Waterhouse Rikki N, Slifstein Mark, Dumont Filip, Zhao Jun, Chang Raymond C, Sudo Yasuhiko, Sultana Abida, Balter Andrew, Laruelle Marc
Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY 10032, USA.
Nucl Med Biol. 2004 Oct;31(7):939-48. doi: 10.1016/j.nucmedbio.2004.03.012.
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.
开发用于测量NMDA离子通道激活变化的成像方法，将为探究药物和基于设备的治疗（如ECT）改变谷氨酸神经传递的机制提供有力手段。为了提供一种潜在的NMDA/PCP受体PET示踪剂，我们合成了放射性配体[11C]GMOM（Ki = 5.2±0.3 nM；log P = 2.34），并在清醒雄性大鼠和异氟烷麻醉的狒狒体内对该配体进行了评估。在大鼠中，[11C]GMOM在脑区的摄取量范围从延髓和脑桥的0.75±0.13% ID/g到枕叶皮质的1.15±0.17% ID/g。静脉注射MK801（1 mg/kg）可使所有脑区的[11C]GMOM摄取量显著降低（24 - 28%）。静脉注射D-丝氨酸（10 mg/kg）可使所有脑区的[11C]GMOM %ID/g值升高（10 - 24%），仅在额叶皮质和小脑中达到显著水平。NR2B配体RO 25 - 6981（10 mg/kg静脉注射）可使除小脑和纹状体以外的所有脑区的[11C]GMOM摄取量显著降低（24 - 38%）。对照组的血液活性为0.11±0.03 %ID/g，各组间无显著差异。用高比活度的[11C]GMOM对异氟烷麻醉的狒狒进行PET成像，得到的脑区分布容积（VT）值相当均匀（12.8 - 17.1 ml g-1）。静脉注射MK801（0.5 mg/kg，n = 1，和1.0 mg/kg，n = 1）未显著改变脑区VT值，表明不存在饱和结合。然而，必须考虑与氯胺酮诱导麻醉及异氟烷维持麻醉相关的潜在混杂效应，因为已知这两种药物都会降低NMDA离子通道的激活。未来将开展精心设计的研究，可能会使用优化的NMDA/PCP位点示踪剂，以进一步探究这些假设。我们得出结论，尽管[11C]GMOM不是一种优化的PCP位点放射性示踪剂，但正如MK801、D-丝氨酸或RO 25 - 6981对NMDA离子通道活性的调节所预期的那样，其在清醒大鼠体内的结合会发生改变。更高亲和力的NMDA/PCP位点放射性配体的开发正在进行中。
