Neutrophil targeting heterobivalent SPECT imaging probe: cFLFLF-PEG-TKPPR-99mTc.
Neutrophil targeting heterobivalent SPECT imaging probe: cFLFLF-PEG-TKPPR-99mTc.
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DOI：
10.1021/bc100063a
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发表时间：
2010-09
影响因子：
4.7
通讯作者：
Yi Zhang;Li Xiao;M. Chordia;L. Locke;Mark B. Williams;S. Berr;D. Pan
中科院分区：
文献类型：
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作者：
Yi Zhang;Li Xiao;M. Chordia;L. Locke;Mark B. Williams;S. Berr;D. Pan
设计了一种新的异二价肽配体，专门针对多形核白细胞（PMN），具有有利的药理学参数，可监测炎症部位进行成像。本文报道了配体的详细合成、表征和药理学评价。基于激活的 PMN 上两种受体的高表达水平，选择甲酰基肽和促吞噬素受体的两个单独的肽结合配体连接在一起。异二价和聚乙二醇化连接被纳入结构设计中，以分别提高检测的灵敏度和改善生物利用度以及血液清除率。在体外评估了两种化学构建体 cFLFLF-(PEG)(n)-TKPPR-(99m)Tc (n = 4, 12) 与人 PMN 的结合亲和力和生物利用度。结果发现，cFLFLF-(PEG)(12)-TKPPR-(99m)Tc具有更有利的药理学特性，因此用于进一步的体内研究。使用小鼠耳部炎症模型的单伽马发射计算机断层扫描 (SPECT) 成像对该药物进行了初步体内评估。这些研究的结果表明cFLFLF-(PEG)(12)-TKPPR-(99m)Tc可能是与PMN结合以通过SPECT识别炎症部位的理想显像剂。
A new heterobivalent peptide ligand specifically targeting polymorphonuclear leukocytes (PMNs) with favorable pharmacological parameters to monitor sites of inflammation for imaging is designed. The detailed synthesis, characterization, and pharmacological evaluation of the ligands are reported here. Two separate peptide binding ligands for formyl peptide and tuftsin receptors were chosen to link together based on the high expression levels of the two receptors on activated PMNs The heterobivalency and pegylated links were incorporated in the structural design to improve the sensitivity of the detection and to improve the bioavailability along with blood clearance profile, respectively. Two chemical constructs, cFLFLF-(PEG)(n)-TKPPR-(99m)Tc (n = 4, 12), were evaluated in vitro with human PMNs for binding affinity and bioavailability. As a result, cFLFLF-(PEG)(12)-TKPPR-(99m)Tc was found to have more favorable pharmacological properties and was therefore used for further in vivo studies. Preliminary in vivo assessment of the agent was performed using single gamma emission computed tomography (SPECT) imaging of a mouse model of ear inflammation. The results of these studies indicate cFLFLF-(PEG)(12)-TKPPR-(99m)Tc may be a desirable imaging agent for binding to PMNs to identify sites of inflammation by SPECT.