Investigation of isomer formation upon coordination of bifunctional histidine analogues with 99mTc/Re(CO)3

Histidine is a convenient tridentate chelator used in the synthesis of technetium-99m radiopharmaceuticals, as it can be pendantly attached to a biomolecule for molecular imaging applications. Once coordinated, it forms a neutral complex that is capable of forming diastereomers at the alpha amine of the histidine. This is demonstrated through the synthesis and characterization of four different histidine chelators; three small molecule chelators, which consist of a benzylated histidine at the alpha amine, and one modified dipeptide, containing a phenylalanine derivative at the C-terminus and a histidine at the N-terminus. Upon rhenium coordination, two products are observed, each having the desired exact mass of the metal-containing species. The two products have been characterized through LC-MS, (1)H, gCOSY, NOESY and ROESY NMR experiments, and the relative stereochemistry determined. The implications of diastereomer formation when using this chelation system for creating molecular imaging agents is also discussed.