New Dopamine D1 Agonists as PET Imaging Agents

作为 PET 成像剂的新型多巴胺 D1 激动剂

• 批准号: 7391136
• 负责人: Onofre DeJesus
• 金额: $ 18.89万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391136
• 关键词: Affinity; Agonist; Avidity; Binding; Binding Sites; Brain; Cognition; Cyclotrons; Development; Disease; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Drug Labeling; Evaluation; Family; Goals; Health; Image; Ions; Isotopes; Label; Ligand Binding; Macaca mulatta; Measures; Methods; Movement; Neurosecretory Systems; Pharmacologic Substance; Positron; Positron-Emission Tomography; Production; Protons; Rewards; Role; Sampling; Site; Work; base; functional status; neurochemistry; neuropsychiatry; novel; receptor binding

DESCRIPTION (provided by applicant): Dopamine is a neurochemical involved in many critical brain functions including movement, cognition, neuroendocrine and reward. There are two families of dopamine receptors, dopamine D1 subtypes and dopamine D2 subtypes. Positron emission tomography (PET) imaging has been very useful in understanding the roles of dopamine receptors in health and disease. While PET imaging agents targeted to dopamine D2 receptors are well developed, the same can not be said for dopamine D1 PET imaging agents. Both dopamine receptor subtypes exist in two binding states- high affinity states and low affinity states. Dopamine has nanomolar affinity for high affinity states and micromolar affinity for low affinity states. Because the high Affinity state is the physiologically functional state, dopamine agonists are preferred as PET imaging agents since they can discriminate between high and low affinity states. In contrast dopamine antagonists bind both high and low affinity states with equal avidity. The understanding of dopamine D2 receptors is more mature than the understanding of dopamine D1 receptors due in part to the paucity of dopamine D1 PET imaging agents. The goal of this proposal is to develop high affinity and highly selective dopamine D1 agonists as PET imaging agents based on a group of 6-chloro-phenylbenzazepines with promising affinities and selectivities. We plan to label these agonists with a novel PET isotope, Cl-34m (tVz = 32 min, 53%.{3+). The specific aims of this project are (1) develop routine Cl-34m production methods using a small 11 Mev proton cyclotron, (2) prepare cold authentic samples of 6-chloro-phenylbenzazepines and their derivatives suitable as precursors for positron labeling, (3) develop routine radiosynthesis of high affinity Cl-34m dopamine D1 agonists and (4) perform preliminary microPET imaging to evaluate and validate Cl-34m-labeled dopamine D1 agonists as PET imaging agents in rhesus macaques. There is currently no reliable Cl-34m production method. Successful development of Cl-34m production methods will allow the evaluation of many chlorinated Pharmaceuticals. In addition, new dopamine D1 agonists labeled with Cl-34m will extend the utility of PET rnaging toward better understanding of the role of dopamine D1 receptors in neuropsychiatric disorders. PET imaging with dopamine D1 agonists will facilitate the understanding and treatment of dopamine D1- related neuropsychiatric disorders.

描述（由申请人提供）：多巴胺是一种神经化学，包括许多关键的大脑功能，包括运动，认知，神经内分泌和奖励。有两个多巴胺受体的家族，多巴胺D1亚型和多巴胺D2亚型。正电子发射断层扫描（PET）成像对于理解多巴胺受体在健康和疾病中的作用非常有用。尽管针对多巴胺D2受体的PET成像剂良好发达，但对于多巴胺D1 PET成像剂来说，这是相同的。两种多巴胺受体亚型都存在于两个结合状态 - 高亲和力状态和低亲和力状态。多巴胺对高亲和力状态具有纳摩尔亲和力，并且对低亲和力状态的微摩尔亲和力。由于高亲和力状态是生理功能状态，因此多巴胺激动剂是宠物成像剂的首选，因为它们可以区分高和低亲和力状态。相比之下，多巴胺拮抗剂与同等相同的高亲和力状态结合。对多巴胺D2受体的理解比对多巴胺D1 PET成像剂的缺乏的理解比对多巴胺D1受体的理解更加成熟。该提案的目的是基于一组具有有希望的亲和力和选择性的6-氯 - 苯基苯甲酰苯二甲酰苯二甲酰苯二甲酰苯二甲酰苯二甲酰苯甲曲基，开发高亲和力和高度选择性的多巴胺D1激动剂作为PET成像剂。我们计划将这些激动剂标记为新型的PET同位素，Cl-34m（TVZ = 32分钟，53％。{3+）。该项目的具体目的是（1）使用小11 MEV质子环状体开发常规的CL-34M生产方法，（2）制备6-氯 - 苯基苯甲酰苯二唑胺及其衍生物作为正电子标记的前代的冷真实样品，（3）开发常规的射放射症，（3）4M型辐射症和4M dopeminim and dopamine dopamine dopamine（4M Dopamine dopamine dopamine dopamine dopamine dopamine dopamine（4M dopamine）（4M dopamine dopamine dopamine（4M dopamine）（（3） MicroPET成像以评估和验证CL-34M标记的多巴胺D1激动剂作为恒河猕猴中的PET成像剂。目前没有可靠的CL-34万生产方法。成功开发CL-34M生产方法将允许评估许多氯化药物。此外，用CL-34M标记的新多巴胺D1激动剂将扩展PET范围的效用，以更好地理解多巴胺D1受体在神经精神疾病中的作用。多巴胺D1激动剂的宠物成像将促进多巴胺D1相关神经精神疾病的理解和治疗。

项目成果

Production of 34m Cl and 38 Cl via the (d,α) reaction on 36 Ar and nat Ar gas at 8.4 MeV.

通过 36 Ar 和 na Ar 气体在 8.4 MeV 下的 (d,α) 反应产生 34m Cl 和 38 Cl。

• DOI: 10.1016/j.apradiso.2010.09.009
• 发表时间: 2011
• 期刊: Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine
• 作者: Engle,JonathanW;Barnhart,ToddE;DeJesus,OnofreT;Nickles,RobertJ
• 通讯作者: Nickles,RobertJ