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 源自药物对多巴胺（DA）转运蛋白的阻断（或 再摄取位点），这导致DA的突触水平升高。因此， 多巴胺转运蛋白可以被视为大脑的“可卡因受体”。 高 最近开发了DA转运蛋白的亲和放射性示踪剂 并且可以安全地提供这种密度的定量测量， 目标部位的位置。 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 评价的[123 I]Beta-CIT（（1 R）-2 β-甲氧羰基-3 β-（4- 碘苯基）托烷）。 符合 已知的多巴胺转运蛋白分布，纹状体具有最大的 研究中心数量，以及非人类中的药理学置换研究 灵长类动物已经证明，纹状体的吸收代表了与 DA传送器 人体[123 I]Beta-CIT示踪剂量研究 受试者表明，它没有明显的主观影响，没有 对血液化学值的毒理学效应，并且可以施用 剂量在研究的辐射暴露指南范围内。 在 一种类似于我们在非人类灵长类动物中进行的药理学研究的方式， 我们建议用[123 I] β-CIT替代纹状体的示踪量， 静脉注射可卡因的药理学剂量。 可卡因（可卡因） 与SPECT [123 I] β- CIT成像）将在治疗前和治疗期间进行， 治疗剂（例如，马吲哚），其占据DA转运蛋白， 可能会阻断可卡因的兴奋作用 施行本 研究是测量DA转运蛋白的百分比， 可卡因的欣快剂量，并确定是否足够 DA转运蛋白的百分比被潜在的药物治疗占据 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.