AZA BICYCLO NONANE SEROTONIN TRANSPORTER RADIOTRACERS

描述(由申请人提供)： 这项研究项目的目标是确定配体的结构和放射性标记，以便通过正电子或单光子发射断层扫描(PET或SPECT)的外部成像来定量测量活体大脑中的5-HTT位点。已知5-羟色胺转运体在几个生理和病理生理学过程中发挥作用，特别是在抑郁症、焦虑和精神病中，尸检和初步成像研究表明。特异性结合5-HTT的放射性示踪剂将在此类疾病的诊断、监测、治疗和研究中发挥重要作用。然而，目前还没有一种合适的示踪剂可以在大脑中5-HTT浓度较低的区域进行定量，比如大脑皮层。 在这个应用中，我们建议测试一个假设，即一个新的结构，氮杂-双环-[3.2.2]-壬烷，将具有转运体结合亲和力和药理特异性的正确组合，使我们能够在低密度区域检测5-羟色胺转运体。 在用经典构效关系(SAR)方法进行的初步实验中，我们发现某些氮杂-双环-[3.2.2]-正庚烷醚对5-HTT表现出纳米分子亲和力。我们将通过并行合成和纯化将这种SAR扩展到更大的文库。将对候选配体进行药理亲和力和对5-HTT与竞争结合位点的特异性的筛选。最有希望的候选分子将被放射性核素F-18或1-123标记，并在专用的PET或SPECT成像设备中通过在非人类灵长类动物体内进行成像进行评估。

DESCRIPTION (provided by applicant): The goal of this research project is to define the structure and radioactive label for ligands that will permit quantitative measurement of serotonin transporter (5-HTT) sites in living brain by external imaging with positron or single-photon emission tomography (PET or SPECT). The serotonin transporter is known to play a role in several physiological and pathophysiological processes, especially in depression, anxiety, and psychosis, as demonstrated by post-mortem and preliminary imaging studies. A radiotracer that bound specifically to 5-HTT would be of great utility in diagnosis, monitoring treatment, and research of such disorders. However, there is not yet a suitable tracer that allows quantitation in areas of the brain with low densities of 5-HTT, such as the cortex. In this application we propose to test the hypothesis that a novel structure, aza-bicyclo-[3.2.2]-nonane, will have the right combination of transporter binding affinity and pharmacological specificity to allow us to detect the serotonin transporter in the region of low density. In preliminary experiments using a classical structure-activity relationship (SAR) approach, we found that certain aza-bicyclo-[3.2.2]-nonane ethers showed nanomolar affinity to 5-HTT. We will extend this SAR to a larger library using parallel synthesis and purification. The ligand candidates will be screened for pharmacological affinity and specificity to 5-HTT versus competing binding sites. The most promising candidates will be radiolabeled with radionuclides, F-18, or 1-123 as appropriate to the molecule, and evaluated by imaging in vivo in non-human primates in a dedicated PET or SPECT imaging device.