Waterhouse Rikki N, Sultana Abida, Laruelle M
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. 2002 Nov;29(8):791-4. doi: 10.1016/s0969-8051(02)00335-9.
Alterations in normal NMDA receptor composition, densities and function have been implicated in the pathophysiology of certain neurological and neuropsychiatric disorders such as Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. In our first effort to provide PET ligands for the NMDA/glycine site, we reported the synthesis of a novel high affinity glycine site ligand, 3-[2-[(3-methoxyphenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid ((3MPICA), Ki = 4.8 +/- 0.9 nM) and the corresponding carbon-11 labeled PET ligand, [11C]3MPICA. We report here the in vivo evaluation of [11C]3MPICA in rats. Biodistribution analysis revealed that [11C]3MPICA exhibited low degree of brain penetration and high blood concentration. The average uptake at two minutes was highest in the cerebellum (0.19 +/- 0.04 %ID/g) and thalamus (0.18 +/- 0.05 %ID/g) and lower in the hippocampus (0.13 +/- 0.03) and frontal cortex (0.11 +/- 0.04 %ID/g). The radioactivity cleared quickly from all brain regions examined. Administration of unlabeled 3MPICA (1 mg/kg, i.v.) revealed at 60 minutes a small general reduction in regional brain radioactivity concentrations in treated animals versus controls, however, the blood radioactivity concentration was also lowered, confounding the assessment of the degree of saturable binding. Warfarin co-administration (100 mg/kg, i.v.) significantly lowered blood activity at 5 minutes post-injection (-27%, P < 0.01) but failed to significantly increase the brain uptake of the radiotracer. In view of these results, and especially considering the low brain penetration of this tracer, [11C]3MPICA does not appear to be a promising PET radiotracer for in vivo use.
正常N-甲基-D-天冬氨酸（NMDA）受体组成、密度和功能的改变与某些神经和神经精神疾病的病理生理学有关，如帕金森病、亨廷顿舞蹈症、精神分裂症、酒精中毒和中风。在我们首次为NMDA/甘氨酸位点提供正电子发射断层扫描（PET）配体的工作中，我们报道了一种新型高亲和力甘氨酸位点配体3-[2-[(3-甲氧基苯基氨基)羰基]乙烯基]-4,6-二氯吲哚-2-羧酸（(3MPICA)，解离常数Ki = 4.8±0.9纳摩尔）以及相应的碳-11标记PET配体[11C]3MPICA的合成。我们在此报告[11C]3MPICA在大鼠体内的评估情况。生物分布分析显示，[11C]3MPICA的脑渗透程度较低且血药浓度较高。两分钟时的平均摄取量在小脑最高（0.19±0.04%注射剂量/克）和丘脑（0.18±0.05%注射剂量/克），在海马体（0.13±0.03）和额叶皮质（0.11±0.04%注射剂量/克）较低。放射性从所有检查的脑区迅速清除。静脉注射未标记的3MPICA（1毫克/千克）显示，在60分钟时，与对照组相比，治疗组动物脑区放射性浓度普遍略有降低，然而，血药放射性浓度也降低了，这使得对可饱和结合程度的评估变得复杂。共同静脉注射华法林（100毫克/千克）在注射后5分钟显著降低了血液活性（-27%，P<0.01），但未能显著增加放射性示踪剂的脑摄取量。鉴于这些结果，特别是考虑到该示踪剂的低脑渗透性，[11C]3MPICA似乎不是一种有前景的用于体内的PET放射性示踪剂。
