Stehouwer Jeffrey, Chopra Arvind
Department of Radiology,, Center for Systems Imaging,, Emory University
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894
Serotonin (5-hydroxytryptamine (5HT)) is a neurotransmitter that is transported across the cell membrane by the serotonin transporter (SERT or 5HTT) (1) and is expressed in several tissues of the body, such as those of the brain, lungs (2-4), bone (5, 6), gastrointestinal tract (7), blood platelets (8, 9), and the cardiovascular system (10-12). Within the brain, the SERT is present primarily on the presynaptic neurons (13-15), and a high density of these transporters has been detected in the caudate, putamen, thalamus, hypothalamus, midbrain, pons, medulla, and amygdala; by comparison, the cortex has a lower density of the SERT (16-22). Alterations in serotonergic neurotransmission and SERT density in the brain have been implicated in the pathophysiology of depression and schizophrenia and may lead to suicide (23-26). Investigators have developed and evaluated the biological activity of several selective serotonin reuptake inhibitors (SSRIs) for the treatment of these neurological conditions (27-30).Several SSRIs approved by the United States Food and Drug Administration (FDA) are available commercially for the treatment of SERT-related conditions. Positron emission tomography imaging is often used as an investigational tool to measure the SERT density and SSRI occupancy of the transporter (these are not approved by the FDA as biomarkers) (31-33), and it is considered a suitable technique to study the pathophysiology of depression and to monitor (34) or develop new SERT therapeutics (35-37). Efforts have also been made to develop and evaluate I-labeled probes that can be used to study the biology and functions of SERT with single-photon emission tomography (SPECT) (38). However, these SERT tracers either did not exhibit any activity or were non-selective for the SERT because they also bound to the dopamine transporter (DAT) and/or the norepinephrine transporter (NET) and often produced low signal/background ratios due to slow clearance from the brain. In a continuing effort to produce radiolabeled compounds that can be used for the non-invasive study of SERT, investigators developed some tropane analogs of cocaine and demonstrated that these compounds had a high selectivity for SERT and exhibited very low affinity for either the DAT or the NET (39, 40). On the basis of these observations, 2β-carbomethoxy-3β-(4´-(()-2-iodoethenyl)phenyl)nortropane (ZIENT) was synthesized, characterized , and labeled with I to obtain [I]ZIENT for evaluation as a possible SPECT imaging agent to detect the SERT in rat and nonhuman primate brains (38, 41).
血清素（5-羟色胺（5HT））是一种神经递质，它通过血清素转运体（SERT或5HTT）跨细胞膜转运（1），并在身体的多个组织中表达，如大脑、肺（2-4）、骨骼（5, 6）、胃肠道（7）、血小板（8, 9）和心血管系统（10-12）。在大脑中，SERT主要存在于突触前神经元上（13-15），在尾状核、壳核、丘脑、下丘脑、中脑、脑桥、延髓和杏仁核中检测到这些转运体的高密度表达；相比之下，皮质中SERT的密度较低（16-22）。大脑中血清素能神经传递和SERT密度的改变与抑郁症和精神分裂症的病理生理学有关，可能导致自杀（23-26）。研究人员已经开发并评估了几种选择性血清素再摄取抑制剂（SSRI）的生物活性，用于治疗这些神经系统疾病（27-30）。美国食品药品监督管理局（FDA）批准的几种SSRI已在市场上用于治疗与SERT相关的疾病。正电子发射断层扫描成像通常用作研究工具，以测量转运体的SERT密度和SSRI占有率（这些未被FDA批准为生物标志物）（31-33），它被认为是研究抑郁症病理生理学以及监测（34）或开发新的SERT治疗药物（35-37）的合适技术。人们还努力开发和评估可用于通过单光子发射断层扫描（SPECT）研究SERT生物学和功能的I标记探针（38）。然而，这些SERT示踪剂要么没有表现出任何活性，要么对SERT没有选择性，因为它们也与多巴胺转运体（DAT）和/或去甲肾上腺素转运体（NET）结合，并且由于从大脑清除缓慢，常常产生低的信号/背景比。为了继续努力生产可用于SERT无创研究的放射性标记化合物，研究人员开发了一些可卡因的托烷类似物，并证明这些化合物对SERT具有高选择性，对DAT或NET表现出非常低的亲和力（39, 40）。基于这些观察结果，合成了2β-甲氧羰基-3β-（4´-（（）-2-碘乙烯基）苯基）降托烷（ZIENT），进行了表征并用I标记以获得[I]ZIENT，用于评估其作为检测大鼠和非人类灵长类动物大脑中SERT的可能SPECT成像剂（38, 41）。
