Neuroimaging of PDE10A

PDE10A 的神经影像学

• 批准号: 10240319
• 负责人: JOEL Synes PERLMUTTER
• 金额: $ 61.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240319
• 关键词: Acute; Agonist; Autopsy; Behavior; Binding Sites; Biological Markers; Blinded; Brain; Carbidopa; Chemicals; Chronic; Clinical Research; Confusion; Contralateral; Corpus striatum structure; DRD2 gene; Data; Disease; Disease Progression; Dopamine; Dopamine Receptor; Dopaminergic Agents; Dose; Drug Exposure; Dystonia; Enzymes; Failure; Family; Functional disorder; Human; Huntington Disease; Immunohistochemistry; In Vitro; Injury; Intracarotid; Investigation; Kinetics; Levodopa; Ligands; Measures; Mediating; Mental disorders; Molecular; Monkeys; Motor; Neurons; Neurotransmitters; Normal Pressure Hydrocephalus; Parkinson Disease; Parkinsonian Disorders; Pathology; Pathway interactions; Pharmaceutical Preparations; Positron-Emission Tomography; Property; Psychoses; Quantitative Autoradiography; Schizophrenia; Side; Signal Transduction; Synapses; Tissues; Tracer; Translating; base; behavior in vitro; brain pathway; dopaminergic neuron; enzyme activity; human imaging; imaging study; in vivo; molecular imaging; motor behavior; nervous system disorder; neuroimaging; nigrostriatal pathway; nonhuman primate; nonhuman tissue; novel therapeutics; phosphoric diester hydrolase; postsynaptic; pramipexol; presynaptic; prevent; radioligand; receptor; uptake; vesicular monoamine transporter

ABSTRACT Multiple neurologic and psychiatric disorders including Parkinson disease (PD), Huntingon disease (HD), dystonia and schizophrenia involve dopaminergic (DA) pathways as part of pathophysiology or treatment. Changes in function of nigrostriatal pathways may reflect either presynaptic or postsynaptic effects. Most previous studies focused on presynaptic changes. This proposal focuses on phosphodiesterases (PDEs) that control signal transduction of both families of DA receptors (D1-like and D2-like). PDE10A, the PDE subtype restricted to striatal medium spiny neurons (MSNs) and is expressed in direct (mosty D1-mediated) and indirect pathway neurons (mostly D2-mediated). PET ligands for PDE10A could facilitate study of pathophysiology, disease progression or target engagement for diseases with striatal pathologies such as PD or HD. However, the interactions among presynaptic nigrostriatal neurons, DA receptors, behavior and PDE10A remain unknown. Failure to understand these relationships led to confusion about interpretation of clinical studies using presynaptic molecular DA biomarkers. Molecular imaging measures also may be altered by either acute or chronic drug exposures, thus investigation of those potential effects also will permit unabmiguous interpretation of human studies. This proposal will help prevent such confusion by directly determining the effects of nigrostriatal injury on striatal PDE10A, comparing with presynaptic measures, D1-like and D2-like DA receptors, other striatal neurotransmitters and motor behavior in nonhuman primates (NHPs). We will leverage previously collected tissues from NHPs that have been treated with varying doses of intracarotid (ic) MPTP that causes graded degrees of nigrostriatal injury. We also will study new NHPs to determine the relationships between in vivo PET measures of PDE10A with other presynaptic and postsynaptic biomarkers. We will use two different PET radioligands for PDE10A that have different tracer kinetic properties. Finally, we will determine the effects of acute or chronic drugs on in vivo PDE10A in striatum since drug effects can be a major confound in human imaging studies, particularly of dopaminergic pathways. These proposed studies will permit unambiguous interpretation of PDE10A PET radioligands to investigate relevant pathophysiologies or provide measures of target engagement of new therapies for PD, HD and possibly psychosis.

摘要 多种神经和精神疾病，包括帕金森病(PD)、亨廷顿病(HD)、 肌张力障碍和精神分裂症涉及多巴胺能(DA)通路，作为病理生理学或治疗的一部分。 黑质纹状体通路功能的改变可能反映突触前或突触后效应。多数 以前的研究主要集中在突触前的变化上。这项建议重点关注磷酸二酯酶(PDE) 两个DA受体家族(D1样和D2样)的控制信号转导。PDE10A，PDE亚型 仅限于纹状体中的棘神经元(MSN)，直接表达(大多数D1介导)和间接表达 通路神经元(主要是D2介导的)。PDE10A的pET配体可以促进病理生理学的研究， 疾病进展或具有纹状体病理的疾病的目标参与，如PD或HD。然而， 突触前黑质纹状体神经元、DA受体、行为和PDE10A之间的相互作用仍然存在 未知。未能理解这些关系导致了对临床研究解释的混乱 使用突触前分子DA生物标记物。分子成像测量也可能因以下两种情况之一而改变 或慢性药物暴露，因此对这些潜在影响的调查也将允许 对人类研究的解释。这项提案将通过直接确定 黑质纹状体损伤对纹状体PDE10A的影响及其与突触前D1样和D2样DA的比较 非人灵长类动物的受体、其他纹状体神经递质和运动行为。 我们将利用以前从NHP收集的组织，这些组织已经用不同剂量的 颈动脉内(Ic)MPTP导致不同程度的黑质纹状体损伤。我们还将研究新的NHP以 确定体内PDE10A的PET测量与其他突触前和突触后的关系 生物标志物。我们将对PDE10A使用两种不同的PET放射性配体，它们具有不同的示踪动力学性质。 最后，我们将确定急性或慢性药物对体内纹状体PDE10A的影响。 可能是人类成像研究中的一个主要困惑，特别是在多巴胺能通路的研究中。这些建议 研究将允许对PDE10A PET放射性配体进行明确的解释，以调查相关 病理生理学或为PD、HD和可能的新疗法提供靶向参与的措施 精神错乱。