New Dopamine D1 Agonists as PET Imaging Agents

描述(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，即多巴胺D1亚型和多巴胺D2亚型。正电子发射断层扫描(PET)成像在了解多巴胺受体在健康和疾病中的作用方面非常有用。虽然针对多巴胺D2受体的PET显像剂已经开发得很好，但对于多巴胺D1PET显像剂就不能说同样的话了。这两种多巴胺受体亚型都存在两种结合状态--高亲和力状态和低亲和力状态。多巴胺在高亲和力状态下具有纳摩尔亲和力，在低亲和力状态下具有微摩尔亲和力。由于高亲和力状态是生理功能状态，因此多巴胺激动剂是首选的PET显像剂，因为它们可以区分高亲和力状态和低亲和力状态。相比之下，多巴胺拮抗剂以同样的亲和力结合高亲和力和低亲和力状态。对多巴胺D2受体的认识比对多巴胺D1受体的认识更成熟，部分原因是由于多巴胺D1PET显像剂的缺乏。这项建议的目标是开发高亲和力和高选择性的多巴胺D1激动剂作为PET显像剂，基于一组具有良好亲和力和选择性的6-氯苯基苯并卓类化合物。我们计划用一种新的PET同位素Cl-34M标记这些激动剂(TVZ=32min，53%.{3+)。该项目的具体目标是(1)开发使用小型11 Mev质子回旋加速器生产氯-34M的常规方法，(2)制备适合作为正电子标记前体的6-氯苯基苯并氮卓及其衍生物的冷样，(3)开发高亲和力氯-34M多巴胺D1激动剂的常规放射合成，以及(4)进行初步的microPET成像，以评估和验证氯-34M标记的多巴胺D1激动剂作为恒河猴PET显像剂的有效性。目前还没有可靠的氯-34M生产方法。氯-34M生产方法的成功开发将使许多氯化药物的评估成为可能。此外，用氯-34M标记的新的多巴胺D1激动剂将扩展PET的用途，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与多巴胺D1相关的神经精神疾病。

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.