Pretargeted Imaging with Gallium-68-Improving the Binding Capability by Increasing the Number of Tetrazine Motifs.
Pretargeted Imaging with Gallium-68-Improving the Binding Capability by Increasing the Number of Tetrazine Motifs.
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DOI：
10.3390/ph11040102
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发表时间：
2018-10-11
期刊：
影响因子：
--
通讯作者：
Decristoforo C
中科院分区：
文献类型：
--
作者：
Summer D;Mayr S;Petrik M;Rangger C;Schoeler K;Vieider L;Matuszczak B;Decristoforo C
1,2,4,5-四嗪 (Tz) 和反式环辛-2-烯 (TCO) 之间的逆电子需求 Diels-Alder 反应由于其极快的反应动力学和对体内预靶向应用（包括 PET 成像）的高选择性，在点击化学的广泛研究中越来越受到关注。利用 TCO 修饰抗体作为靶向结构的简便两步法尚未进入临床。与小鼠相比，人类血容量的增加似乎是主要限制。本研究旨在证明通过螯合剂支架设计多聚 Tz 配体是否可以提高结合能力，并可能导致镓 68 增强 PET 成像。为此，我们利用了大环铁载体 Fusarinine C (FSC)，由于可用于位点特异性修饰的三个伯胺，它允许最多三个 Tz 残基缀合。所得单聚体和三聚体缀合物用镓 68 进行放射性标记，并进行体外（logD、蛋白质结合、稳定性、与 TCO 修饰的利妥昔单抗 (RTX) 的结合）和体内（使用简化的 RTX-TCO 肿瘤替代物在正常 BALB/c 小鼠中进行的生物分布和成像研究）进行表征。 68Ga标记的基于FSC的Tz配体表现出合适的亲水性、高稳定性和高靶向特异性。与RTX-TCO的结合能力根据多聚化程度而增加。相应的体内研究显示多聚化的典型特征，但通常具有合适的药代动力学，在非靶组织中的积累较低。对带有 RTX-TCO 肿瘤替代物的 BALB/c 小鼠的成像研究证实了这一趋势，并揭示了随着观察到 RTX-TCO 阳性组织中积累的增加，多聚化的靶向性得到改善。
The inverse electron-demand Diels-Alder reaction between 1,2,4,5-tetrazine (Tz) and trans-cyclooct-2-ene (TCO) has gained increasing attraction among extensive studies on click chemistry due to its exceptionally fast reaction kinetics and high selectivity for in vivo pretargeting applications including PET imaging. The facile two-step approach utilizing TCO-modified antibodies as targeting structures has not made it into clinics yet. An increase in the blood volume of humans in comparison to mice seems to be the major limitation. This study aims to show if the design of multimeric Tz-ligands by chelator scaffolding can improve the binding capacity and may lead to enhanced PET imaging with gallium-68. We utilized for this purpose the macrocyclic siderophore Fusarinine C (FSC) which allows conjugation of up to three Tz-residues due to three primary amines available for site specific modification. The resulting mono- di- and trimeric conjugates were radiolabelled with gallium-68 and characterized in vitro (logD, protein binding, stability, binding towards TCO modified rituximab (RTX)) and in vivo (biodistribution- and imaging studies in normal BALB/c mice using a simplified RTX-TCO tumour surrogate). The 68Ga-labelled FSC-based Tz-ligands showed suitable hydrophilicity, high stability and high targeting specificity. The binding capacity to RTX-TCO was increased according to the grade of multimerization. Corresponding in vivo studies showed a multimerization typical profile but generally suitable pharmacokinetics with low accumulation in non-targeted tissue. Imaging studies in RTX-TCO tumour surrogate bearing BALB/c mice confirmed this trend and revealed improved targeting by multimerization as increased accumulation in RTX-TCO positive tissue was observed.
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影响因子：
4.7
作者：
Meyer JP;Houghton JL;Kozlowski P;Abdel-Atti D;Reiner T;Pillarsetty NV;Scholz WW;Zeglis BM;Lewis JS
通讯作者：
Lewis JS
影响因子：
4.6
作者：
Bailly C;Bodet-Milin C;Rousseau C;Faivre-Chauvet A;Kraeber-Bodéré F;Barbet J
通讯作者：
Barbet J
影响因子：
5.6
作者：
Jauw YW;Menke-van der Houven van Oordt CW;Hoekstra OS;Hendrikse NH;Vugts DJ;Zijlstra JM;Huisman MC;van Dongen GA
通讯作者：
van Dongen GA
DOI：
10.1039/c3cc49530b
发表时间：
2014-05-25
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Nichols B;Qin Z;Yang J;Vera DR;Devaraj NK
通讯作者：
Devaraj NK
影响因子：
3.1
作者：
Laeppchen, Tilman;Rossin, Raffaella;Robillard, Marc S.
通讯作者：
Robillard, Marc S.