Leung Kam
National Center for Biotechnology Information, NLM, NIH
5-Hydroxytryptamine (5-HT), commonly known as serotonin, has diverse physiological roles as a neurotransmitter in the central nervous system (1). 5-HT is involved in regulation and modulation of sleep, affective and personality behaviors, and pain. It also is a regulator of smooth muscle function and platelet aggregation. The brain cortical 5-HT system has been implicated in several neuropsychiatric disorders, including major depression, anxiety, schizophrenia, and obsessive-compulsive disorder (2, 3). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT to 5-HT), many of which include several subtypes (4). There are five receptor subtypes within the G-protein–coupled 5-HT receptor family: 5-HT, 5-HT, 5-HT, 5-HT, and 5-HT. 5-HT receptors are abundantly present in the hippocampus, entorhinal cortex, frontal cortex, raphe nucleus, and septum; the lowest densities are observed in the basal ganglia, substantia nigra, and cerebellum (5). Some thalamic and hypothalamic nuclei have intermediate densities. 5-HT receptors are involved in the mediation of emotion and the function of the hypothalamus. 5-HT receptors are implicated in anxiety, depression, hallucinogenic behavior, motion sickness, and eating disorders (6). Thus, there is a need for selective ligands to investigate the pharmacological role of 5-HT receptors. There have been several studies to develop specific 5-HT radioligands [PubMed] for positron emission tomography (PET) imaging, such as [-C]WAY 100635, [F]FPWAY, and [F]MPPF. However, none of these antagonists distinguishes between the high- and low-affinity states of the 5-HT receptors. The high-affinity state of the receptor is coupled to G-proteins, which mediate cell functions by providing intracellular signals. 2-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2,4)dione (MMP) was reported to be a potent agonist of 5-HT receptors ( = 0.15 nM) (7). This led to the development of [O--C]MMP ([C]MMP, also known as [C]CUMI-101) as a useful tool for PET imaging of the 5-HT receptor (8-10). However, [C]CUMI-101 was shown to be a partial 5-HT agonist and therefore was less efficient in mediating cell function (11, 12). 3-Chloro-4-[F]fluorophenyl-(4-fluoro-4-[[((5-methyl-4-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl)methanone ([F]F13714) was evaluated as a PET probe for the 5-HT receptor because unlabeled F13714 was found to be a selective 5-HT agonist with subnanomolar affinity for the 5-HT receptor (13).
5-羟色胺（5-HT），通常称为血清素，作为中枢神经系统中的一种神经递质具有多种生理作用（1）。5-HT参与睡眠、情感和人格行为以及疼痛的调节和调制。它也是平滑肌功能和血小板聚集的调节剂。大脑皮质5-HT系统与多种神经精神疾病有关，包括重度抑郁症、焦虑症、精神分裂症和强迫症（2,3）。5-HT的作用由多达七类受体群体（5-HT₁至5-HT₇）介导，其中许多包括几种亚型（4）。G蛋白偶联5-HT受体家族中有五种受体亚型：5-HT₁、5-HT₂、5-HT₃、5-HT₄和5-HT₅。5-HT₁受体大量存在于海马体、内嗅皮质、额叶皮质、中缝核和隔区；在基底神经节、黑质和小脑中观察到的密度最低（5）。一些丘脑和下丘脑核具有中等密度。5-HT₂受体参与情绪调节和下丘脑功能。5-HT₃受体与焦虑、抑郁、致幻行为、晕动病和饮食失调有关（6）。因此，需要选择性配体来研究5-HT受体的药理学作用。已经有几项研究开发用于正电子发射断层扫描（PET）成像的特异性5-HT放射性配体[PubMed]，例如[-¹¹C]WAY 100635、[¹⁸F]FPWAY和[¹⁸F]MPPF。然而，这些拮抗剂都无法区分5-HT₂受体的高亲和力和低亲和力状态。受体的高亲和力状态与G蛋白偶联，G蛋白通过提供细胞内信号来介导细胞功能。据报道，2-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁基)-4-甲基-1,2,4-三嗪-3,5(2H,4H)-二酮（MMP）是5-HT₂受体的强效激动剂（K₀ = 0.15 nM）（7）。这导致开发出[¹⁸O-¹¹C]MMP（[¹¹C]MMP，也称为[¹¹C]CUMI-101）作为用于5-HT₂受体PET成像的有用工具（8 - 10）。然而，[¹¹C]CUMI-101被证明是一种部分5-HT₂激动剂，因此在介导细胞功能方面效率较低（11,12）。3-氯-4-[¹⁸F]氟苯基-(4-氟-4-[[((5-甲基-4-甲基氨基吡啶-2-基甲基)-氨基]-甲基]-哌啶-1-基)甲酮（[¹⁸F]F13714）被评估为5-HT₂受体的PET探针，因为未标记的F13714被发现是一种对5-HT₂受体具有亚纳摩尔亲和力的选择性5-HT₂激动剂（13）。
