DRUG RECEPTORS IN VIVO--ANIMAL MODELS AND IMAGING

药物受体很容易在体外进行研究。然而，可能会有 作为受体的环境在体内的差异可能是相当大的 不一样。因此，我们的项目之一就是研究受体。 活着。这涉及到开发研究受体的方法。 滥用药物。 RTI-121是一种有效的、选择性的多巴胺转运体类似物。 在另一份项目报告中，我们注意到该项目的无线电标记形式 化合物是一种很好的体外结合配体，它是有效的和 对多巴胺转运体有选择性。我们还表明， 碳11标记的RTI-121是一种有用的PET扫描配体 多巴胺转运体。因为它比许多其他的产品更具选择性 在配体方面，人们对RTI-121作为结合配体有很大的兴趣。 它可以用来研究成瘾过程中转运蛋白的变化 或在各种神经退行性疾病中，如帕金森氏症 疾病。 滥用药物的合理标准是它们是 长长的演技。此功能在日程安排方面提供了便利 在剂量和总体治疗效率方面。我们之前在 可以使用与放射性配体的活体受体结合竞争 为确定药物结合部位的占用时间， 相关药物。在过去的一年里，我们使用了这种PET方法 用放射性标记的可卡因扫描狒狒显示RTI-55是 很长的演技。它被绑在传送器上大约一天。这 支持这样的观点，即RTI-55或类似的物质可能是 对吸毒者有用的药物。 PET扫描和SPECT扫描是一个非常有用的程序，主要是 因为它的非侵入性。方法中的一个严重缺陷 就是缺乏细胞分辨率。因此，我们已经利用 用于研究多巴胺转运体定位的抗体 首先，用免疫组织化学方法检测大鼠体内的多巴胺转运体。 我们发现转运蛋白定位于多巴胺能神经元 预期中。然而，并不是所有的神经元组都拥有相同的 传送器数量。在中脑的多巴胺能细胞体中， 例如，多巴胺转运蛋白高度集中。通过 相比之下，在弓形核中，细胞体含有令人惊讶的 几乎没有免疫反应物质，而神经末梢区域含有 数量多。这表明转运蛋白是在细胞中制造的。 身体的速度很低，但被运送到神经末梢区域 得到保留和稳定。这些研究正在进行中，特别是 在电子显微镜层面上，我们希望找到更多的信息 这将澄清转运蛋白的细胞定位。

Drug receptors are readily studied in vitro. However, there may be differences in vivo as the environment of the receptor may be quite different. Accordingly, one of our projects is to study receptors in vivo. This involves developing methods for the study of receptors for drugs of abuse. RTI-121 is a potent and selective analog for the dopamine transporter. In another project report, we note that the radiolabeled form of this compound is an excellent in vitro binding ligand which is potent and selective for the dopamine transporter. We have also shown that carbon-11 labeled RTI-121 is useful as a PET scanning ligand for the dopamine transporter. Because of its greater selectivity than many other ligands, there is significant interest in RTI-121 as a binding ligand. It can be used to study changes in transporters during the addictive process or in various neurodegenerative diseases such as Parkinson's disease. A reasonable criteria for medications for drugs of abuse is that they be long acting. This feature allows convenience in terms of scheduling doses and in overall treatment efficiency. We previously showed that in vivo receptor binding competition with radioactive ligands could be used to establish the duration of occupancy of a drug binding site by a relevant drug. In the past year, we utilized this approach of PET scanning in baboons with radiolabeled cocaine to show that RTI-55 was very long acting. It bound to the transporter for about a day. This supports the notion that RTI-55, or a substance like it, might be a useful medication for drug abusers. PET scanning and SPECT scanning is a very useful procedure, primarily because of its noninvasive nature. A serious deficiency in the approach is the lack of cellular resolution. Accordingly, we have utilized antibodies for the dopamine transporter to study the localization of the dopamine transporter by immunohistochemical methods in, at first, rats. We find that the transporter is localized to dopaminergic neurons as expected. However, all of the neuronal groups do not possess the same amount of transporter. In the dopaminergic cell bodies in the midbrain, for example, the dopamine transporter is highly concentrated. By contrast, in the arcuate nucleus, the cell bodies contain surprisingly little immunoreactive material while the nerve terminal regions contain high quantities. This suggests that the transporter is made in the cell body at a low rate but transported to the nerve terminal region where it is retained and stabilized. These studies are ongoing, and particularly at the electron microscopic level, we hope to find additional information which will clarify the cellular localization of the transporter protein.