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    COMPOSITIONS AND METHODS FOR LEUKOCYTE-TARGETING MULTI-VALENT IMAGING PROBES
    2.
    发明申请
    COMPOSITIONS AND METHODS FOR LEUKOCYTE-TARGETING MULTI-VALENT IMAGING PROBES 审中-公开
    用于低成本定位多成像成像探针的组合物和方法

    公开(公告)号：US20130144035A1

    公开(公告)日：2013-06-06

    申请号：US13642670

    申请日：2011-04-21

    申请人： Dongfeng Pan ,  Stuart S. Berr ,  Yi Zhang

    发明人： Dongfeng Pan ,  Stuart S. Berr ,  Yi Zhang

    IPC分类号： A61K51/08

    CPC分类号： A61K51/088 ,  A61K49/0002 ,  A61K49/0034 ,  A61K51/06

    摘要： The present application discloses a new multivalent peptide ligand specifically targeting polymorphonuclear leukocytes (PMNs) with favorable pharmacological parameters to monitor sites of inflammation for imaging. 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-99mTc (n=4, 12) were evaluated in vitro with human PMNs for binding affinity and bioavailability. As a result, FLFLF-(PEG)12-TKPPR99mTc 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-99mTc may be a desirable imaging agent for binding to PMNs to identify sites of inflammation by SPECT.

    摘要翻译： 本申请公开了一种特异靶向多形核白细胞（PMN）的新型多价肽配体，具有良好的药理学参数，用于监测成像的炎症部位。 这里报道了配体的详细合成，表征和药理学评估。 基于激活的PMN上的两种受体的高表达水平，选择两种单独的用于甲酰肽和簇状蛋白受体的肽结合配体连接在一起。将异源和聚乙二醇化的链接并入结构设计中，以提高检测的灵敏度和改善 分别具有生物利用度和血液清除曲线。 两种化学构建体：cFLFLF-（PEG）n-TKPPR-99mTc（n = 4,12）在体外用人PMNs进行了评估，用于结合亲和力和生物利用度。 结果发现FLFLF-（PEG）12-TKPPR99mTc具有更好的药理学特性，因此用于进一步的体内研究。 使用单发伽马发射计算机断层扫描（SPECT）成像小鼠耳炎的模型进行药物的初步体内评估。 这些研究的结果表明，cFLFLF-（PEG）12-TKPPR-99mTc可能是用于结合PMN的理想显像剂，以通过SPECT鉴定炎症部位。