New Dopamine D1 Agonists as PET Imaging Agents

作为 PET 成像剂的新型多巴胺 D1 激动剂

基本信息

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
项目类别：
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

项目摘要

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物质，参与许多关键的大脑功能，包括运动、认知、神经内分泌和奖励。多巴胺受体有两个家族：多巴胺 D1 亚型和多巴胺 D2 亚型。正电子发射断层扫描 (PET) 成像对于了解多巴胺受体在健康和疾病中的作用非常有用。虽然针对多巴胺 D2 受体的 PET 显像剂已得到很好的开发，但多巴胺 D1 PET 显像剂却并非如此。两种多巴胺受体亚型都以两种结合状态存在——高亲和力状态和低亲和力状态。多巴胺对于高亲和力状态具有纳摩尔亲和力，对于低亲和力状态具有微摩尔亲和力。因为高亲和力状态是生理功能状态，所以多巴胺激动剂优选作为PET成像剂，因为它们可以区分高亲和力状态和低亲和力状态。相反，多巴胺拮抗剂以相同的亲合力结合高亲和力状态和低亲和力状态。对多巴胺 D2 受体的认识比对多巴胺 D1 受体的认识更为成熟，部分原因是多巴胺 D1 PET 显像剂的缺乏。该提案的目标是开发高亲和力和高选择性多巴胺 D1 激动剂作为 PET 成像剂，基于一组具有良好亲和力和选择性的 6-氯苯基苯并氮杂卓。我们计划用新型 PET 同位素 Cl-34m（tVz = 32 分钟，53%。{3+）标记这些激动剂。该项目的具体目标是 (1) 使用小型 11 Mev 质子回旋加速器开发常规 Cl-34m 生产方法，(2) 制备适合作为正电子标记前体的 6-氯苯基苯并氮杂卓及其衍生物的冷真实样品，(3 ) 开发高亲和力 Cl-34m 多巴胺 D1 激动剂的常规放射合成，并且 (4) 进行初步 microPET 成像以评估和验证 Cl-34m 标记的多巴胺 D1激动剂作为恒河猴的 PET 显像剂。目前尚无可靠的Cl-34m生产方法。 Cl-34m 生产方法的成功开发将允许对许多氯化药物进行评估。此外，用 Cl-34m 标记的新型多巴胺 D1 激动剂将扩展 PET 分析的效用，以更好地了解多巴胺 D1 受体在神经精神疾病中的作用。使用多巴胺 D1 激动剂进行 PET 成像将有助于了解和治疗多巴胺 D1 相关的神经精神疾病。