DRUG RECEPTORS IN VIVO--ANIMAL MODELS AND IMAGING

我们对药物受体的认识几乎都来自于体外 实验 然而，在体内研究受体对于 很多原因 因此，我们的目标之一是开发配体， 研究人群中药物受体位点的方法， 成像技术。 在人类成像之前，配体需要被 在体外和动物体内进行了开发和测试。 在我们对可卡因受体的结构-活性研究中，RTI-55是 被鉴定为一种非常有效的化合物，对 多巴胺转运体 它也对血清素有亲和力 运输机也是。 因此，我们以前的出版物表明， RTI-55是研究多巴胺的良好PET和SPECT配体 体内转运蛋白。 它已获得专利，许可，目前 在几个中心用作诊断的成像试剂， 帕金森氏症。 由于其对5-羟色胺转运蛋白的显著亲和力， 可能使用RTI-55作为体内结合配体来研究 相关药物对5-羟色胺转运体的占用。 我们曾研究 重要的新型抗抑郁药物， 5-羟色胺转运体 给予放射性标记的RTI-55， 用氟西汀、帕罗西汀和 舍曲林 在行为有效剂量下，很明显， 药物占据了血清素转运体。 还有氟西汀 已知在人类受试者中具有更长的半衰期， 在这些动物研究中的半衰期比其他化合物长。 这些 结果表明，RTI-55可用于血清素的研究 转运蛋白，特别是鉴定与该位点结合药物， 确定相对入住率，并确定持续时间 化合物在这个部位的作用。 我们先前已经利用放射性标记的WIN-35，428作为PET配体， 与体内多巴胺转运蛋白结合。 在最近的一项研究中，我们检查了 这种结合在动物和人类中的动力学和药理学。 我们 清楚地表明，这种化合物是一种有前途的放射性配体， 研究涉及多巴胺的神经精神疾病 转运站点。

Almost all of our knowledge of drug receptors comes from in vitro experiments. However, it is important to study receptors in vivo for many reasons. Accordingly, one of our goals is to develop ligands and approaches for studying drug receptor sites in human populations by imaging techniques. Prior to imaging in humans, ligands need to be developed and tested in vitro and in vivo in animals. In our structure-activity studies of the cocaine receptor, RTI-55 was identified as a very potent compound with a high affinity for the dopamine transporter. It also has some affinity for the serotonin transporter as well. Accordingly, our previous publications show that RTI-55 is an excellent PET and SPECT ligand for studying dopamine transporters in vivo. It has been patented, licensed and is currently being used in several centers as an imaging reagent for diagnosing Parkinson's disease. Because of its significant affinity for serotonin transporters, it is possible to use RTI-55 as an in vivo binding ligand to study the occupancy of serotonin transporters by relevant drugs. We have examined the important newer antidepressant drugs which have a selective affinity for the serotonin transporter. Radiolabeled RTI-55 was administered and in vivo competition was carried out with fluoxetine, paroxetine and sertraline. At behaviorally effective doses, it was clear that these drugs occupied the serotonin transporter. Also, fluoxetine which is known to have a longer half-life in human subjects, had a much longer half-life in these animal studies than the other compounds. These results indicate that RTI-55 can be used to study the serotonin transporter, in particular to identify drugs that bind to that site, to determine the relative rate of occupancy, and also determine the duration of action of compounds at this site. We have previously utilized radiolabeled WIN-35,428 as a PET ligand to bind to dopamine transporters in vivo. In a recent study, we examined the kinetics and pharmacology of this binding in animals and humans. We clearly show that this compound is a promising radioligand for future studies of neuropsychiatric disorders that involve the dopamine transporter site.