POSITRON-EMITTING RADIOTRACERS FOR MAPPING NEURORECEPTOR

用于绘制神经感受器的正电子发射放射性示踪剂

• 批准号: 3410991
• 负责人: DONALD M WIELAND
• 金额: $ 19.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3410991
• 关键词: Alzheimer's disease; Huntington's disease; Macaca mulatta; NMDA receptors; PCP receptor; anticonvulsants; autoradiography; benzodiazepine receptor; chemical binding; clinical depression; convulsions; dogs; drug metabolism; laboratory rat; neuropharmacology; neurotransmitters; phencyclidine; positron emission tomography; psychotomimetic drug; radiopharmacology; tritium

This proposal is a two-part study aimed at developing radiopharmaceuticals that probe the actions of specific brain neurotransmitters. Significant changes in binding of the neurotransmitter glutamate occur in the brains of patients with senile dementia of the Alzheimer's type and Huntington's Disease. The first major goal of this proposal is to develop a positron- emitting radiotracer that will permit regional quantitation of glutamate receptor density (NMDA subset) in the human brain. Non-radioactive analogs of the dissociative anesthetic phencyclidine (PCP) and the anti-convulsant MK-801 that are clearly amenable to positron labeling will be synthesized and screened in vivo for pharmacological (PCP-like) potency using the mouse platform test. Relative binding affinities (IC-50 values) of these compounds for the NMDA-linked ion channel will be determined by in vitro quantitative autoradiography using a competitive H-3-ligand assay. The most promising agents will be H-3-labeled and their in vivo metabolism and temporal pattern of whole brain uptake determined in rats; regional brain distribution and receptor-site specificity will be determined by H-3- autoradiography. The best agent(s) will be labeled with F-18 or C-11 and its regional distribution in monkey brain determined by positron emission tomography (PET) under normal and drug challenge conditions. Dosimetric and toxicity studies will be conducted in animals in pursuit of human use approval for this agent for studying Alzheimer's and presymptomatic Huntington's Disease and convulsive disorders. Preliminary pharmacological screening of 3-amino-4-fluoro-PCP shows this compound to be as pharmacologically potent as PCP. Initial experiments indicate that this agent can be labeled with F-18 in high specific activity. The second major goal of this proposal is to develop a positron- emitting radiotracer that will map alpha-2 receptors in the human brain. The two potent alpha 2 antagonists, 2-methoxyidazoxan and the structurally related 1,4-benzodioxan RS-21361, will be H- 3-labeled and their metabolism, pharmacokinetics and regional brain distribution determined in rats. A quantitative tracer kinetic model will be developed to derive kinetic parameters from the regional brain distribution of these radiotracer(s). The superior agent will be C-11-labeled and its regional distrubition in the monkey brain assessed by PET. Human use approval will be sought for study of alpha 2 receptor alteration in depression.

该提案是一项由两部分组成的研究，旨在开发 探测特定大脑活动的放射性药物 神经递质。 约束力的重大变化 神经递质谷氨酸存在于患者的大脑中 阿尔茨海默病型老年痴呆症和亨廷顿病。 该提案的第一个主要目标是开发一种正电子 发射放射性示踪剂，允许区域定量 人脑中谷氨酸受体密度（NMDA 子集）。 解离麻醉剂的非放射性类似物 苯环己哌啶 (PCP) 和抗惊厥药 MK-801 将合成明显适合正电子标记的 使用以下方法在体内筛选药理学（PCP 样）效力 鼠标平台测试。 相对结合亲和力（IC-50 值） 这些 NMDA 连接离子通道的化合物将是 通过体外定量放射自显影法测定 竞争性 H-3-配体测定。 最有前途的代理商将是 H-3标记及其体内代谢和时间模式 在大鼠中测定全脑摄取；大脑区域分布 受体位点特异性将由 H-3- 决定 放射自显影。 最好的特工将被贴上 F-18 或 C-11 及其在猴脑中的区域分布由 正常和药物状态下的正电子发射断层扫描（PET） 挑战条件。 剂量测定和毒性研究将 在动物身上进行，以寻求人类使用批准 研究阿尔茨海默氏症和症状前亨廷顿舞蹈症的药物 疾病和惊厥性疾病。 初步药理 3-氨基-4-氟-PCP 的筛选表明该化合物为 药理作用与 PCP 相同。 初步实验表明 该试剂可以高比活性地标记F-18。 该提案的第二个主要目标是开发一种正电子 发射放射性示踪剂，绘制人体 α-2 受体图谱 脑。 两种有效的 α2 拮抗剂，2-甲氧基达唑克生 和结构相关的 1,4-苯并二恶烷 RS-21361，将是 H- 3-标记及其代谢、药代动力学和区域 在大鼠中测定大脑分布。 定量示踪剂 将开发动力学模型以导出动力学参数 这些放射性示踪剂的大脑区域分布。 这 优质药剂将被标记为C-11，其区域分布在 通过 PET 评估猴脑。 人类使用批准将 寻求研究抑郁症中α2受体的改变。