DRUG RECEPTORS IN VIVO--ANIMAL MODELS AND IMAGING

药物受体很容易在体外研究。 然而， 体内的差异，因为受体的环境可能相当 不同. 因此，我们的一个项目是研究受体， vivo. 这涉及开发研究受体的方法， 滥用药物。 RTI-121是多巴胺转运蛋白的有效和选择性类似物。 在另一个项目报告中，我们注意到， 化合物是一种优良的体外结合配体， 对多巴胺转运蛋白有选择性 我们还表明， 碳-11标记的RTI-121可用作PET扫描配体， 多巴胺转运体 由于其比许多其他的选择性更大， 作为结合配体，RTI-121作为结合配体具有显著的兴趣。 它可用于研究成瘾过程中转运蛋白的变化 过程或各种神经退行性疾病，例如帕金森氏症 疾病 药物滥用药物的合理标准是， 长效 该功能在调度方面提供了便利 剂量和总体治疗效率。 我们先前表明，在 可以使用与放射性配体的体内受体结合竞争 为了确定药物结合位点被药物结合位点的持续时间， 相关药物。 在过去的一年里，我们利用PET的这种方法， 用放射性标记的可卡因扫描狒狒，显示RTI-55是 非常长的表演。 它和传送器绑定了一天左右。 这 支持RTI-55或类似物质可能是一种 对药物滥用者有用的药物。 PET扫描和SPECT扫描是非常有用的程序，主要 因为它的非侵入性。 方法的严重缺陷 是缺乏细胞分辨率。 因此，我们利用 多巴胺转运蛋白的抗体，以研究多巴胺转运蛋白的定位。 多巴胺转运蛋白的免疫组织化学方法，首先，大鼠。 我们发现转运蛋白定位于多巴胺能神经元， 预期 然而，并非所有的神经元都具有相同的功能。 运输量。 在中脑的多巴胺能细胞体中， 例如多巴胺转运蛋白是高度浓缩的。 通过 相比之下，在弓状核中，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 更高的数量。 这表明转运蛋白是在细胞中制造的 身体以较低的速度，但运输到神经末梢区域， 保持稳定。 这些研究正在进行中，特别是 在电子显微镜的水平上，我们希望找到更多的信息， 这将阐明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.