'Click-to-Chelate':In Vitro and In Vivo Comparison of a ~(99m)Tc(CO)3-Labeled N(r)-Histidine Folate Derivative with Its Isostructural,Clicked 1,2,3-Triazole Analogue

摘要

A side-by-side comparison of the synthesis,radiolabeling,and in vitro and in vivo characterization of two new and isostructural ~(99m)Tc-tricarbonyl folic acid radiotracers comprising either a N(T)-functionalized histidine(His)chelator or a 1,4-bifunctionalized 1,2,3-triazole His analogue is described.The 1,2,3-triazole-containing folic acid derivative was synthesized in approximately 80% yield by a short reaction sequence including application of click chemistry(the Cu(I)-catalyzed cycloaddition of azides and terminal alkynes).The synthesis of the ligand system and the functionalization of the folic acid derivative were accomplished simultaneously,which prompted us to call this approach"click-to-chelate".In comparison,the reported regioselective synthesis of the N(tau)-His compound provided the final product in only very low yields(<1%).While the efficiency of the syntheses differs considerably,the two isostructural folate derivatives exhibit virtually identical properties with respect to Tc-99m radiolabeling and in vitro and in vivo characteristics as shown by experiments performed with FR-positive KB cells and xenografted mice bearing folate receptor overexpressing tumors.We have demonstrated herein for the first time that a ligand system known to be an excellent chelator for the stable complexation of the organometallic core[M(CO)3]~+(M=Tc-99m,Re)can be replaced by an isostructural 1,2,3-triazole analogue without influencing the characteristics of the radiometal conjugate.The"click-to-chelate"strategy provides a highly efficient and convenient entry to metal conjugates suitable for diagnostic and potentially therapeutic applications.The described procedures should be readily applicable to any azide-functionalized(bio)molecule and,thus,are likely to represent the method of choice for the future development of radiopharmaceuticals radiolabeled with the organometallic precursors[M(CO)3(H2O)3]+(M=~(99m)Tc,~(188)Re).