Yazdani Abdolreza, Bilton Holly, Vito Alyssa, Genady Afaf R, Rathmann Stephanie M, Ahmad Zainab, Janzen Nancy, Czorny Shannon, Zeglis Brian M, Francesconi Lynn C, Valliant John F
Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
Department of Chemistry, Hunter College , 695 Park Avenue New York, New York 10065, United States.
J Med Chem. 2016 Oct 27;59(20):9381-9389. doi: 10.1021/acs.jmedchem.6b00938. Epub 2016 Oct 5.
A high yield synthesis of a novel, small molecule, bisphosphonate-modified trans-cyclooctene (TCO-BP, 2) that binds to regions of active bone metabolism and captures functionalized tetrazines in vivo, via the bioorthogonal inverse electron demand Diels-Alder (IEDDA) cycloaddition, was developed. A Tc-labeled derivative of 2 demonstrated selective localization to shoulder and knee joints in a biodistribution study in normal mice. Compound 2 reacted rapidly with a Lu-labeled tetrazine in vitro, and pretargeting experiments in mice, using 2 and the Lu-labeled tetrazine, yielded high activity concentrations in shoulder and knee joints, with minimal uptake in other tissues. Pretargeting experiments with 2 and a novel Tc-labeled tetrazine also produced high activity concentrations in the knees and shoulders. Critically, both radiolabeled tetrazines showed negligible uptake in the skeleton and joints when administered in the absence of 2. Compound 2 can be utilized to target functionalized tetrazines to bone and represents a convenient reagent to test novel tetrazines for use with in vivo bioorthogonal pretargeting strategies.
开发了一种新型小分子双膦酸盐修饰的反式环辛烯（TCO-BP，2）的高产率合成方法，该化合物通过生物正交逆电子需求狄尔斯-阿尔德（IEDDA）环加成反应，与活跃骨代谢区域结合并在体内捕获功能化四嗪。在正常小鼠的生物分布研究中，2的锝标记衍生物显示出在肩部和膝关节的选择性定位。化合物2在体外与镥标记的四嗪迅速反应，在小鼠中使用2和镥标记的四嗪进行预靶向实验，在肩部和膝关节产生高活性浓度，而在其他组织中的摄取极少。用2和一种新型锝标记的四嗪进行的预靶向实验在膝盖和肩部也产生了高活性浓度。至关重要的是，当在没有2的情况下给药时，两种放射性标记的四嗪在骨骼和关节中的摄取均可忽略不计。化合物2可用于将功能化四嗪靶向到骨骼，是测试用于体内生物正交预靶向策略的新型四嗪的便捷试剂。
