SPECT MEASUREMENT OF DA TRANSPORTER OCCUPANCY BY COCAINE AND THERAPEUTIC AGENTS

可卡因的兴奋和成瘾特性被认为是 源于药物对多巴胺(DA)转运体的阻断(或 重摄取部位)，导致DA突触水平升高。因此， DA转运蛋白可以被视为大脑的“可卡因受体”。高 最近已经开发出用于DA转运体的亲和放射性示踪剂 并可以安全地提供对此的密度的定量测量 活着的人脑中的靶点。使用经济实惠的SPECT (单光子发射计算机断层扫描)方法，我们有 [123I]Beta-CIT((1R)-2Beta-Caromethoxy-3beta-(4- (碘苯基)托烷)在人类和非人类灵长类动物的脑中。与一致 已知的DA转运体分布以纹状体最大 在非人类中的部位数量和药理置换研究 灵长类动物已经证明，纹状体摄取代表与 DA传送器。人体内~(123)I-β-CIT示踪剂量的研究 受试者已经表明，它没有明显的主观影响，没有 毒理作用对血液化学值的影响，并可以 在研究辐射暴露指南范围内的剂量。在……里面 类似于我们对非人类灵长类动物的药理学研究， 我们建议将纹状体[123I]Beta-CIT的示踪量替换为 静脉注射的药理剂量。可卡因。这一方案(可卡因 结合SPECT[123I]Beta-进行的药理学挑战 CT成像)将在潜在的治疗前和治疗期间进行 占据DA转运体的治疗剂(例如，马吲哚)和 可能会阻断可卡因的兴奋作用。这些措施的目的是 研究将衡量DA转运者在 使人兴奋的可卡因剂量，并确定是否足够 DA转运体的百分比被潜在的药物疗法占据 它们在这个地方活动。

The euphorogenic and addictive properties of cocaine are believed to derive from the drug's blockade of the dopamine (DA) transporter (or reuptake site), which causes elevated synaptic levels of DA. Thus, the DA transporter may be viewed as the brain's 'cocaine receptor'. High affinity radiotracers for the DA transporter have recently been developed and can safely provide quantitative measurements of the density of this target site in the living human brain. Using cost effective SPECT (single photon emission computed tomographic) methodologies, we have evaluated [123I]Beta-CIT ((1R)-2Beta-carbomethoxy-3Beta-(4- iodophenyl)tropane) in human and nonhuman primate brain. Consistent with the known distribution of the DA transporter, striatum has the greatest number of sites, and pharmacological displacement studies in nonhuman primates have demonstrated that striatal uptake represents binding to the DA transporter. Studies with tracer doses of [123I]Beta-CIT in human subjects have shown that it has no noticeable subjective effects, no toxicological effects on blood chemistry values, and can be administered in doses within radiation exposure guidelines for research studies. In a manner analogous to our pharmacological studies in nonhuman primates, we propose to displace tracer amounts of striatal [123I]Beta-CIT with pharmacological doses of i.v. cocaine. This protocol (cocaine pharmacological challenge performed in conjunction with SPECT [123I]Beta- CIT imaging) will be performed before and during treatment with potential therapeutic agents (e.g., mazindol) which occupy the DA transporter and may block the euphorogenic effects of cocaine. The purposes of these studies are to measure the percentage of DA transporters occupies by euphorogenic doses of cocaine and to determine whether adequate percentage of DA transporters are occupied by potential pharmacotherapies which act at this site.