DRUG RECEPTORS IN VIVO--ANIMAL MODELS AND IMAGING

体内药物受体——动物模型和成像

• 批准号: 3838611
• 负责人: M J KUHAR
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3838611
• 关键词: analog; autoradiography; biological models; chemical structure function; cocaine; dopamine receptor; drug receptors; ligands; positron emission tomography; radionuclide imaging /scanning; radiotracer; receptor binding; serotonin receptor; single photon emission computed tomography; tropanes

The goal of this project is to develop in vivo receptor binding procedures whereby drug receptors can be studied in vivo. Most receptor studies are carried out in vitro where membrane preparations from brain are incubated in physiological buffer along with binding ligands. obviously, receptors normally function in vivo and we therefore must have the capability of studying receptors in vivo. In the procedure of in vivo labeling, radiolabeled ligands are injected systemically into animals and the ligands preferentially localize to drug receptor sites in the intact functioning animal. In our structure-activity studies, it was found that addition of a para-iodine to the phenyl group in the phenyltropane series (RTI-55) resulted in a compound with very high affinity for the dopamine transporter. Subsequent experiments with radiolabeled RTI-55 showed that it was a useful ligand in in vitro binding experiments. Accordingly, we have tested for its suitability as an in vivo binding ligand. By using radiolabeled RTI-55, it was shown that this compound does indeed bind to dopamine transporters after in vivo injection. Thus, it was possible to utilize RTI-55 as an imaging agent in a SPECT, PET or autoradiographic study. In these experiments, it was noted also that RTI-55 is not specific for dopamine transporters but also binds to serotonin transporters. Thus, while this compound is not specific, it may be possible under certain conditions, to image both serotonin and dopamine transporters at the same time by examining regions where the respective terminals are highly concentrated. Because of the lack in specificity, detailed studies are underway to find more specific binding ligands for both dopamine and serotonin transporters. The availability of these ligands will allow additional and more precise imaging studies of cocaine receptors in human populations.

本项目的目标是开发体内受体结合 可以在体内研究药物受体的程序。 大多数受体 在体外进行研究， 与结合配体一起沿着在生理缓冲液中孵育。 显然，受体在体内正常发挥作用，因此我们必须 研究体内受体的能力。 在程序中， 体内标记，将放射性标记的配体全身注射到 动物和配体优先定位于药物受体位点， 功能完整的动物 在我们的结构-活性研究中，发现添加 苯基托烷系列（RTI-55）中苯基的对位碘 产生了一种对多巴胺有很高亲和力的化合物 传送器。 随后用放射性标记的RTI-55进行的实验表明， 它是体外结合实验中有用的配体。 因此我们 已经测试了其作为体内结合配体的适用性。 通过使用 放射性标记的RTI-55，显示该化合物确实与 体内注射后的多巴胺转运蛋白。 因此，有可能 在SPECT、PET或放射自显影中使用RTI-55作为显像剂 study. 在这些实验中，还注意到RTI-55不是 对多巴胺转运蛋白有特异性， 运输机 因此，虽然该化合物不是特异性的，但它可以是 在某些条件下，可以同时想象血清素和多巴胺 运输商在同一时间通过检查地区， 终端高度集中。 由于缺乏特异性， 正在进行详细的研究，以寻找更特异的结合配体， 多巴胺和血清素转运蛋白 网站或资源的可用性 配体将允许更多和更精确的可卡因成像研究 人类的受体。