TACN Ligands – A journey through radiopharmaceutical applications

The design of tailor-made bifunctional copper radionuclide-complexing agents for nuclear medical application as well as acquisition of reliable information about the biodistribution of different materials represents an intensive and rapidly developing field of research. In this context, the tridentate macrocycle 1,4,7-triazacyclononane (TACN) is of special interest since it forms stable complexes with Cu(II) and the ligand structure can be easily modified. The introduction of further donor groups on the ligand scaffold, such as pyridine units, significantly enhances the thermodynamic stability as well as the kinetic inertness of the Cu(II) complexes formed. TACN ligands containing one or two pendant 2-picolyl arms prefer the formation of square-pyramidal coordination geometry with Cu(II). A hexadentate ligand with two picoline coordination groups as well as a carboxylic functionality, 2-[4,7-bis(2-pyridylmethyl)-1,4,7-triazacyclononan-1-yl]acetic acid (DMPTACN-COOH), enforces a six-coordinate, distorted octahedral structure. DMPTACN-based ligands rapidly chelate copper(II) radionuclides under ambient conditions and the resulting complexes show high in vivo stability. The carboxylic acid group in DMPTACN-COOH allows for the ready introduction of linker groups, such as maleimide or isothiocyanate, thereby facilitating coupling of targeting molecules and bio(nano)materials.

Examples of target-specific peptides and bio(nano)materials equipped with DMPTACN ligands for labeling with 64Cu as an ideal positron emitter are discussed. This enables tumor imaging and the biodistribution of the materials to be studied over a period of days via positron emission tomography (PET).