Piperidine Derivatives as Radiotracers for Serotonin Transporters

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（PET）或单光子（SPECT）发射断层扫描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、季节性情感障碍、贪食症和精神病中，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。基于使用经典结构-活性关系方法的初步体外结合结果，我们发现苯基托烷的某些4 '-联苯类似物显示出对5-HTT的纳摩尔亲和力和相对于其他单胺转运蛋白的>50倍选择性。在本申请中，我们提出测试以下假设：1）在4-苯基哌啶的4 ′-位上具有π-供体取代基的衍生物相对于多巴胺转运体（DAT）和去甲肾上腺素转运体（NET）将有利于与5-HTT结合;和2）消除托烷的C6-C7桥（以产生哌啶类似物）将降低我们的化合物的亲脂性，并且具有比相应的托烷或去甲托烷化合物更低的非特异性结合。

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 (PET) or single photon (SPECT) emission tomography. The serotonin transporter is known to play a role in several physiological and pathophysiological processes, especially in depression, anxiety, seasonal affective disorder, bulimia, 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. Based on preliminary in vitro binding results using a classical structure-activity relationship approach, we found that certain 4'-biphenyl analogs of phenyltropanes showed nanomolar affinity to 5-HTT and >50-fold selectivity with respect to other monoamine transporters. In this application we propose to test the following hypotheses: 1) derivatives with pi-donor substituents on the 4'-position of 4-phenyl piperidine will favor binding to 5-HTT relative to dopamine transporter (DAT) and norepinephrine transporter (NET); and 2) elimination of the C6-C7 bridge of the tropane (to yield piperidine analogs) will reduce the lipophilicity of our compounds and have lower nonspecific binding than the corresponding tropane or nor-tropane compound.