A New Bifunctional Chelator Enables Facile Biocoupling and Radiolabeling as the Basis for a Bioconjugation Kit

Abstract

A new tridentate bifunctional chelator, N-(-2-picolyl)(-4-hydroxy)(-3-amino)benzoic acid (PHAB), was designed to efficiently coordinate the [(99m)Tc(CO)3](+) core and facilitate coupling reactions to biomolecules. The chelator can be procured in the form of the corresponding benzotriazole ester (PHAB-OBT), which can be stored and used as a bioconjugation kit. PHAB-OBT reacts with modified carbohydrates with high selectivity and efficiency in a single step in both aqueous and organic media. As is desirable for a kit, no complicated chemical bench work is required. Glycoconjugate postlabeling resulted in neutral radiolabeled glycans with high radiochemical yields. Prelabeling approaches were assessed by successive reaction of PHAB-OBT with the [(99m)Tc(CO)3](+) core and a modified galactose model. The radiolabeled galactose was obtained in 84% yield as defined by HPLC analysis. Biodistribution of the radioactive (99m)Tc-labeled chelator, as well as the glycoconjugates, were examined in mice. Noticeably different biodistribution patterns were observed that reflect trends in the uptake of carbohydrate analogues by various organs.

Glycoconjugated Rhenium(I) and 99m‐Technetium(I) Carbonyl Complexes from Pyridyltriazole Ligands Obtained by “Click Chemistry”

“…Connection of either monoamino‐monoamide dithiol (MAMA) or mercaptoacetylglycylglycylglycine (MAG 3 ) to 2‐deoxy‐2‐aminoglucose (DG), galactose (Gal) or glucose (Glc) with different linking units and radiolabeling with 99m Tc yielded radiotracers with a sugar‐dependent biodistribution in vivo, displaying promising tumor‐to‐muscle ratios ( 99m Tc‐MAG 3 ‐DG in MA891 breast‐tumor‐bearing mice;22 99m Tc‐MAG 3 ‐Glc in Ehrlich‐tumor‐bearing mice23,24) or enrichment in the liver as potential imaging agent for hepatic function ( 99m Tc‐MAG 3 ‐Gal in healthy Swiss mice25). Moreover, additional binding functionalities such as 1,3‐diamines,26 3‐hydroxypyridone,27 2‐hydroxybenzyl,28 pyridyltriazole,29,30 2,2′‐dipycolylamine,31 bis(2‐pyridylmethyl)amine (DPA),32,33 bis(2‐quinolylmethyl)amine (DQA),32 N ‐(2‐pyridylmethyl)glycine (NPG),32 2,2′‐bipyridine,34 N ‐(2‐picolyl‐4‐hydroxy‐3amino)benzoic acid (PHAB),35 and tripodal amines,36 functionalized with sugar moieties (limited to specific monosaccharides), have been used as ligands and reported as promising chelators for Tc I and Re I cores.…”