RADIOLIGANDS FOR CENTRAL NORADRENERGIC UPTAKE SITES

中央去甲肾上腺素能摄取位点的放射性配体

• 批准号: 3385211
• 负责人: SHANAZ MOHAMMEDALI TEJANI-BUTT
• 金额: $ 8.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3385211
• 关键词: adrenergic receptor; antidepressants; autoradiography; brain metabolism; chemical binding; chemical synthesis; laboratory rat; neurotransmitter metabolism; norepinephrine; radiopharmacology; radiotracer; receptor binding; serotonin; tritium

Much research into either biochemical abnormalities associated with depression and related psychiatric disorders or the mechanism(s) of action of psychotropic drugs has focused on brain monoamines, in particular norepinephrine and serotonin (5HT). The tricyclic antidepressants and some of the newer second generation drugs are potent inhibitors of the neuronal uptake of norepinephrine (NE) and/or serotonin. These effects are important since neuronal uptake is the primary inactivating mechanism for released monoamines and alterations in neuronal uptake may be related to the clinical action of these drugs. A major advance in recent years has been the identification of high affinity binding sites for tricyclic antidepressants, in particular, sites in the brain to which labelled imipramine binds. These binding sites have been found to be associated with uptake sites for 5HT. The development of this tool has facilitated greatly our ability to study the regulation of the 5HT uptake site and whether it shows alterations in neuropsychiatric disorders. Post-mortem samples from suicides have shown a decreased density of sites in brain compared with control samples. Also, imipramine binding sites are present on human platelets and several studies have shown a decrease in the density of these sites in depressed patients. The NE uptake site in brain has been studied far less than the uptake site for 5HT. Most probably, this is due to the absence of a suitable radioligand for this site. So far, studies have been done with labelled desipramine and more recently with labelled mazindol. Labelled desipramine is not an ideal ligand for labelling uptake sites associated with NE as it gives a high amount of non-specific binding and binds to low affinity sites in addition to high affinity sites. These low affinity sites are unrelated to NE uptake sites. Labelled mazindol is also not suitable for labelling uptake sites for NE since in most brain areas only a small proportion of its binding is to these sites. Both ligands are unsuitable for studying the NE uptake sites in vivo as the binding in vivo decreases at physiological temperatures. We propose to develop radioligands for the measurement of sites associated with the uptake of NE in the brain. Compounds selected for study have been reported previously to have high affinity and selectivity for NE uptake sites. Potential ligands will be radiolabelled with tritium to high specific activity and their binding properties will be investigated both in vitro and in vivo. In vitro binding will be assessed using both homogenate preparations and quantitative autoradiography of slide-mounted thin brain sections. If successfully developed, such a ligand would allow many types of studies to be performed on this uptake site, analogous to those reported already on the uptake site for 5HT.

对与以下疾病相关的生化异常进行了大量研究 抑郁症和相关精神疾病或作用机制 精神药物的重点是脑单胺，特别是 去甲肾上腺素和血清素（5HT）。三环类抗抑郁药和一些 较新的第二代药物是神经元的有效抑制剂 去甲肾上腺素（NE）和/或血清素的摄取。这些影响很重要 因为神经元摄取是释放的主要失活机制 单胺和神经元摄取的改变可能与 这些药物的临床作用。近年来的一个重大进展是 三环化合物高亲和力结合位点的鉴定 抗抑郁药，特别是大脑中标记的部位 丙咪嗪结合。已发现这些结合位点与 5HT 的吸收位点。这个工具的开发极大的方便了 我们研究 5HT 摄取位点调节的能力以及它是否 显示神经精神疾病的改变。尸检样本来自 与自杀者相比，自杀者大脑中的部位密度有所降低 控制样品。此外，丙咪嗪结合位点存在于人体上 血小板和一些研究表明这些血小板的密度下降 抑郁症患者的部位。 脑内 NE 摄取位点的研究远少于 NE 摄取位点 对于5HT。这很可能是由于没有合适的 该位点的放射性配体。到目前为止，研究已经完成了标记 地昔帕明和最近的标记马吲哚。标记地昔帕明 不是标记 NE 相关摄取位点的理想配体，因为它 提供大量非特异性结合并结合低亲和力位点 除了高亲和力位点。这些低亲和力位点是不相关的 到 NE 摄取位点。标记的马吲哚也不适合标记 NE 的摄取位点，因为在大多数大脑区域中只有一小部分 它的绑定是这些网站。两种配体都不适合研究 体内 NE 摄取位点在生理条件下随着体内结合减少 温度。 我们建议开发放射性配体来测量相关位点 随着大脑中 NE 的摄取。选择用于研究的化合物已 先前报道对 NE 摄取具有高亲和力和选择性 网站。潜在的配体将用氚进行放射性标记以达到高 比活性及其结合特性将在 体外和体内。将使用匀浆和匀浆评估体外结合 载玻片薄脑的制备和定量放射自显影 部分。如果成功开发，这样的配体将允许多种类型 在此摄取位点进行的研究，类似于那些 已经报道了 5HT 的吸收位点。