RADIOLIGANDS FOR CENTRAL NORADRENERGIC UPTAKE SITES

对与以下两种疾病相关的生化异常的大量研究 抑郁症及其相关精神障碍或作用机制(S) 精神药物的研究主要集中在大脑中的单胺类药物 去甲肾上腺素和5-羟色胺(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物 摄取去甲肾上腺素(NE)和/或5-羟色胺。这些影响是重要的 由于神经元摄取是释放的主要失活机制 单胺类物质和神经元摄取的改变可能与 这些药物的临床作用。近年来的一项重大进展是 三环化合物高亲和力结合部位的鉴定 抗抑郁药，尤其是大脑中标记的位置 丙咪嗪结合在一起。这些结合位点已被发现与 5-羟色胺的摄取部位。该工具的开发极大地方便了用户的使用 我们研究5-羟色胺摄取部位调节的能力以及它是否 显示了神经精神障碍的变化。验尸样本来自 与自杀者相比，自杀者大脑中的部位密度降低 对照样品。此外，丙咪嗪结合位点也存在于人类身上。 血小板和几项研究表明，这些细胞的密度下降 抑郁症患者的网站。 对脑内NE摄取部位的研究远远少于对摄取部位的研究 对于5HT来说。很可能，这是由于没有合适的 这个部位的放射性配基。到目前为止，已经对LABLED进行了研究 地昔帕明，以及最近标记的马吲哚。标记地昔帕明 不是标记NE相关摄取部位的理想配体，因为它 提供大量的非特异性结合，并结合到低亲和力部位 除了高亲和力的站点。这些低亲和力的站点是无关的 到NE摄取部位。标记的马吲哚也不适合贴标签 去甲肾上腺素的摄取部位，因为在大多数大脑区域只有一小部分 它与这些位点结合。这两种配体都不适合研究 体内摄取Ne的部位随着生理状态下体内结合量的减少而减少 温度。 我们建议开发放射性配基来测量相关部位 与大脑中NE的摄取有关。选择进行研究的化合物已经被 先前报道对去甲肾上腺素摄取具有高亲和力和选择性 网站。潜在的配体将被放射性标记为氚到高 特定的活性和它们的结合性质将在 体外和体内。体外结合将使用两种匀浆进行评估 载玻片薄脑的制备及定量放射自显影 横断面。如果开发成功，这样的配体将允许许多类型 在这个摄取部位进行的研究，类似于 已经有关于5-羟色胺摄取部位的报道。

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.