SPECT MEASUREMENT OF DA TRANSPORTER OCCUPANCY BY COCAINE AND THERAPEUTIC AGENTS

可卡因和治疗剂对 DA 转运蛋白占用情况的 SPECT 测量

• 批准号: 6104098
• 负责人: ROBERT B INNIS
• 金额: $ 11.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6104098
• 关键词: cocaine; dopamine; dopamine agonists; human subject; iodine; magnetic resonance imaging; neurotransmitter transport; radiochemistry; radiotracer; receptor binding; single photon emission computed tomography

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.

可卡因的欣快感和成瘾特性被认为 源自药物对多巴胺 (DA) 转运蛋白的阻断（或 再摄取位点），这会导致 DA 突触水平升高。 因此， DA 转运蛋白可被视为大脑的“可卡因受体”。 高的 最近开发了 DA 转运蛋白的亲和放射性示踪剂 并可以安全地提供该密度的定量测量 活人大脑中的目标位点。 使用具有成本效益的 SPECT （单光子发射计算机断层扫描）方法，我们有 评估了 [123I]Beta-CIT ((1R)-2Beta-甲甲氧基-3Beta-(4- 人类和非人类灵长类动物大脑中的碘苯基）托烷）。 符合 已知 DA 转运蛋白的分布，纹状体具有最大 非人类中的位点数量和药理学位移研究 灵长类动物已证明纹状体摄取代表与 DA 转运蛋白。 [123I]Beta-CIT 人体示踪剂剂量研究 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影响，并且可以施用 剂量在研究辐射暴露指南范围内。 在 类似于我们对非人类灵长类动物的药理学研究， 我们建议用以下物质取代纹状体 [123I]Beta-CIT 的示踪量 静脉注射的药理学剂量可卡因。 该协议（可卡因 与 SPECT [123I]Beta- 结合进行的药理学挑战 CIT 成像）将在治疗前和治疗期间进行，具有潜在的 占据 DA 转运蛋白的治疗剂（例如马吲哚）和 可能会阻断可卡因的欣快感。 这些的目的 研究的目的是测量 DA 转运蛋白所占的百分比 可卡因的欣快剂量并确定是否足够 DA 转运蛋白被潜在药物疗法占据的百分比 在此站点上起作用。