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F_18 Labeled D2 Agonist Ligands for PET Imaging of Dopaminergic Dysfunction

F_18 标记的 D2 激动剂配体用于多巴胺能功能障碍的 PET 成像

基本信息

批准号：
8929299
负责人：
ANNA Waclawa SROMEK
金额：
$ 24.65万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-19 至 2017-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to develop 18F PET radioligands for "molecular targets that are implicated in the pathophysiology of brain and behavioral disorders (e.g. receptors, intracellular messengers, and disease related proteins)." Our immediate goal is to synthesize and biologically characterize an 18F-labeled dopamine D2 agonist radioligand that will ultimately be used for the in vivo evaluation of the role of changes n D2 receptor status in several neurological disorders such as schizophrenia. The D2 receptor has been shown to exist in two states, D2high and D2low. Dopamine supersensitivity, which is marked by an increase in the percentage of D2 receptors in the "high" state, is implicated in neurological disorders such as schizophrenia and Parkinson's disease, among others. Existing [D2/3] radiotracers, such as [11C] raclopride or [18F] fallypride, are D2 antagonists and show equal affinity for D2high and D2low, and cannot, therefore be used to assess increases in D2high. In contrast, D2 agonists show a higher affinity for D2high than for D2low and can, therefore, is used to measure these differences in vivo. At the present time, however, there are no [suitable] 18F-labeled D2 agonist radioligands available. The goal of this project is to develop such compounds. We have identified MCL-524 as a promising starting point for the development of this radioligand. Preliminary in vitro studies carried out in our laboratories showed that the nonradioactive compound is, in fact, a D2 agonist and that MCL-524 can be radiolabeled with 18F. The objective of this project is to extend these very promising preliminary results, laying the groundwork for future human evaluation of this compound. This objective forms the basis for the hypothesis that will be tested: An 18F-labeled D2 agonist radioligand can be used to assess the changes in D2 receptor status that characterize D2-related neurological diseases such as schizophrenia and Parkinson's disease. Fulfillment of this objective will provide a solid basis for advancing the best 18F PET D2 agonist radioligand into humans. Such a radioligand, if developed, would allow a way to study D2 receptor dynamics in relation to the DA system as well as other neurotransmitter systems, and thus allow us to advance our understanding of different neurological disorders.

描述（由申请方提供）：本项目的总体目标是开发18 F PET放射性配体，用于“与脑和行为障碍的病理生理学有关的分子靶标（例如受体、细胞内信使和疾病相关蛋白）”。“我们的近期目标是合成和生物学表征18F标记的多巴胺D2激动剂放射性配体，最终将用于体内评估D2受体状态变化在几种神经系统疾病（如精神分裂症）中的作用。D2受体有两种状态，D2高和D2低。多巴胺超敏性的特征是处于“高”状态的D2受体的百分比增加，与精神分裂症和帕金森病等神经系统疾病有关。现有的[D2/3]放射性示踪剂，如[11 C]雷氯必利或[18 F]法利必利，是D2拮抗剂，对D2高和D2低显示出相同的亲和力，因此不能用于评估D2高的增加。相比之下，D2激动剂对D2 high的亲和力比对D2 low的亲和力高，因此可以用于测量体内的这些差异。然而，目前还没有[合适的] 18F标记的D2激动剂放射性配体可用。该项目的目标是开发这样的化合物。我们已经确定MCL-524作为开发这种放射性配体的有希望的起点。在我们实验室进行的初步体外研究表明，非放射性化合物实际上是一种D2激动剂，MCL-524可以用18 F进行放射性标记。该项目的目标是扩展这些非常有希望的初步结果，为未来人类对该化合物的评估奠定基础。这一目标构成了将要检验的假设的基础：18F标记的D2激动剂放射性配体可用于评估D2受体状态的变化，这些变化表征了D2相关神经系统疾病，如精神分裂症和帕金森病。这一目标的实现将为将最好的18F PET D2激动剂放射性配体推进到人体中提供坚实的基础。这种放射性配体，如果开发出来，将允许一种方法来研究D2受体动力学与DA系统以及其他神经递质系统，从而使我们能够推进我们对不同神经系统疾病的理解。