DRUG RECEPTORS IN VIVO--ANIMAL MODELS AND IMAGING

虽然大多数受体是通过体外结合技术研究的， 实验，显然重要的是进行类似的研究， 体内受体正常发挥功能的地方。 我们的目标之一就是学习 通过配体结合和成像在体内与成瘾相关的药物受体 技术. 在体内标记过程中， 被全身性地注射到动物体内， 优先定位于药物受体位点。 在我们的结构中- 可卡因受体与可卡因类似物的活性研究，我们发现， RTI-55是一种非常有效的化合物， 多巴胺转运体 在体内进行的实验表明，RTI-55 确实可以在体内与多巴胺转运蛋白结合。 它积累在 具有高密度转运蛋白的脑区域如纹状体， 在这些区域的积累被药物阻断， 转运蛋白和这些多巴胺能神经末梢的损伤导致 减少这些地区的积累。 然而，配体如RTI- 55，虽然它们是有用的成像剂，但对肿瘤细胞没有选择性。 多巴胺转运体 例如，RTI-55还与相对多核苷酸结合。 对5-羟色胺转运体有很高的亲和力 非常希望 产生非常选择性的结合化合物。 因此，我们有 开发了一些对多巴胺有选择性的化合物 传送器。 其中一种化合物RTI-121尤其有前途 并可能取代RTI-55作为体外结合配体， 也可能作为体内结合配体。 我们也取得了 在进一步发展更古老、更成熟的 化合物. 我们利用碳-11标记的WIN 35，428作为PET 扫描配体，并进行了初步的建模研究，以及 作为药理学研究。 结果清楚地表明， 化合物可以有效地用于定位多巴胺转运蛋白， 通过PET扫描的人。总而言之，我们取得了重大进展， 在鉴定和开发结合配体方面的进展， 研究体内药物受体。

While most receptors are studied by binding techniques in vitro experiments, it is obviously important to carry out similar studies in vivo where receptors function normally. One of our goals is to study drug receptors related to addiction in vivo by ligand binding and imaging techniques. In the procedure of in vivo labeling, radioactive ligands are injected systemically into animals such that the ligands preferentially localize to drug receptor sites. In our structure- activity studies of the cocaine receptor with cocaine analogs, we found that RTI-55 was a very potent compound with high affinity for the dopamine transporter. Experiments carried out in vivo shows that RTI-55 can indeed bind to dopamine transporters in vivo. It accumulates in brain regions having high densities of transporter such as the striatum, accumulation in these regions are blocked by drugs which bind to the transporter and lesions of these dopaminergic nerve terminals result in a reduced accumulation in these regions. However, ligands such as RTI- 55, while they are useful imaging agents, are not selective for the dopamine transporter. For example, RTI-55 also binds with a relatively high affinity to the serotonin transporter. It is highly desirable that very selective binding compounds be generated. Accordingly, we have developed a number of compounds which are selective for the dopamine transporter. One of these compounds, RTI-121, is especially promising and will probably replace RTI-55 as an in vitro binding ligand and perhaps as an in vivo binding ligand as well. We have also made significant progress in further developing older, more established compounds. We have utilized carbon-11 labeled WIN 35,428 as a PET scanning ligand and have carried out preliminary modeling studies as well as pharmacological studies. The results clearly indicate that the compound can be used effectively to localize dopamine transporters in human populations by PET scanning. In summary, we have made significant progress in identifying and developing binding ligands which will allow us to study drug receptors in vivo.