F_18 Labeled D2 Agonist Ligands for PET Imaging of Dopaminergic Dysfunction

描述（由申请人提供）：该项目的总体目标是为“涉及脑和行为障碍病理生理学的分子靶标（例如受体、细胞内信使和疾病相关蛋白）”开发18F PET放射配体。我们的近期目标是合成一种18f标记的多巴胺D2激动剂放射配体并对其进行生物学表征，该配体最终将用于体内评估D2受体状态变化在精神分裂症等几种神经系统疾病中的作用。D2受体以两种状态存在，D2高和D2低。多巴胺超敏感，以D2受体处于“高”状态的比例增加为标志，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[11C] raclopride或[18F] fallypride，是D2拮抗剂，对D2high和D2low具有相同的亲和力，因此不能用于评估D2high的增加。相比之下，D2激动剂对D2high的亲和力高于对D2low的亲和力，因此可以用来测量体内的这些差异。然而，目前还没有合适的18f标记的D2受体激动剂放射配体可用。这个项目的目标是发展

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.