Piperidine Derivatives as Radiotracers for Serotonin Transporters

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(PET)或单光子(SPECT)发射断层扫描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过程中发挥作用，特别是在抑郁、焦虑、季节性情感障碍、暴食症和精神病中，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。基于经典构效关系方法的初步体外结合结果，我们发现某些苯基托烷的4‘-联苯类似物对5-HTT和~gt；的纳摩尔亲和力是其他单胺转运体的50倍。在这一应用中，我们建议检验以下假设：1)4-苯基哌啶4‘-位带有pi-给体取代基的衍生物将有利于与5-HTT相对于多巴胺转运体(DAT)和去甲肾上腺素转运体(NET)的结合；以及2)消除托烷的C6-C7桥(以生成哌啶类似物)将降低化合物的亲脂性，并且与相应的托烷或去甲托烷化合物相比，非特异性结合更低。

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.