PET Radiotracers for Imaging the Dopamine D3 Receptor

用于多巴胺 D3 受体成像的 PET 放射性示踪剂

• 批准号: 9263928
• 负责人: ROBERT H MACH
• 金额: $ 52.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263928
• 关键词: Affinity; Agonist; Applications Grants; Benzamides; Binding; Binding Sites; Brain; Carbon; Clinical Trials; Collaborations; Complement; Data; Development; Disease; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug abuse; Family; Fluorine; Funding; G-Protein-Coupled Receptors; Goals; Grant; High Pressure Liquid Chromatography; Human; Image; In Vitro; Joints; Kinetics; Label; Ligand Binding; Ligands; Lorazepam; Measures; Methods; Molecular Conformation; Mus; Noise; Pharmacology; Phase; Play; Positron-Emission Tomography; Progress Reports; Property; Publications; Radiolabeled; Reporting; Research; Research Personnel; Research Project Grants; Rodent; Role; Sequence Homology; Series; Signal Transduction; Site; Specificity; Structure-Activity Relationship; Synapses; Testing; Toxic effect; base; density; dopamine D3 receptor; dosimetry; flexibility; human subject; imaging study; in vivo; in vivo imaging; man; monoamine; neurological pathology; neuropsychiatry; nonhuman primate; novel; pre-clinical; public health relevance; radioligand; radiotracer; receptor; receptor density; uptake

 DESCRIPTION (provided by applicant): The dopamine D3 receptor has continued to be one of the most challenging targets for PET radiotracer development in the field of CNS receptor research. This difficulty has been largely based on the high degree of sequence homology between D2 and D3 receptors in the ligand binding region of each receptor. Although the past decade has witnessed a number of compounds having a high affinity and selectivity for D3 vs. D2 receptors, and many of these have been labeled with either carbon-11 or fluorine-18, none has proven to be successful in imaging the D3 receptor without the cross-over labeling of the D2 receptor. As described in the progress report, we have developed a D3-selective radiotracer, [18F] Fluortriopride (FTP) that has shown promising results in preliminary first-in-human PET studies. One of the conclusions reached in the progress report is that [18F]FTP binds to the orthosteric site in the D3 receptor, which results in a competition between dopamine (DA) and radiotracer for binding to the D3 receptor. Therefore, [18F] FTP measures D3 availability, which represents the number of D3 receptors that does not have DA bound to the orthosteric site. The first goal of the research described in this competing renewal is to conduct a detailed first- in-man study to fully characterize the ability of [18F] FTP to measure D3 receptor availability. A second goal is to identify a PET radiotracer that is insensitive to endogenous dopamine levels so that it is capable of imaging the density of D3 receptor in vivo. The project described in this grant proposal involves the continuation of a long-standing collaboration with the P.I. (RH Mach) and an expert in the field of dopamine receptor pharmacology (R.R. Luedtke). These investigators have a total of 38 joint publications in the field of dopamine receptor pharmacology. This project consists of five Specific Aims. The first Specific Aim consists of the first-in-human studies of [18F] FTP. The second Specific Aim describes a detailed structure-activity relationship study that will be conducted on two series of compounds with the goal of identifying the properties needed to develop a D3- selective probe whose in vivo binding is not influenced by synaptic dopamine levels. The compounds synthesized in Aim 2 will be screened in a series of in vitro binding studies described in Specific Aim 3. Specific Aim 4 involves the development of the radiosynthetic methods needed to conduct the rodent and nonhuman primate imaging described in Specific Aim 5. We anticipate generating one PET radiotracer that displays the affinity, specificity, and in vivo kinetics needed for translational imaging studies i human subjects by the completion of this 5-year research project.

 描述（由申请人提供）：多巴胺D3受体仍然是CNS受体研究领域PET放射性示踪剂开发中最具挑战性的靶点之一。这种困难主要是基于D2和D3受体在每个受体的配体结合区中的高度序列同源性。尽管在过去的十年中已经发现了许多对D3受体和D2受体具有高亲和力和选择性的化合物，并且其中许多已经用碳-11或氟-18标记，但是没有一种化合物被证明在没有D2受体的交叉标记的情况下成功地对D3受体进行成像。 正如进展报告中所述，我们开发了一种D3选择性放射性示踪剂，[18F] Fluortriopride（FTP），在初步的首次人体PET研究中显示出有希望的结果。进展报告中得出的结论之一是，[18 F]FTP与D3受体中的正构位点结合，导致多巴胺（DA）和放射性示踪剂之间竞争与D3受体结合。因此，[18 F] FTP测量D3可用性，其代表没有DA结合到正构位点的D3受体的数量。本竞争性更新中描述的研究的第一个目标是进行详细的首次人体研究，以充分表征[18 F] FTP测量D3受体可用性的能力。第二个目标是鉴定对内源性多巴胺水平不敏感的PET放射性示踪剂，使得其能够对体内D3受体的密度成像。 本文所述的项目 赠款提案涉及与P.I.的长期合作的延续。(RH马赫）和多巴胺受体药理学领域的专家（R.R. Luedtke）。这些研究者在多巴胺受体药理学领域共有38篇联合出版物。 该项目包括五个具体目标。第一个特定目的包括[18F] FTP的首次人体研究。第二个具体目标描述了一个详细的结构-活性关系的研究，将进行两个系列的化合物，其目标是确定所需的属性，以开发一种D3-选择性探针，其体内结合不受突触多巴胺水平的影响。目标2中合成的化合物将在具体目标3中描述的一系列体外结合研究中进行筛选。具体目标4涉及开发进行具体目标5中所述的啮齿动物和非人灵长类动物成像所需的放射合成方法。我们预计产生一个PET放射性示踪剂，显示的亲和力，特异性，并在人体受试者的翻译成像研究所需的体内动力学完成这个5年的研究项目。