Ding Yu-Shin, Lin Kuo-Shyan, Garza Victor, Carter Pauline, Alexoff David, Logan Jean, Shea Colleen, Xu Youwen, King Payton
Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
Synapse. 2003 Dec 15;50(4):345-52. doi: 10.1002/syn.10281.
Reboxetine is a specific norepinephrine transporter (NET) inhibitor and has been marketed in several countries as a racemic mixture of the (R,R) and (S,S) enantiomers for the treatment of depression. Its methyl analog (methylreboxetine, MRB) has been shown to be more potent than reboxetine itself. We developed a nine-step synthetic procedure to prepare the normethyl precursor, which was used to synthesize [11C]O-methylreboxetine ([11C]MRB). We also developed a convenient resolution method using a chiral HPLC column to resolve the racemic precursor to obtain enantiomerically pure individual precursors that lead to the individual enantiomers (R,R)-[11C]MRB and (S,S)-[11C]MRB. Here we report an evaluation of the racemate and individual enantiomers of [11C]MRB as radioligands for PET imaging studies of NET systems in baboons both in brain and in peripheral organs. The relative regional distribution of the radioactivity after injection of [11C]MRB in baboon brain is consistent with the known distribution of NET. For a NET-poor region such as striatum, there were no significant changes in the striatal uptakes with and without the nisoxetine pretreatment. In contrast, a significant blocking effect was observed in NET-rich regions such as thalamus and cerebellum after injection of racemic [11C]MRB, with an even more dramatic effect after injection of (S,S)-[11C]MRB. These results, along with the fact that there was no regional specificity and no blocking effect by nisoxetine for (R,R)-[11C]MRB, suggest the enantioselectivity of MRB in vivo, consistent with previous in vitro and in vivo studies in rodents. PET studies of baboon torso revealed a blocking effect by desipramine only in the heart, a NET-rich organ, after injection of (S,S)-[11C]MRB, but not the (R,R)-isomer. These studies demonstrate that the use of (S,S)-[11C]MRB would allow a better understanding of the role that NET plays in living systems.
瑞波西汀是一种特异性去甲肾上腺素转运体（NET）抑制剂，已在多个国家作为（R,R）和（S,S）对映体的外消旋混合物上市，用于治疗抑郁症。其甲基类似物（甲基瑞波西汀，MRB）已被证明比瑞波西汀本身更有效。我们开发了一种九步合成方法来制备去甲基前体，该前体用于合成[11C]O-甲基瑞波西汀（[11C]MRB）。我们还开发了一种使用手性HPLC柱的简便拆分方法，以拆分外消旋前体，从而获得对映体纯的单个前体，进而得到单个对映体（R,R）-[11C]MRB和（S,S）-[11C]MRB。在此，我们报告了对[11C]MRB的外消旋体和单个对映体作为放射性配体用于狒狒脑和外周器官中NET系统PET成像研究的评估。在狒狒脑中注射[11C]MRB后，放射性的相对区域分布与已知的NET分布一致。对于像纹状体这样NET含量低的区域，无论有无去甲替林预处理，纹状体摄取均无显著变化。相比之下，注射外消旋[11C]MRB后，在像丘脑和小脑这样NET含量高的区域观察到显著的阻断作用，注射（S,S）-[11C]MRB后效果更显著。这些结果，以及去甲替林对（R,R）-[11C]MRB没有区域特异性和阻断作用这一事实，表明MRB在体内具有对映选择性，这与之前在啮齿动物中的体外和体内研究一致。对狒狒躯干的PET研究显示，注射（S,S）-[11C]MRB后，仅在富含NET的心脏器官中观察到地昔帕明的阻断作用，而（R,R）-异构体则没有。这些研究表明，使用（S,S）-[11C]MRB将有助于更好地理解NET在生物系统中的作用。
