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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >Tripodal tris(hydroxypyridinone) ligands for immunoconjugate PET imaging with Zr-89(4+): comparison with desferrioxamine-B
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Tripodal tris(hydroxypyridinone) ligands for immunoconjugate PET imaging with Zr-89(4+): comparison with desferrioxamine-B

机译：三脚架三（羟基吡啶酮）配体用于Zr-89（4+）免疫偶联PET成像：与去铁胺-B的比较

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摘要

Due to its long half-life (78 h) and decay properties (77% electron capture, 23% beta(+), E-max = 897 keV, E-av = 397 keV, E gamma = 909 keV, I gamma = 100%) Zr-89 is an appealing radionuclide for immunoPET imaging with whole IgG antibodies. Derivatives of the siderophore desferrioxamine-B (H3DFO) are the most widely used bifunctional chelators for coordination of Zr-89(4+) because the radiolabeling of the resulting immunoconjugates is rapid under mild conditions. Zr-89-DFO complexes are reportedly stable in vitro but there is evidence that Zr-89(4+) is released in vivo, and subsequently taken up by the skeleton. We have evaluated a novel tripodal tris(hydroxypyridinone) chelator, H(3)CP256 and its bifunctional maleimide derivative, H(3)YM103, for coordination of Zr4+ and compared the NMR spectra, and the Zr-89(4+) radiolabeling, antibody conjugation, serum stability and in vivo distribution of radiolabelled immunoconjugates with those of H3DFO and its analogues. H(3)CP256 coordinates Zr-89(4+) at carrier-free concentrations forming [Zr-89(CP256)](+). Both H3DFO and H(3)CP256 were efficiently radiolabelled using [Zr-89(C2O4)(4)](4-) at ambient temperature in quantitative yield at pH 6-7 at millimolar concentrations of chelator. Competition experiments demonstrate that Zr-89(4+) dissociates from [Zr-89(DFO)](+) in the presence of one equivalent of H(3)CP256 (relative to H3DFO) at pH 6-7, resulting largely in [Zr-89(CP256)](+). To assess the stability of H3DFO and H(3)YM103 immunoconjugates radiolabelled with Zr-89, maleimide derivatives of the chelators were conjugated to the monoclonal antibody trastuzumab via reduced cysteine side chains. Both immunoconjugates were labelled with Zr-89(4+) in >98% yield at high specific activities and the labeled immunoconjugates were stable in serum with respect to dissociation of the radiometal. In vivo studies in mice indicate that Zr-89(4+) dissociates from YM103-trastuzumab with significant amounts of activity becoming associated with bones and joints (25.88 0.58% ID g(-1) 7 days post-injection). In contrast, <8% ID g(-1) of Zr-89 activity becomes associated with bone in animals administered Zr-89-DFO-trastuzumab over the course of 7 days. The tris(hydroxypyridinone) chelator, H(3)CP256, coordinates Zr-89(4+) rapidly under mild conditions, but the Zr-89-labelled immunoconjugate, Zr-89-YM103-trastuzumab was observed to release appreciable amounts of Zr-89(4+) in vivo, demonstrating inferior stability when compared with Zr-89-DFO-trastuzumab. The significantly lower in vivo stability is likely to be a result of lower kinetic stability of the Zr4+ tris(hydroxypyridinone complex) relative to that of DFO and its derivatives.
机译：由于其较长的半衰期（78 h）和衰变特性（77％电子捕获，23％beta（+），E-max = 897 keV，E-av = 397 keV，Eγ= 909 keV，Iγ= 100％Zr-89是一种具有吸引力的放射性核素，可用于使用完整IgG抗体进行免疫PET成像。铁载体去铁草胺-B（H3DFO）的衍生物是用于Zr-89（4+）配位的最广泛使用的双功能螯合剂，因为在温和的条件下，放射性标记物的放射性标记很快。据报道Zr-89-DFO复合物在体外稳定，但有证据表明Zr-89（4+）在体内释放，随后被骨架吸收。我们已经评估了新型三脚架三（羟基吡啶酮）螯合剂H（3）CP256及其双功能马来酰亚胺衍生物H（3）YM103对Zr4 +的配位并比较了NMR光谱和Zr-89（4+）放射性标记，放射性标记的免疫偶联物与H3DFO及其类似物的抗体偶联，血清稳定性和体内分布。 H（3）CP256在无载体浓度下协调Zr-89（4+）形成[Zr-89（CP256）]（+）。 H3DFO和H（3）CP256均使用[Zr-89（C2O4）（4）]（4-）在环境温度下以毫摩尔浓度的螯合剂在pH 6-7下定量收率进行了有效的放射性标记。竞争实验表明，在pH值为6-7的一当量H（3）CP256（相对于H3DFO）存在下，Zr-89（4+）从[Zr-89（DFO）]（+）上解离， [Zr-89（CP256）]（+）。为了评估用Zr-89放射性标记的H3DFO和H（3）YM103免疫缀合物的稳定性，将螯合剂的马来酰亚胺衍生物通过减少的半胱氨酸侧链缀合至单克隆抗体曲妥珠单抗。两种免疫偶联物都以高比活度用Zr-89（4+）标记，产率> 98％，并且标记的免疫偶联物在血清中相对于放射性金属的解离是稳定的。小鼠体内研究表明Zr-89（4+）从YM103-曲妥珠单抗中解离出来，并具有大量与骨骼和关节相关的活性（注射后7天为25.88 0.58％ID g（-1））。相反，在7天的过程中，施用Zr-89-DFO-曲妥珠单抗的动物的Zr-89活性<8％ID g（-1）与骨骼相关。三（羟基吡啶酮）螯合剂H（3）CP256在温和条件下迅速协调Zr-89（4+），但观察到Zr-89标记的免疫偶联物Zr-89-YM103-曲妥珠单抗释放出适量的Zr。 -89（4+）体内，与Zr-89-DFO-曲妥珠单抗相比，稳定性较差。体内较低的稳定性可能是Zr4 + tris（羟基吡啶酮配合物）相对于DFO及其衍生物较低的动力学稳定性的结果。

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