Development of Dopamine D1 Receptor Agonists for PET Imaging

用于 PET 成像的多巴胺 D1 受体激动剂的开发

基本信息

批准号：
8263752
负责人：
Balasubramaniam Easwaramoorthy
金额：
$ 23.99万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-10 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8263752
关键词：
Affinity Agonist Alcohol dependence Animals Area Attention deficit hyperactivity disorder Benzazepines Binding Binding Sites Biodistribution Biological Assay Blood - brain barrier anatomy Brain Characteristics Chemical Structure Chemistry Clinical Research Cognitive Computer Simulation Concentration measurement Corpus striatum structure Cyclic AMP Cyclotrons DRD2 gene Detection Development Disease Dopamine Dopamine D1 Receptor Dopamine Receptor Dose Drug Addiction Effectiveness Evaluation Fluorides Functional disorder Future G-Protein-Coupled Receptors Goals HTR2A gene High Pressure Liquid Chromatography Human Image Image Analysis In Vitro Investigation Label Lead Ligands Locomotion Mass Spectrum Analysis Methods Modification National Institute of Mental Health Neuraxis Normal saline Nucleus Accumbens Parkinson Disease Performance Permeability Plasma Play Positron-Emission Tomography Preclinical Drug Evaluation Primates Procedures Property Prosencephalon Radioactive Radioactivity Radiolabeled Rattus Reagent Research Research Project Grants Resolution Rodent Role Scheme Schizophrenia Screening procedure Skeleton Specificity Spiperone Structure-Activity Relationship Substantia nigra structure Testing Thalamic structure Therapeutic Tracer base caudate nucleus cognitive enhancement design drug development frontal lobe in vivo interest neuropsychiatry neurotransmission nonhuman primate novel nucleophilic substitution olfactory bulb pharmacophore pre-clinical programs public health relevance putamen radioligand radiotracer receptor therapeutic target three dimensional structure tool uptake

项目摘要

DESCRIPTION (provided by applicant): The Dopamine D1 receptor (D1R) plays an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Parkinson's disease and is an important target for cognitive enhancement strategies. The currently available D1R radioligands, [11C]NNC112 and [11C]SCH23390, are antagonists. It is our goal to synthesize a selective, full D1R agonist utilizing known chemical structures, modifying them to introduce pendent groups for radiolabeling, resulting in the synthesis of D1R-PET-ligands, and to assess them in rodents and non-human primates for suitability as D1R imaging agents. Dihydrexidine and doxanthrine are potent, highly selective and fully efficacious D1R agonists. In addition, many ligand-based computational modeling approaches, such as pharmacophore detection and interaction of ligands at the binding sites of the D1R, have been used and highlight the effectiveness of designing D1R agonists using the -phenyldopamine pharmacophore template. In this regard, we propose to synthesize four 18F labeled PET ligands for imaging D1R in vivo. The in vitro binding affinities of these agents will be determined and used to characterize the potency and selectivity of the new compounds. A high purity, high yield radiolabeling procedure will be developed using 18F-fluoride from a cyclotron and respective precursors. Dynamic PET studies with the 18F- D1R-PET-ligands will be performed in rats using a microPET scanner. The D1R agonist binding characteristics of the radiotracers will be calculated in animals that are vehicle-treated or pre-blocked with receptor-saturating doses of SCH23390. Non-human primate PET studies will be carried out with the 18F- D1R-PET-ligands that demonstrate sufficient potential in the rat studies. Ligands that are shown to have appropriate properties in these preclinical rodent and primate PET studies will be candidates for future examination as tracers in human clinical studies, with further support to continue the project sought through the R01 mechanism. PUBLIC HEALTH RELEVANCE: The dopamine D1 receptor (D1R) is the most abundant dopamine receptor in the central nervous system. Specifically, the D1R has been implicated in a variety of neuropsychiatric disorders such as schizophrenia and Parkinson's disease, and is a target for therapeutics and drug development. In this project, we propose to develop D1R agonist PET ligands to allow in vivo investigation of the functional state of the receptor.

描述（由申请人提供）：多巴胺D1受体（D1R）在神经精神疾病的病理生理学中起重要作用，例如精神分裂症和帕金森氏病，是认知增强策略的重要目标。当前可用的D1R放射线，[11C] NNC112和[11C] SCH23390是拮抗剂。我们的目标是使用已知的化学结构合成选择性的，完整的D1R激动剂，并修改它们以引入放射性标记的吊坠组，从而导致D1R-PET-Ligands的合成，并在啮齿动物和非人类灵长类动物中评估它们作为D1R成像的适合性。二羟化和doxanthrine是有效的，高度选择性且完全有效的D1R激动剂。此外，已经使用了许多基于配体的计算建模方法，例如在D1R的结合位点进行的药效团检测和配体的相互作用，并突出了使用 - 苯二胺药物团模板设计D1R激动剂的有效性。在这方面，我们建议在体内合成四个标记为D1R的PET配体的四个18F标记的PET配体。这些药物的体外结合亲和力将被确定并用于表征新化合物的效力和选择性。将使用来自回旋子和各个前体的18F-氟化物开发高纯度，高屈服的放射性标记程序。使用MicroPET扫描仪在大鼠中将对18F-D1R-PET配体进行动态PET研究。放射性示踪剂的D1R激动剂结合特性将在用媒介物处理或预封闭受体饱和剂量的SCH23390的动物中计算。非人类灵长类动物的宠物研究将使用18f-d1r-pet-tigands进行，在大鼠研究中表现出足够的潜力。在这些临床前啮齿动物和灵长类动物的宠物研究中，证明具有适当特性的配体将成为人类临床研究中的示踪剂的候选者，并进一步支持继续通过R01机制寻求该项目。公共卫生相关性：多巴胺D1受体（D1R）是中枢神经系统中最丰富的多巴胺受体。具体而言，D1R与精神分裂症和帕金森氏病等多种神经精神疾病有关，并且是治疗和药物开发的目标。在这个项目中，我们建议开发D1R激动剂PET配体，以允许对受体功能状态进行体内研究。