PET Radiotracers for Imaging the Dopamine D3 Receptor

 描述(申请人提供)：在中枢神经系统受体研究领域，多巴胺D3受体一直是PET放射性示踪剂开发中最具挑战性的目标之一。这一困难在很大程度上是由于D2和D3受体在每个受体的配体结合区的高度序列同源性。尽管在过去的十年里，许多化合物对D3和D2受体具有高亲和力和选择性，其中许多化合物被标记了碳-11或氟-18，但没有一种化合物被证明在没有D2受体交叉标记的情况下能够成功地对D3受体进行成像。正如进展报告中所描述的，我们已经开发了一种D3选择性放射性示踪剂，[18F]氟曲必利(Ftp)，在初步的人类PET研究中显示了令人振奋的结果。进展报告中得出的结论之一是，[18F]ftp与D3受体中的邻位位置结合，导致多巴胺(DA)与放射性示踪剂竞争结合D3受体。因此，[18F]ftp测量D3的可用性，它代表没有DA结合到正位的D3受体的数量。在这项竞争性更新中描述的研究的第一个目标是进行一项详细的第一人研究，以充分表征[18F]ftp测量D3受体可用性的能力。第二个目标是确定一种对内源性多巴胺水平不敏感的PET放射性示踪剂，以便它能够成像体内D3受体的密度。本文件中描述的项目 格兰特的提议涉及继续与P.I.(Rh Mach)和一位多巴胺受体药理学领域的专家(R.R.Luedtke)长期合作。这些研究人员在多巴胺受体药理学领域共发表了38篇联合出版物。该项目由五个具体目标组成。第一个具体目标是首次对[18F]ftp进行人体研究。第二个具体目标描述了一项详细的结构-活性关系研究，该研究将在两个系列的化合物上进行，目的是确定开发D3选择性探针所需的性质，其体内结合不受突触多巴胺水平的影响。在目标2中合成的化合物将在特定目标3中描述的一系列体外结合研究中进行筛选。特定目标4涉及进行特定目标5中描述的啮齿动物和非人类灵长类动物成像所需的放射合成方法的开发。我们预计在完成这项为期5年的研究项目后，将产生一种显示人类受试者翻译成像研究所需的亲和力、特异性和体内动力学的PET放射性示踪剂。

 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.