Zhuang Z, Choi S, Hou C, Mu M, Kung M, Acton P D, Kung H F
Departments of Radiology and Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Nucl Med Biol. 2000 Feb;27(2):169-75. doi: 10.1016/s0969-8051(99)00093-1.
The serotonin transporters (SERT) are the primary binding sites for selective serotonin reuptake inhibitors, commonly used antidepressants such as fluoxetine, sertraline, and paroxetine. Imaging of SERT with positron emission tomography and single photon emission computed tomography in humans would provide a useful tool for understanding how alterations of this system are related to depressive illnesses and other psychiatric disorders. In this article the synthesis and characterization of [(125)I]ODAM [(5-iodo-2-(2-dimethylaminomethylphenoxy)-benzyl alcohol, 9)] as an imaging agent in the evaluation of central nervous system SERT are reported. A new reaction scheme was developed for the preparation of compound 9, ODAM, and the corresponding tri-n-butyltin derivative 10. Upon reacting 10 with hydrogen peroxide and sodium[(125)I]iodide, the radiolabeled [(125)95%). In an initial binding study using cortical membrane homogenates of rat brain, ODAM displayed a good binding affinity with a value of K(i) = 2.8 +/- 0.88 nM. Using LLC-PK(1) cells specifically expressing the individual transporter (i.e. dopamine [DAT], norepinephrine [NET], and SERT, respectively), ODAM showed a strong inhibition on SERT (K(i) = 0.12 +/- 0.02 nM). Inhibition constants for the other two transporters were lower (K(i) = 3.9 +/- 0.7 microM and 20.0 +/- 1.9 nM for DAT and NET, respectively). Initial biodistribution study in rats after an intravenous (IV) injection of [(125)I]ODAM showed a rapid brain uptake and washout (2.03, 1.49, 0.79, 0.27, and 0.07% dose/organ at 2, 30, 60, 120, and 240 min, respectively). The hypothalamus region where the serotonin neurons are located exhibited a high specific uptake. Ratios of hypothalamus-cerebellum/cerebellum based on percent dose per gram of these two regions showed values of 0.35, 0. 86, 0.86, 0.63, and 0.34 at 2, 30, 60, 120, and 240 min, post-IV injection, respectively. The specific uptake in hypothalamus can be effectively blocked by pretreatment of known SERT ligands. The results suggest that this novel ligand displays desirable in vitro and in vivo properties as a potential SERT imaging agent.
血清素转运体（SERT）是选择性血清素再摄取抑制剂的主要结合位点，这些抑制剂是常用的抗抑郁药，如氟西汀、舍曲林和帕罗西汀。利用正电子发射断层扫描和单光子发射计算机断层扫描对人体SERT进行成像，将为理解该系统的改变如何与抑郁症及其他精神障碍相关提供一个有用的工具。本文报道了[(125)I]ODAM[(5-碘-2-(2-二甲基氨基甲基苯氧基)-苄醇，9)]作为一种成像剂在评估中枢神经系统SERT中的合成与表征。开发了一种新的反应方案来制备化合物9（ODAM）和相应的三正丁基锡衍生物10。将10与过氧化氢和[（125）I]碘化钠反应后，得到放射性标记的[(125)I]ODAM，产率>95%。在使用大鼠脑皮质膜匀浆的初步结合研究中，ODAM显示出良好的结合亲和力，K(i)值为2.8±0.88 nM。使用分别特异性表达单个转运体（即多巴胺转运体[DAT]、去甲肾上腺素转运体[NET]和SERT）的LLC-PK(1)细胞，ODAM对SERT表现出强烈的抑制作用（K(i)=0.12±0.02 nM）。对另外两种转运体的抑制常数较低（DAT和NET的K(i)分别为3.9±0.7 microM和20.0±1.9 nM）。在大鼠静脉注射[(125)I]ODAM后的初步生物分布研究表明，脑摄取和清除迅速（在2、30、60、120和240分钟时，分别为2.03、1.49、0.79、0.27和0.07%剂量/器官）。血清素神经元所在的下丘脑区域表现出较高 的特异性摄取。基于这两个区域每克剂量百分比的下丘脑-小脑/小脑比值在静脉注射后2、30、60、120和240分钟时分别为0.35、0.86、0.86、0.63和0.34。下丘脑的特异性摄取可通过已知SERT配体的预处理有效阻断。结果表明，这种新型配体作为一种潜在的SERT成像剂具有理想的体外和体内特性。
