Tripodal tris(hydroxypyridinone) ligands for immunoconjugate PET imaging with (89)Zr(4+): comparison with desferrioxamine-B.
Tripodal tris(hydroxypyridinone) ligands for immunoconjugate PET imaging with (89)Zr(4+): comparison with desferrioxamine-B.
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DOI：
10.1039/c4dt02978j
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发表时间：
2015-03-21
期刊：
影响因子：
--
通讯作者：
Blower PJ
中科院分区：
文献类型：
--
作者：
Ma MT;Meszaros LK;Paterson BM;Berry DJ;Cooper MS;Ma Y;Hider RC;Blower PJ
三（羟基吡啶酮）螯合剂在环境条件下快速定量地与PET成像同位素89 Zr 4+配位，但89 Zr标记的三（羟基吡啶酮）-免疫缀合物对体内二甲双胍不稳定。由于其半衰期长（78 h）和衰变特性（77%电子捕获，23% β+，E max = 897 keV，E av = 397 keV，Eγ = 909 keV，Iγ = 100%），89 Zr是一种有吸引力的放射性核素，可用于全IgG抗体的免疫PET成像。铁载体去铁胺-B（H3 DFO）的衍生物是最广泛使用的双功能螯合剂，用于89 Zr 4+的配位，因为所得免疫缀合物的放射性标记在温和条件下是快速的。据报道，89 Zr-DFO复合物在体外是稳定的，但有证据表明，89 Zr 4+在体内释放，随后被骨骼吸收。我们已经评估了一种新的三脚架三（羟基吡啶酮）螯合剂，H3CP 256和它的双功能马来酰亚胺衍生物，H3 YM 103，为协调的Zr 4+和比较的NMR光谱，和89 Zr 4+放射性标记，抗体结合，血清稳定性和体内分布的放射性标记的免疫缀合物与H3 DFO及其类似物。H3CP 256在无载体浓度下与89 Zr 4+配位形成[89 Zr（CP 256）]+。H3 DFO和H3CP 256均在环境温度下使用[89 Zr（C2 O 4）4]4-以定量产率在pH 6-7下以毫摩尔浓度的螯合剂有效地放射性标记。竞争实验表明，在pH 6-7下，在1当量的H3CP 256（相对于H3 DFO）存在下，89 Zr 4+从[89 Zr（DFO）]+解离，主要产生[89 Zr（CP 256）]+。为了评估用89 Zr放射性标记的H3 DFO和H3 YM 103免疫缀合物的稳定性，将螯合剂的马来酰亚胺衍生物通过还原的半胱氨酸侧链缀合至单克隆抗体曲妥珠单抗。两种免疫缀合物均以>98%的产率以高比活度标记有89 Zr 4+，并且标记的免疫缀合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，89 Zr 4+与YM 103-曲妥珠单抗解离，具有显著量的活性，与骨和关节相关（注射后7天为25.88 ± 0.58%ID g-1）。相比之下，在7天的过程中施用89 Zr-DFO-曲妥珠单抗的动物中，<8%ID g-1的89 Zr活性变得与骨相关。三（羟基吡啶酮）螯合剂H3CP 256在温和条件下快速配位89 Zr 4+，但观察到89 Zr标记的免疫缀合物89 Zr-YM 103-曲妥珠单抗在体内释放可观量的89 Zr 4+，表明与89 Zr-DFO-曲妥珠单抗相比稳定性较差。显著较低的体内稳定性可能是Zr 4+三（羟基吡啶酮络合物）相对于DFO及其衍生物的动力学稳定性较低的结果。
A tris(hydroxypyridinone) chelator coordinates the PET imaging isotope, 89Zr4+, rapidly and quantitatively under ambient conditions, but a 89Zr-labelled tris(hydroxypyridinone)-immunoconjugate is not stable to in vivo demetallation. Due to its long half-life (78 h) and decay properties (77% electron capture, 23% β+, E max = 897 keV, E av = 397 keV, Eγ = 909 keV, Iγ = 100%) 89Zr 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 89Zr4+ because the radiolabeling of the resulting immunoconjugates is rapid under mild conditions. 89Zr-DFO complexes are reportedly stable in vitro but there is evidence that 89Zr4+ is released in vivo, and subsequently taken up by the skeleton. We have evaluated a novel tripodal tris(hydroxypyridinone) chelator, H3CP256 and its bifunctional maleimide derivative, H3YM103, for coordination of Zr4+ and compared the NMR spectra, and the 89Zr4+ radiolabeling, antibody conjugation, serum stability and in vivo distribution of radiolabelled immunoconjugates with those of H3DFO and its analogues. H3CP256 coordinates 89Zr4+ at carrier-free concentrations forming [89Zr(CP256)]+. Both H3DFO and H3CP256 were efficiently radiolabelled using [89Zr(C2O4)4]4– at ambient temperature in quantitative yield at pH 6–7 at millimolar concentrations of chelator. Competition experiments demonstrate that 89Zr4+ dissociates from [89Zr(DFO)]+ in the presence of one equivalent of H3CP256 (relative to H3DFO) at pH 6–7, resulting largely in [89Zr(CP256)]+. To assess the stability of H3DFO and H3YM103 immunoconjugates radiolabelled with 89Zr, maleimide derivatives of the chelators were conjugated to the monoclonal antibody trastuzumab via reduced cysteine side chains. Both immunoconjugates were labelled with 89Zr4+ 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 89Zr4+ 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 89Zr activity becomes associated with bone in animals administered 89Zr-DFO-trastuzumab over the course of 7 days. The tris(hydroxypyridinone) chelator, H3CP256, coordinates 89Zr4+ rapidly under mild conditions, but the 89Zr-labelled immunoconjugate, 89Zr-YM103-trastuzumab was observed to release appreciable amounts of 89Zr4+ in vivo, demonstrating inferior stability when compared with 89Zr-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.
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影响因子：
14.8
作者：
Cohen, Ruth;Vugts, Danielle J.;van Dongen, Guus A. M. S.
通讯作者：
van Dongen, Guus A. M. S.
影响因子：
3.1
作者：
Abou DS;Ku T;Smith-Jones PM
通讯作者：
Smith-Jones PM
影响因子：
3.5
作者：
Liu, ZD;Piyamongkol, S;Hider, RC
通讯作者：
Hider, RC
原位和转移性乳腺肿瘤中的89ZR-Radiolab曲妥珠单抗成像。
DOI：
10.3390/ph5010079
发表时间：
2012-01-05
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Chang AJ;Desilva R;Jain S;Lears K;Rogers B;Lapi S
通讯作者：
Lapi S
影响因子：
9.3
作者：
Costantini, Danny L.;McLarty, Kristin;Reilly, Raymond M.
通讯作者：
Reilly, Raymond M.