Imaging the D2/A2A Heterodimer with PET

使用 PET 对 D2/A2A 异二聚体进行成像

基本信息

批准号：
9791192
负责人：
ROBERT H MACH
金额：
$ 44.73万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9791192
关键词：
ADORA2A gene Adenosine Affinity Applications Grants Attention BRAIN initiative Binding Biological Blood - brain barrier anatomy Brain Brain imaging Carrier Proteins Cells Central Nervous System Diseases Chemistry Complex Coupled Development Dopamine Dopamine D2 Receptor Female Fluorides G-Protein-Coupled Receptors Goals Human Image In Vitro Knockout Mice Label Ligands Link Measurement Methodology Methods Mus Organic Synthesis P-Glycoprotein Piperazines Positron-Emission Tomography Primates Procedures Production Property Radioactivity Radiolabeled Research Research Project Grants Sensory Receptors Series Serotonin Serotonin Receptor 5-HT1A Signal Transduction Site Structure Structure-Activity Relationship Testing analog cycloaddition falls high risk imaging modality imaging probe imaging study in vivo in vivo imaging male metabolic abnormality assessment microPET monomer next generation nonhuman primate novel strategies protein transport radiotracer receptor uptake

项目摘要

PROJECT SUMMARY The goal of this research project is to determine if it is possible to develop a PET radiotracer capable of imaging GPCR heterodimers and not their corresponding homodimeric complexes. GPCR heterodimers represent the functional state of these receptors, yet there is currently no method for imaging these receptors in vivo with PET. Our initial strategy will focus on the development of probes for imaging the dopamine D2- adenosine A2A (i.e, D2/A2A) heterodimer. This heterodimer was chosen since it is currently thought to represent the main D2-coupled heterodimer in the CNS, and alterations in the D2/A2A heterodimer have been linked to a number of CNS disorders. Our strategy involves a novel approach that is focused on developing probes having an adequate affinity for binding to the D2/A2A heterodimer in vivo, but the affinity for the corresponding D2- and A2A homodimers is below the threshold needed to produce a signal in PET imaging studies. If successful, this proof-of-concept study will provide a new method for neuroreceptor imaging, PET imaging studies of GPCR heterodimers. Furthermore, the method we will develop can be applied to other orthosteric ligands to produce bivalent PET radiotracers capable of imaging different GPCR heterodimers, thereby ushering in a new era of PET radiotracer development for imaging this biologically important class of receptors.

项目摘要该研究项目的目的是确定是否有可能开发能够成像GPCR异二聚体，而不是其相应的同型二聚体复合物。 GPCR异二聚体表示这些受体的功能状态，但目前尚无对这些受体进行成像的方法在体内和宠物。我们的最初策略将着重于成像多巴胺D2-的探针的开发。腺苷A2A（即D2/A2A）异二聚体。选择此异二聚体，因为目前认为它代表CNS中的主要D2耦合异二聚体，D2/A2A异二聚体的改变已是链接到许多CNS疾病。我们的策略涉及一种专注于发展的新颖方法在体内与D2/A2A异二聚体结合具有足够亲和力的探针，但对相应的D2-和A2A同型二聚体低于在PET成像中产生信号所需的阈值研究。如果成功，这项概念验证研究将为神经感受器成像提供一种新的方法 GPCR异二聚体的成像研究。此外，我们将开发的方法可以应用于其他定性配体产生能够成像不同GPCR异二聚体的二价PET放射性示例剂，从而迎来了一个新的宠物放射性示踪剂开发时代受体。