DRUG RECEPTORS IN VIVO--ANIMAL MODELS AND IMAGING

我们几乎所有关于药物受体的知识都来自于体外 实验。然而，在体内研究受体是很重要的。 原因有很多。因此，我们的目标之一是开发配体和 通过以下方法研究人群中的药物受体位置 成像技术。在对人类进行成像之前，配体需要 在体外和动物体内开发和测试。 在我们的可卡因受体构效关系研究中，RTI-55是 被认为是一种非常有效的化合物，对 多巴胺转运体。它对5-羟色胺也有一定的亲和力 传送员也是。因此，我们之前的出版物表明， RTI-55是研究多巴胺的一种优良的PET和SPECT配体 体内的转运蛋白。它已经获得了专利，获得了许可，目前 在多个中心用作诊断的显像剂 帕金森氏症。 因为它对5-羟色胺转运体有很大的亲和力，所以它是 用RTI-55作为体内结合配体的可能性研究 相关药物对5-羟色胺转运体的占有率。我们已经检查了 具有选择性亲和力的重要新型抗抑郁药物 对于5-羟色胺转运体。使用放射性标记的RTI-55 体内竞争与氟西汀、帕罗西汀和 舍曲林。在行为有效剂量下，很明显，这些 药物占据了5-羟色胺的转运体。还有，氟西汀，它是 已知在人类受试者中有更长的半衰期，有更长的 在这些动物研究中的半衰期比其他化合物要少。这些 结果表明，rti-55可用于5-羟色胺的研究。 转运体，特别是识别与该部位结合的药物，以 确定相对入住率，并确定持续时间 在这个地方的化合物的作用。 我们之前已经使用放射性标记的Win-35,428作为PET配体来 与体内的多巴胺转运体结合。在最近的一项研究中，我们检查了 在动物和人类中这种结合的动力学和药理学。我们 清楚地表明该化合物是一种很有前途的放射性配体 与多巴胺有关的神经精神障碍的研究 传送器现场。

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.