PET RADIOTRACERS FOR IMAGING THE DOPAMINE D3 RECEPTOR

用于多巴胺 D3 受体成像的 PET 放射示踪剂

• 批准号: 8096550
• 负责人: ROBERT H MACH
• 金额: $ 33.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096550
• 关键词: Adenylate Cyclase; Affinity; Alzheimer' s Disease; Applications Grants; Autopsy; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain imaging; Carbon; Cell Line; Cells; Central Nervous System Diseases; Chronic; Communities; Complement; Data; Development; Disease; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug abuse; Fluorine; Functional Imaging; Funding; Future; Goals; Grant; Human; Image; Imaging Techniques; Label; Lead; Life; Ligands; Macaca; Measurement; Measures; Monkeys; Neuraxis; Neurologic; Neurosciences Research; Parkinson Disease; Play; Positron-Emission Tomography; Property; Protocols documentation; Raclopride; Radiation Toxicity; Radiolabeled; Radiometry; Regulation; Reporting; Research; Research Project Grants; Role; Sampling; Schizophrenia; Series; Study Section; Ventral Striatum; base; cocaine exposure; design; dopamine D3 receptor; dopamine D4 receptor; genetically modified cells; imaging probe; in vivo; interest; neuropsychiatry; novel; novel strategies; programs; public health relevance; putamen; radioligand; radiotracer; receptor; receptor binding; receptor density; receptor function; sigma receptors; single photon emission computed tomography

DESCRIPTION (provided by applicant): PET imaging studies measuring the change in dopamine D2-class of receptors function have historically used radiotracers that are not capable of discriminating between D2/ and D3 receptors. For example, [11C] raclopride, [18F] fallypride and [11C] PHNO bind with high affinity to dopamine D2 and D3 receptors. Therefore, measurement of "D2 receptor binding potential" obtained with these radiotracers consists of a composite of D2 and D3 receptor density. A number of studies have provided evidence suggesting that D2 and D3 receptors are regulated in an opposing manner in a variety of CNS disorders. For example, it has been reported that there is a 45% reduction in D3 receptors in the ventral striatum and a 15% increase in D2 receptors the caudate/putamen of postmortem brain samples of Parkinson's Disease. Other studies have shown an increase in D3 receptors and a decrease in D2 receptors in brain samples obtained following chronic exposure to cocaine. Therefore, the development of radiotracers having a high affinity for D3 versus D2 receptors, and vice versa, would be of tremendous interest to the PET imaging and neuroscience research community since it would enable the independent measurement of D2 and D3 receptors in a variety of CNS disorders. Our group is currently funded (through PA-03-112) to develop PET radiotracers having a high affinity and selectivity for D2 versus D3 receptors. The function of the current research project is to develop PET radiotracers selective for the D3 receptor which would complement our ongoing research in the development of D2-selective radiotracers. The ultimate goal of our research effort is to develop a novel strategy for imaging the change in D3 and D2 receptors in a variety of CNS disorders. PUBLIC HEALTH RELEVANCE: An alteration in the function of the dopamine D3 receptor is thought to play a key role in a variety of pathological conditions including schizophrenia, Parkinson's Disease, Alzheimer's Disease, and drug abuse. However, the precise role of this receptor in these brain disorders is currently not known. The goal of the research described in this grant is to develop novel probes for imaging the D3 receptor in the living human brain with the functional imaging technique Positron Emission Tomography or PET. These probes are expected to provide valuable information on the role of the D3 receptor in disorders of the central nervous system.

描述（由申请人提供）：测量多巴胺D2类受体功能变化的PET成像研究过去使用的放射性示踪剂不能区分D2/和D3受体。例如，[11 C]雷氯必利、[18 F]法利必利和[11 C] PHNO以高亲和力结合多巴胺D2和D3受体。因此，用这些放射性示踪剂获得的“D2受体结合潜力”的测量由D2和D3受体密度的复合物组成。许多研究提供的证据表明，D2和D3受体在各种CNS疾病中以相反的方式调节。例如，据报道，帕金森病的死后脑样品的腹侧纹状体中的D3受体减少45%，尾状核/壳核中的D2受体增加15%。其他研究表明，在长期接触可卡因后获得的大脑样本中，D3受体增加，D2受体减少。因此，开发对D3和D2受体具有高亲和力的放射性示踪剂，反之亦然，将引起PET成像和神经科学研究界的极大兴趣，因为它将能够独立测量各种CNS疾病中的D2和D3受体。我们的团队目前获得资助（通过PA-03-112），以开发对D2和D3受体具有高亲和力和选择性的PET放射性示踪剂。目前研究项目的功能是开发对D3受体具有选择性的PET放射性示踪剂，这将补充我们正在进行的D2选择性放射性示踪剂开发研究。我们研究工作的最终目标是开发一种新的策略，用于成像各种CNS疾病中D3和D2受体的变化。 公共卫生相关性：多巴胺D3受体功能的改变被认为在包括精神分裂症、帕金森病、阿尔茨海默病和药物滥用在内的多种病理状况中起关键作用。然而，这种受体在这些大脑疾病中的确切作用目前尚不清楚。这项研究的目的是开发新的探针，用于使用功能成像技术正电子发射断层扫描（PET）对活体人脑中的D3受体进行成像。这些探针有望提供有关D3受体在中枢神经系统疾病中的作用的有价值的信息。