A new positron emission tomography imaging agent for the serotonin transporter:: synthesis, pharmacological characterization, and kinetic analysis of [11C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine ([11C]AFM)
A new positron emission tomography imaging agent for the serotonin transporter:: synthesis, pharmacological characterization, and kinetic analysis of [11C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine ([11C]AFM)
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DOI：
10.1016/j.nucmedbio.2003.11.008
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发表时间：
2004-07-01
影响因子：
3.1
通讯作者：
Laruelle, M
中科院分区：
文献类型：
--
作者：
Huang, YY;Hwang, DR;Laruelle, M
报道了一种新的5-羟色胺转运体（SERT）的正电子发射断层显像（PET）放射性配体[C-11]2-[2-（二甲氨基甲基）苯硫基]-5-氟甲基苯胺（[C-11]AFM）的合成、标记及体内外评价。以4-氯-3-硝基苄基乙酸酯和硫代水杨酸为原料，经五步合成得到AFM。在与克隆的人转运蛋白的体外结合研究中，AFM显示出对SERT的高亲和力（对hSERT的Ki为1.04 nmol/L）和良好的选择性（对hNET的Ki为664 nmol/L，对hDAT的Ki> 10，000 nmol/L）。放射性标记化合物[C-11]AFM由其单甲胺前体通过与高比活度[C-11]碘甲烷反应在30-37分钟内制备。放射化学产率为12.3 +/- 8.1%（基于[C-11]碘甲烷），合成结束时的比活度为1733 +/- 428 Ci/mmol（EOS，n = 14）。最终产物的放射化学和化学纯度> 97%。大鼠的生物分布研究表明，[C-11]AFM很容易进入大脑，并定位于已知含有高浓度SERT的区域，具有高特异性与非特异性结合率。此外，[C-11]AFM在SERT富集区的结合被冷化合物AFM和选择性5-羟色胺再摄取抑制剂西酞普兰阻断，但不被选择性去甲肾上腺素再摄取抑制剂nisoxetine或选择性多巴胺再摄取抑制剂GBR 12935阻断。在注射后30分钟，>95%的脑活性对应于母体化合物，表明大鼠脑中不存在放射性标记的代谢物。狒狒的PET成像实验显示，[C-11]AFM的脑分布模式与SERT的区域浓度一致，在中脑和丘脑中检测到最高水平的放射性，在海马和纹状体中检测到中等水平的放射性，在皮质区域中检测到低水平的放射性。用西酞普兰（4和6 mg/kg，静脉注射）预处理狒狒可将局部脑分布体积降低至低而均匀的水平，从而强调了[C-11]AFM在体内对SERT的结合特异性。血液样本分析表明，放射性配体快速代谢成亲水性更强的组分，以及不存在放射性标记的亲脂性代谢产物。以动脉血药浓度为输入函数，采用动力学和图形分析方法分析局部时间-活性曲线。两种方法返回相似的动力学参数，并记录了[C-11]AFM的高特异性与非特异性平衡系数（V-3”）。用简单的参考组织方法也得到了相同的V-3”值，这表明用[C-11]AFM可以在没有动脉血采样的情况下实现SERT的定量。总之，[C-11]AFM似乎是一个很好的PET放射性配体的可视化和可靠的定量SERT在体内。(C)2004爱思唯尔公司All rights reserved.
The synthesis, radiolabeling, and in vitro and in vivo evaluation of a new positron emission tomography (PET) radioligand for the serotonin transporter (SERT), [C-11]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine ([C-11]AFM) is reported. AFM was prepared from 4-chloro-3-nitrobenzyl acetate and thiosalicylic acid in a five-step synthetic sequence. In binding studies in vitro with cloned human transporters, AFM displayed high binding affinity (Ki 1.04 nmol/L for hSERT) and good selectivity (Ki 664 nmol/L for hNET and >10,000 nmol/L for hDAT) for SERT. The radiolabled compound [C-11]AFM was prepared in 30-37 minutes from its monomethylamine precursor by reaction with high specific activity [C-11]iodomethane. Radiochemical yield was 12.3 +/- 8.1% based on [C-11]iodomethane and specific activity was 1733 +/- 428 Ci/mmol at end of synthesis (EOS, n = 14). Radiochemical and chemical purity of the final product was >97%. Biodistribution studies in rats indicated that [C-11]AFM entered the brain readily and localized in regions known to contain high concentrations of SERT, with high specific to nonspecific binding ratios. Furthermore, binding of [C-11]AFM in SERT-rich regions was blocked by the cold compound AFM and the selective serotonin reuptake inhibitor citalopram but not by the selective norepinephrine reuptake inhibitor nisoxetine or the selective dopamine reuptake inhibitor GBR 12935. At 30 minutes after injection, >95% of the brain activity corresponded to the parent compound, indicating the absence of radiolabeled metabolites in the rat brain. PET imaging experiments in baboons showed a brain distribution pattern of [C-11]AFM consistent with the regional concentrations of SERT, with the highest levels of radioactivity detected in the midbrain and thalamus, moderate levels in the hippocampus and striatum, and the low levels in the cortical regions. Pretreatment of the baboons with citalopram (4 and 6 mg/kg, intravenously) reduced regional brain distribution volumes to low and homogeneous levels, thus underlining the binding specificity of [C-11]AFM for SERT in vivo. Analysis of blood samples indicated a fast metabolism of the radioligand into more hydrophilic components, as well as the absence of radiolabeled lipophilic metabolites. Regional time-activity curves were analyzed with kinetic and graphical analysis methods using the arterial concentrations as input function. Both methods returned similar kinetic parameters and documented high specific to nonspecific equilibrium coefficients (V-3") for [C-11]AFM. Identical V-3" values were also derived with the simple reference tissue method, indicating that quantification of SERT with [C-11]AFM can be achieved without arterial blood sampling. In summary, [C-11]AFM appears to be an excellent PET radioligand for the visualization and reliable quantification of SERT in vivo. (C) 2004 Elsevier Inc. All rights reserved.