Spreckelmeyer Sarah, Ramogida Caterina F, Rousseau Julie, Arane Karen, Bratanovic Ivica, Colpo Nadine, Jermilova Una, Dias Gemma M, Dude Iulia, Jaraquemada-Peláez Maria de Guadalupe, Bénard François, Schaffer Paul, Orvig Chris
Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Department of Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen , Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands.
Bioconjug Chem. 2017 Aug 16;28(8):2145-2159. doi: 10.1021/acs.bioconjchem.7b00311. Epub 2017 Aug 1.
Potentially nonadentate (NO) bifunctional chelator p-SCN-Bn-Hneunpa and its immunoconjugate Hneunpa-trastuzumab for In radiolabeling are synthesized. The ability of p-SCN-Bn-Hneunpa and Hneunpa-trastuzumab to quantitatively radiolabel InCl at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In, Bi, and La resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both In complexes to have high stability over 5 days. Mouse biodistribution of [In][In(p-NO-Bn-neunpa)], compared to that of [In][In(p-NH-Bn-CHX-A″-diethylenetriamine pentaacetic acid (DTPA))], 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 In-neunpa-trastuzumab and In-CHX-A″-DTPA-trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of In-neunpa-trastuzumab compared to that of In-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-Hneunpa to be a promising chelator for In (and other radiometals) with high in vitro stability and also show Hneunpa-trastuzumab to be an excellent In chelator with promising biodistribution in mice.
合成了潜在的非齿状（NO）双功能螯合剂对异硫氰酸苄基-羟乙基乙二胺-N,N,N′,N′,N″-五乙酸（p-SCN-Bn-Hneunpa）及其用于放射性标记的免疫缀合物Hneunpa-曲妥珠单抗。介绍了p-SCN-Bn-Hneunpa和Hneunpa-曲妥珠单抗分别在室温下15分钟或30分钟内对氯化铟（InCl）进行定量放射性标记的能力。用铟（In）、铋（Bi）和镧（La）进行的热力学稳定性测定得到了较高的条件稳定常数（pM）值。体外人血清稳定性试验表明，两种铟配合物在5天内都具有很高的稳定性。与[铟][铟（对氨基苄基-环己二胺-N,N,N′,N′,N″-五乙酸（DTPA））]相比，[铟][铟（对异硫氰酸苄基-羟乙基乙二胺-N,N,N′,N′,N″-五乙酸）]在1、4和24小时的小鼠体内分布显示，两种配合物在24小时内都能从小鼠体内快速清除。在第二项小鼠体内分布研究中，免疫缀合物铟-Hneunpa-曲妥珠单抗和铟-环己二胺-N,N,N′,N′,N″-五乙酸-曲妥珠单抗显示出相似的分布情况，但铟-Hneunpa-曲妥珠单抗的肿瘤摄取量略低于铟-环己二胺-N,N,N′,N′,N″-五乙酸-曲妥珠单抗。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-Hneunpa是一种具有很高体外稳定性的用于铟（及其他放射性金属）的有前景的螯合剂，同时也表明Hneunpa-曲妥珠单抗是一种在小鼠体内具有良好生物分布的优秀铟螯合剂。
