Evaluation of fluorine-labeled gastrin-releasing peptide receptor (GRPR) agonists and antagonists by LC/MS.
Evaluation of fluorine-labeled gastrin-releasing peptide receptor (GRPR) agonists and antagonists by LC/MS.
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DOI：
10.1007/s00726-012-1238-6
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发表时间：
2012-10
期刊：
影响因子：
3.5
通讯作者：
Chen, Xiaoyuan
中科院分区：
文献类型：
--
作者：
Ma, Ying;Yang, Min;Gao, Haokao;Niu, Gang;Yan, Yongjun;Lang, Lixin;Kiesewetter, Dale O.;Chen, Xiaoyuan
使用LC/MS方法评估2-氟丙酰基（FP）和4-氟苯甲酰基（FB）修饰的bombsin肽：GRPR激动剂[fQWAVGHL-NH 2]和拮抗剂[fQWAVGHL-NHEt]，以及它们的亲水性接头修饰的具有GGGRDN序列连接的对应物。本研究开发了评价各种GRPR激动剂和拮抗剂的体外受体介导的细胞摄取和代谢概况的策略。我们鉴定了大鼠肝细胞产生的代谢产物，并定量分析了PC-3人前列腺癌细胞对配体的摄取和内化。GRPR激动剂和拮抗剂的主要代谢产物是WA和AV之间的肽键水解的结果。激动剂还形成由C-末端酰胺水解产生的独特代谢物。在大鼠肝细胞中，与激动剂相比，拮抗剂显示出显著更高的代谢稳定性。与未修饰的激动剂（BBN）相比，直接修饰的激动剂（FP-BBN和FB-BBN）具有更高的内化，具有相似的细胞结合，而亲水性接头修饰的激动剂（G-BBN和FG-BBN）具有低得多的总细胞摄取。标记的拮抗剂（FP-NBBN、FB-NBBN、G-NBBN和FP-G-NBBN）表现出较低的内化。最佳成像剂将取决于体内配体代谢、细胞摄取和内化的相互作用。
An LC/MS method was used to evaluate 2-fluoropropionyl (FP) and 4-fluorobenzoyl (FB) modified bombsin peptides: GRPR agonist [Aca-QWAVGHLM-NH2] and antagonist [fQWAVGHL-NHEt], and their hydrophilic linker modified counterparts with the attachment of GGGRDN sequence. This study developed strategies to evaluate the in vitro receptor mediated cell uptake and metabolic profile of the various GRPR agonists and antagonists. We identified the metabolites produced by rat hepatocytes, and quantitatively analyzed the uptake and internalization of the ligands in PC-3 human prostate cancer cells. The major metabolites of both GRPR agonists and antagonists were the result of peptide bond hydrolysis between WA and AV. The agonists also formed a unique metabolite resulting from hydrolysis of the C-terminal amide. The antagonists showed significantly higher stability against metabolism compared to the agonists in rat hepatocytes. The directly modified agonists (FP-BBN and FB-BBN) had higher internalization with similar cell binding compared to the unmodified agonist (BBN), whereas the hydrophilic linker modified agonists (G-BBN and FG-BBN) had much lower total cell uptake. The labeled antagonist (FP-NBBN, FB-NBBN, G-NBBN and FP-G-NBBN) displayed lower internalization. The optimal imaging agent will depend on the interplay of ligand metabolism, cellular uptake, and internalization in vivo.
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DOI：
10.1007/s00259-002-1040-x
发表时间：
2003-02-01
影响因子：
9.1
作者：
Nock, B;Nikolopoulou, A;Maina, T
通讯作者：
Maina, T
影响因子：
3.1
作者：
Ma, Ying;Lang, Lixin;Kiesewetter, Dale O.
通讯作者：
Kiesewetter, Dale O.
影响因子：
3.1
作者：
Smith, CJ;Volkert, WA;Hoffman, TJ
通讯作者：
Hoffman, TJ
影响因子：
11.5
作者：
Mansi, Rosalba;Wang, Xuejuan;Maecke, Helmut R.
通讯作者：
Maecke, Helmut R.
影响因子：
3.5
作者：
Yan, Yongjun;Chen, Kai;Yang, Min;Sun, Xilin;Liu, Shuanglong;Chen, Xiaoyuan
通讯作者：
Chen, Xiaoyuan