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p-NO2–Bn–H4neunpa and H4neunpa–Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and 111In Immuno-Single Photon Emission Computed Tomography Imaging
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-08-01 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00311 Sarah Spreckelmeyer 1, 2 , Caterina F. Ramogida 3 , Julie Rousseau 4 , Karen Arane 1 , Ivica Bratanovic 3 , Nadine Colpo 4 , Una Jermilova 3 , Gemma M. Dias 4 , Iulia Dude 4 , Maria de Guadalupe Jaraquemada-Peláez 1 , François Bénard 4 , Paul Schaffer 3 , Chris Orvig 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-08-01 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00311 Sarah Spreckelmeyer 1, 2 , Caterina F. Ramogida 3 , Julie Rousseau 4 , Karen Arane 1 , Ivica Bratanovic 3 , Nadine Colpo 4 , Una Jermilova 3 , Gemma M. Dias 4 , Iulia Dude 4 , Maria de Guadalupe Jaraquemada-Peláez 1 , François Bénard 4 , Paul Schaffer 3 , Chris Orvig 1
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Potentially nonadentate (N5O4) bifunctional chelator p-SCN–Bn–H4neunpa and its immunoconjugate H4neunpa–trastuzumab for 111In radiolabeling are synthesized. The ability of p-SCN–Bn–H4neunpa and H4neunpa–trastuzumab to quantitatively radiolabel 111InCl3 at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In3+, Bi3+, and La3+ resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both 111In complexes to have high stability over 5 days. Mouse biodistribution of [111In][In(p-NO2–Bn–neunpa)]−, compared to that of [111In][In(p-NH2–Bn–CHX-A″–diethylenetriamine pentaacetic acid (DTPA))]2–, at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates 111In-neunpa–trastuzumab and 111In–CHX-A″–DTPA–trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of 111In-neunpa–trastuzumab compared to that of 111In–CHX-A″–DTPA–trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator p-SCN–Bn–H4neunpa to be a promising chelator for 111In (and other radiometals) with high in vitro stability and also show H4neunpa–trastuzumab to be an excellent 111In chelator with promising biodistribution in mice.
中文翻译：
p -NO 2 –Bn–H 4 neunpa和H 4 neunpa–Trastuzumab：用于放射性金属药物和111免疫单光子发射计算机断层成像的双功能螯合剂
合成了潜在的非齿状（N 5 O 4）双功能螯合剂p -SCN-Bn-H 4 neunpa及其免疫结合物111 In放射性标记H 4 neunpa-曲妥珠单抗。的能力p -SCN-BN-H 4 neunpa和H 4 neunpa -曲妥单抗定量放射性标记111的InCl 3在15或30分钟内的环境温度下，分别被呈现。用In 3+，Bi 3+和La 3+进行热力学稳定性测定可得到较高的条件稳定性常数（pM）值。体外人血清稳定性测定法已证明这两种111 In复合物在5天内都具有很高的稳定性。[ 111 In] [In（p -NO 2 -Bn–neunpa）] -的小鼠生物分布与[ 111 In] [In（p -NH 2 -Bn–CHX-A”-二亚乙基三胺五乙酸（DTPA）相比））] – 2，1、4和24 h处显示24 h内两种复合物均从小鼠中快速清除。在第二项小鼠生物分布研究中，免疫结合物111 In-neunpa-trastuzumab和111In–CHX-A″ –DTPA–曲妥珠单抗显示相似的分布特征，但与111 In–CHX-A″ –DTPA–曲妥珠单抗相比，其111 In-neunpa–曲妥珠单抗的肿瘤吸收略低。通过体内免疫单光子发射计算机断层扫描（immuno-SPECT）成像也证实了这些结果。这些初步研究表明，无环双功能螯合剂p -SCN–Bn–H 4 neunpa是111 In（及其他放射性金属）的有前途的螯合剂，具有很高的体外稳定性，还显示H 4 neunpa–trastuzumab是出色的111 In螯合剂在小鼠中具有良好的生物分布。
更新日期：2017-08-02
中文翻译：
p -NO 2 –Bn–H 4 neunpa和H 4 neunpa–Trastuzumab：用于放射性金属药物和111免疫单光子发射计算机断层成像的双功能螯合剂
合成了潜在的非齿状（N 5 O 4）双功能螯合剂p -SCN-Bn-H 4 neunpa及其免疫结合物111 In放射性标记H 4 neunpa-曲妥珠单抗。的能力p -SCN-BN-H 4 neunpa和H 4 neunpa -曲妥单抗定量放射性标记111的InCl 3在15或30分钟内的环境温度下，分别被呈现。用In 3+，Bi 3+和La 3+进行热力学稳定性测定可得到较高的条件稳定性常数（pM）值。体外人血清稳定性测定法已证明这两种111 In复合物在5天内都具有很高的稳定性。[ 111 In] [In（p -NO 2 -Bn–neunpa）] -的小鼠生物分布与[ 111 In] [In（p -NH 2 -Bn–CHX-A”-二亚乙基三胺五乙酸（DTPA）相比））] – 2，1、4和24 h处显示24 h内两种复合物均从小鼠中快速清除。在第二项小鼠生物分布研究中，免疫结合物111 In-neunpa-trastuzumab和111In–CHX-A″ –DTPA–曲妥珠单抗显示相似的分布特征，但与111 In–CHX-A″ –DTPA–曲妥珠单抗相比，其111 In-neunpa–曲妥珠单抗的肿瘤吸收略低。通过体内免疫单光子发射计算机断层扫描（immuno-SPECT）成像也证实了这些结果。这些初步研究表明，无环双功能螯合剂p -SCN–Bn–H 4 neunpa是111 In（及其他放射性金属）的有前途的螯合剂，具有很高的体外稳定性，还显示H 4 neunpa–trastuzumab是出色的111 In螯合剂在小鼠中具有良好的生物分布。
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