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[11C]MADAM用作理解用于正电子发射断层扫描（PET）的二苯硫醚放射性配体放射性代谢的模型。

[11C]MADAM Used as a Model for Understanding the Radiometabolism of Diphenyl Sulfide Radioligands for Positron Emission Tomography (PET).

作者信息

Gourand Fabienne, Amini Nahid, Jia Zhisheng, Stone-Elander Sharon, Guilloteau Denis, Barré Louisa, Halldin Christer

机构信息

Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, SE-171 76 Stockholm, Sweden; CEA, DSV/I2BM, LDM-TEP Group, GIP Cyceron, Bd Henri Becquerel, BP 5229, F-14074 Caen, France; Université de Caen Basse-Normandie, Caen, France; CNRS, UMR ISTCT 6301, LDM-TEP Group, GIP Cyceron, Caen, France.

Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, SE-171 76 Stockholm, Sweden.

出版信息

PLoS One. 2015 Sep 14;10(9):e0137160. doi: 10.1371/journal.pone.0137160. eCollection 2015.

DOI:10.1371/journal.pone.0137160
PMID:26367261
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4569384/
Abstract

In quantitative PET measurements, the analysis of radiometabolites in plasma is essential for determining the exact arterial input function. Diphenyl sulfide compounds are promising PET and SPECT radioligands for in vivo quantification of the serotonin transporter (SERT) and it is therefore important to investigate their radiometabolism. We have chosen to explore the radiometabolic profile of [11C]MADAM, one of these radioligands widely used for in vivo PET-SERT studies. The metabolism of [11C]MADAM/MADAM was investigated using rat and human liver microsomes (RLM and HLM) in combination with radio-HPLC or UHPLC/Q-ToF-MS for their identification. The effect of carrier on the radiometabolic rate of the radioligand [11C]MADAM in vitro and in vivo was examined by radio-HPLC. RLM and HLM incubations were carried out at two different carrier concentrations of 1 and 10 μM. Urine samples after perfusion of [11C]MADAM/MADAM in rats were also analysed by radio-HPLC. Analysis by UHPLC/Q-ToF-MS identified the metabolites produced in vitro to be results of N-demethylation, S-oxidation and benzylic hydroxylation. The presence of carrier greatly affected the radiometabolism rate of [11C]MADAM in both RLM/HLM experiments and in vivo rat studies. The good concordance between the results predicted by RLM and HLM experiments and the in vivo data obtained in rat studies indicate that the kinetics of the radiometabolism of the radioligand [11C]MADAM is dose-dependent. This issue needs to be addressed when the diarylsulfide class of compounds are used in PET quantifications of SERT.

摘要

在定量PET测量中，分析血浆中的放射性代谢物对于确定准确的动脉输入函数至关重要。二苯硫醚化合物是用于5-羟色胺转运体（SERT）体内定量的有前景的PET和SPECT放射性配体，因此研究它们的放射性代谢很重要。我们选择探索[11C]MADAM的放射性代谢概况，[11C]MADAM是这些广泛用于体内PET-SERT研究的放射性配体之一。使用大鼠和人肝微粒体（RLM和HLM）结合放射性高效液相色谱法或超高效液相色谱/四极杆飞行时间质谱法（UHPLC/Q-ToF-MS）来研究[11C]MADAM/MADAM的代谢以进行代谢物鉴定。通过放射性高效液相色谱法检测载体对放射性配体[11C]MADAM体外和体内放射性代谢率的影响。RLM和HLM孵育在1和10μM两种不同的载体浓度下进行。对大鼠灌注[11C]MADAM/MADAM后的尿液样本也通过放射性高效液相色谱法进行分析。通过UHPLC/Q-ToF-MS分析确定体外产生的代谢物是N-去甲基化、S-氧化和苄基羟基化的结果。在RLM/HLM实验和体内大鼠研究中，载体的存在都极大地影响了[11C]MADAM的放射性代谢率。RLM和HLM实验预测结果与大鼠研究中获得的体内数据之间的良好一致性表明，放射性配体[11C]MADAM的放射性代谢动力学是剂量依赖性的。当二芳基硫醚类化合物用于SERT的PET定量时，这个问题需要得到解决。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/53f8c2e8a603/pone.0137160.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/1a3eca1a9b38/pone.0137160.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/175c8a3e474b/pone.0137160.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/8b492d202b51/pone.0137160.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/db6386c7be75/pone.0137160.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/f0502a28c56e/pone.0137160.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/53f8c2e8a603/pone.0137160.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/1a3eca1a9b38/pone.0137160.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/175c8a3e474b/pone.0137160.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/8b492d202b51/pone.0137160.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/db6386c7be75/pone.0137160.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/f0502a28c56e/pone.0137160.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24c6/4569384/53f8c2e8a603/pone.0137160.g006.jpg

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Nucl Med Biol. 2014 Jul;41(6):501-6. doi: 10.1016/j.nucmedbio.2014.03.022. Epub 2014 Apr 2.
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Anal Bioanal Chem. 2013 Feb;405(4):1303-10. doi: 10.1007/s00216-012-6541-2. Epub 2012 Nov 21.
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Investigation of the metabolites of (S,S)-[(11)C]MeNER in humans, monkeys and rats.
对（S,S）-[（11）C]MeNER在人、猴和大鼠体内代谢物的研究。
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Evaluation of the Serotonin Transporter Ligand 123I-ADAM for SPECT Studies on Humans.用于人体单光子发射计算机断层扫描（SPECT）研究的5-羟色胺转运体配体123I-ADAM的评估。
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Estimation of serotonin transporter parameters with 11C-DASB in healthy humans: reproducibility and comparison of methods.健康人体中用11C-DASB估算血清素转运体参数：方法的可重复性及比较
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