Knol Remco J J, de Bruin Kora, van Eck-Smit Berthe L F, Pimlott Sally, Wyper David J, Booij Jan
Department of Nuclear Medicine, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.
Synapse. 2009 Jul;63(7):557-64. doi: 10.1002/syn.20629.
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 [(123)I]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 [(123)I]CNS-1261 binding in rats, we performed a time course biodistribution study using dissection techniques. [(123)I]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 [(123)I]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 [(123)I]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 [(123)I]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.
大脑中谷氨酸能神经递质系统的活性紊乱存在于许多神经精神疾病中。N-甲基-D-天冬氨酸（NMDA）受体是谷氨酸能系统中最丰富的受体。在阿尔茨海默病的神经退行性病变中，NMDA受体的过度激活可能导致神经元死亡。抑制NMDA受体激活可能具有神经保护作用，对激活系统进行（半）定量成像可能有助于选择适合此类抑制疗法的患者。在本研究中，我们评估了[(123)I]CNS-1261在大鼠脑中的结合情况。这种放射性示踪剂在体内与激活的NMDA受体的MK801结合位点结合。为了确定推注[(123)I]CNS-1261后大鼠体内进行离体评估的最佳时间点，我们使用解剖技术进行了时间进程生物分布研究。还通过储存磷光成像放射自显影术在大鼠脑中研究了[(123)I]CNS-1261的结合情况，在注射强效共激动剂D-丝氨酸促进NMDA受体激活之前以及在D-丝氨酸预处理的大鼠中注射MK801阻断NMDA受体结合位点之后进行研究。[(123)I]CNS-1261摄取量的测量结果与用于NMDA受体MK801结合位点的类似示踪剂的分布情况相符，并揭示了注射后2小时是评估大鼠脑中示踪剂分布的最佳时间点。阻断实验表明[(123)I]CNS-1261与NMDA受体有特异性结合，但也存在相当数量的非特异性结合。通过放射自显影术测量，与未处理组相比，D-丝氨酸促进NMDA受体激活并未导致富含NMDA受体的大鼠海马体中放射性示踪剂结合增加。总之，我们的研究表明[(123)I]CNS-1261的结合受NMDA受体可用性的影响。然而，高非特异性结合限制了定量，并且不太可能检测到受体可用性的微小变化。
