 0.75+/-0.13% ID/g in the medulla and pons to 1.15+/-0.17% ID/g in the occipital cortex. MK801 (1 mg/kg i.v.) significantly reduced (24-28%) [11C]GMOM uptake in all regions. D-serine (10 mg/kg i.v.) increased [11C]GMOM %ID/g values in all regions (10-24%) reaching significance in the frontal cortex and cerebellum only. The NR2B ligand RO 25-6981 (10 mg/kg i.v.) reduced [11C]GMOM uptake significantly (24-38%) in all regions except for the cerebellum and striatum. Blood activity was 0.11+/-0.03 %ID/g in the controls group and did not vary significantly across groups. PET imaging in isoflurane-anesthetized baboons with high specific activity [11C]GMOM provided fairly uniform regional brain distribution volume (VT) values (12.8-17.1 ml g(-1)). MK801 (0.5 mg/kg, i.v., n = 1, and 1.0 mg/kg, i.v., n = 1) did not significantly alter regional VT values, indicating a lack of saturable binding. However, the potential confounding effects associated with ketamine induction of anesthesia along with isoflurane maintenance must be considered because both agents are known to reduce NMDA ion channel activation. Future and carefully designed studies, presumably utilizing an optimized NMDA/PCP site tracer, will be carried out to further explore these hypotheses. We conclude that, even though [11C]GMOM is not an optimized PCP site radiotracer, its binding is altered in vivo in awake rats as expected by modulation of NMDA ion channel activity by MK801, D-serine or RO 25-6981. The development of higher affinity NMDA/PCP site radioligands is in progress.