AZA BICYCLO NONANE SEROTONIN TRANSPORTER RADIOTRACERS

描述（由申请人提供）： 本研究项目的目标是定义配体的结构和放射性标记，从而允许通过正电子或单光子发射断层扫描（PET或SPECT）的外部成像定量测量活体脑中的5-羟色胺转运体（5-HTT）位点。5-羟色胺转运蛋白在多种生理和病理生理过程中发挥作用，特别是在抑郁症、焦虑症和精神病中，如尸检和初步成像研究所示。特异性结合5-HTT的放射性示踪剂将在此类疾病的诊断、监测治疗和研究中具有很大的实用性。然而，还没有合适的示踪剂，允许定量的大脑区域与低密度的5-HTT，如皮质。 在本申请中，我们提出测试的假设，一种新的结构，氮杂-双环-[3.2.2]-壬烷，将有正确的组合的转运蛋白结合亲和力和药理学特异性，使我们能够检测到的血清素转运蛋白的低密度区域。 在使用经典结构-活性关系（SAR）方法的初步实验中，我们发现某些氮杂-双环-[3.2.2]-壬烷醚对5-HTT显示出纳摩尔亲和力。我们将使用平行合成和纯化将该SAR扩展到更大的文库。将筛选候选配体对5-HTT与竞争性结合位点的药理学亲和力和特异性。最有希望的候选物将用放射性核素、F-18或I-123（视分子情况而定）进行放射性标记，并通过在专用PET或SPECT成像装置中对非人灵长类动物进行体内成像进行评价。

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.