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High in Vivo Stability of 64Cu-Labeled Cross-Bridged Chelators Is a Crucial Factor in Improved Tumor Imaging of RGD Peptide Conjugates
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-03 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01671 Swarbhanu Sarkar 1 , Nikunj Bhatt 1 , Yeong Su Ha 1 , Phuong Tu Huynh 1 , Nisarg Soni 1 , Woonghee Lee 1 , Yong Jin Lee 2 , Jung Young Kim 2 , Darpan N. Pandya 1 , Gwang Il An 2 , Kyo Chul Lee 2 , Yongmin Chang 1 , Jeongsoo Yoo 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-03 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01671 Swarbhanu Sarkar 1 , Nikunj Bhatt 1 , Yeong Su Ha 1 , Phuong Tu Huynh 1 , Nisarg Soni 1 , Woonghee Lee 1 , Yong Jin Lee 2 , Jung Young Kim 2 , Darpan N. Pandya 1 , Gwang Il An 2 , Kyo Chul Lee 2 , Yongmin Chang 1 , Jeongsoo Yoo 1
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Although the importance of bifunctional chelators (BFCs) is well recognized, the chemophysical parameters of chelators that govern the biological behavior of the corresponding bioconjugates have not been clearly elucidated. Here, five BFCs closely related in structure were conjugated with a cyclic RGD peptide and radiolabeled with Cu-64 ions. Various biophysical and chemical properties of the Cu(II) complexes were analyzed with the aim of identifying correlations between individual factors and the biological behavior of the conjugates. Tumor uptake and body clearance of the 64Cu-labeled bioconjugates were directly compared by animal PET imaging in animal models, which was further supported by biodistribution studies. Conjugates containing propylene cross-bridged chelators showed higher tumor uptake, while a closely related ethylene cross-bridged analogue exhibited rapid body clearance. High in vivo stability of the copper–chelator complex was strongly correlated with high tumor uptake, while the overall lipophilicity of the bioconjugate affected both tumor uptake and body clearance.
中文翻译：
64 Cu标记的跨桥螯合剂的体内高稳定性是RGD肽缀合物改善肿瘤成像的关键因素
尽管双功能螯合剂（BFCs）的重要性已得到公认，但支配相应化学偶联物生物学行为的螯合剂的化学物理参数尚未明确阐明。在这里，将五个结构密切相关的BFC与环状RGD肽偶联，并用Cu-64离子进行放射性标记。分析了Cu（II）配合物的各种生物物理和化学性质，目的是确定各个因素与结合物生物学行为之间的相关性。肿瘤的吸收和体内清除率64在动物模型中通过动物PET成像直接比较了Cu标记的生物结合物，这得到了生物分布研究的进一步支持。含有丙烯桥联螯合剂的结合物显示出更高的肿瘤吸收，而密切相关的乙烯桥联类似物表现出快速的体内清除。铜-螯合剂复合物的高体内稳定性与高肿瘤吸收密切相关，而生物结合物的整体亲脂性影响肿瘤吸收和体内清除率。
更新日期：2018-01-03
中文翻译：
64 Cu标记的跨桥螯合剂的体内高稳定性是RGD肽缀合物改善肿瘤成像的关键因素
尽管双功能螯合剂（BFCs）的重要性已得到公认，但支配相应化学偶联物生物学行为的螯合剂的化学物理参数尚未明确阐明。在这里，将五个结构密切相关的BFC与环状RGD肽偶联，并用Cu-64离子进行放射性标记。分析了Cu（II）配合物的各种生物物理和化学性质，目的是确定各个因素与结合物生物学行为之间的相关性。肿瘤的吸收和体内清除率64在动物模型中通过动物PET成像直接比较了Cu标记的生物结合物，这得到了生物分布研究的进一步支持。含有丙烯桥联螯合剂的结合物显示出更高的肿瘤吸收，而密切相关的乙烯桥联类似物表现出快速的体内清除。铜-螯合剂复合物的高体内稳定性与高肿瘤吸收密切相关，而生物结合物的整体亲脂性影响肿瘤吸收和体内清除率。
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