Preclinical evaluation of the D2 receptor agonist MCL-524 as diagnostic marker for presymptomatic Parkinson's Disease

D2 受体激动剂 MCL-524 作为症状前帕金森病诊断标志物的临床前评估

• 批准号: 10644168
• 负责人: SIVAN SUBBURAJU
• 金额: $ 24.6万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644168
• 关键词: Address; Affinity; Agonist; Animal Model; Binding; Biological Markers; Brain imaging; Cells; Clinical; Corpus striatum structure; Data; Development; Diagnosis; Diagnostic; Disease; Disease Management; Disease Progression; Dopamine D2 Receptor; Dopamine Receptor; Early Diagnosis; Early treatment; Economic Burden; Exclusion; Family; Female; Fluorine; Functional disorder; Goals; Human; Idiopathic Parkinson Disease; In Vitro; Injections; Intervention; Intravenous; Ligands; Measures; Metabolic; Modeling; Motor; Movement; Nerve Degeneration; Neurodegenerative Disorders; Oxidopamine; Parkinson Disease; Pathologic; Patients; Phase; Positron-Emission Tomography; Protocols documentation; Publishing; Quantitative Autoradiography; Radiopharmaceuticals; Rattus; Safety; Saline; Site; Specificity; Structure; Substantia nigra structure; Symptomatic Parkinsonism; Symptoms; Tail; Therapeutic Intervention; Up-Regulation; Veins; antagonist; blood-brain barrier crossing; clinical application; clinical diagnosis; density; diagnostic biomarker; diagnostic tool; disease diagnosis; dopamine transporter; dopaminergic neuron; efficacy evaluation; in vivo; male; median forebrain bundle; nanomolar; neuroprotection; new therapeutic target; nigrostriatal pathway; pars compacta; preclinical evaluation; prognostic; putamen; radioligand; radiotracer; receptor; receptor binding; receptor expression; receptor function; research clinical testing; single photon emission computed tomography; socioeconomics

Summary Parkinson`s disease (PD) is characterized by a progressive loss of dopaminergic (DA) neurons in the nigrostriatal region which starts 4-7 years before symptoms such as movement disturbances become manifest. Diagnosis of the disease in the asymptomatic phase is ideal, as it would enable earlier treatment and provide new targets for therapeutic intervention. We have developed a highly specific agonist, MCL-524, for the active form of the dopamine receptor, D2high, which is up-regulated in early PD. This early, transient upregulation is an opportunity to use it as a biomarker. We aim to characterize MCL-524 in a moderate animal model of pre-symptomatic PD. In this model, by injection of 6-OHDA into three discrete sites in the striatum, a progressive but incomplete loss of DA neurons in the nigrostriatal pathway is induced, which resembles early stages of PD. In our first specific aim, we will use [3H]MCL-524 to detect the up-regulation of the D2high receptor in 6-OHDA rats compared with sham operated controls. D2 receptor binding will be evaluated through quantitative autoradiography. In the second aim, we will confirm specificity of MCL-524 by intravenous pre-treatment with a specific D2 receptor antagonist, N-(methyl) benperidol, which should abolish all binding of [3H]MCL-524 to D2; or a specific D3 receptor antagonist, SB277011A, which should not interfere with binding of MCL-524 to D2high. Completion of these aims will: a) validate MCL-524 as a highly selective and specific agonist ligand which can unambiguously detect early, key changes to D2 receptor expression and function; and b) allow for development of a robust protocol for diagnosing Parkinson’s disease in the prodromal stage. The overarching goal is to develop MCL-524 as a positron emission tomography (PET) radiotracer for early clinical diagnosis of PD. Early detection of this neurodegenerative disease will allow for earlier and better treatment opportunities for the patient, and will help alleviate the socio-economic burden for PD patients and their families.

总结 帕金森病（PD）的特征是黑质纹状体多巴胺能（DA）神经元的进行性丢失 该区域在运动障碍等症状出现之前4 - 7年开始。诊断 处于无症状阶段的疾病是理想的，因为它可以更早地治疗，并提供新的靶点， 治疗干预我们已经开发了一种高度特异性的激动剂，MCL-524，用于活性形式的 多巴胺受体，D2high，在早期PD中上调。这种早期短暂的上调是一个机会， 将其作为生物标记物。我们的目的是在症状前PD的中度动物模型中表征MCL-524。 在该模型中，通过将6-OHDA注射到纹状体中的三个离散位点， 黑质纹状体通路中的DA神经元被诱导，这类似于PD的早期阶段。 在我们的第一个具体目标中，我们将使用[3H] MCL-524检测6-OHDA大鼠中D2high受体的上调 与假手术对照组相比。将通过定量分析评价D2受体结合。 放射自显影 在第二个目标中，我们将通过用特异性D2受体进行静脉内预处理来确认MCL-524的特异性 拮抗剂，N-（甲基）苯哌利多，其应消除[3H] MCL-524与D2的所有结合;或特异性D3受体 拮抗剂SB277011A，其不应干扰MCL-524与D2high的结合。 实现这些目标将： a）验证MCL-524作为高选择性和特异性激动剂配体，其可以明确地检测早期、关键的 D2受体表达和功能的变化;以及 B）允许开发用于诊断前驱期帕金森病的稳健方案。 总体目标是开发MCL-524作为正电子发射断层扫描（PET）放射性示踪剂，用于早期诊断。 PD的临床诊断。早期发现这种神经退行性疾病将允许更早，更好地 为患者提供治疗机会，并将有助于减轻PD患者的社会经济负担， 家人