Cyclam propionates: Stable copper(II) chelates for radiopharmaceutical application

Due to their ability to form thermodynamically stable complexes with copper(II), ligands based on 1,4,8,11-tetraazacyclotetradecane (cyclam) are important for radiopharmaceutical applications [1]. Of particular interest are ligands that enable the simultaneous introduction of targeting molecules, e.g. peptides and/or fluorescence units, to construct effective radiopharmaceuticals for diagnostic and therapeutic purposes. In this context, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetracetic acid (TETA) is widely used for the development of copper-based target-specific radiopharmaceuticals.

Herein, we present a comprehensive study of CuII-cyclam complexes with propionic acid arms [2]. The influence of the number of pendant arms on structural features of CuII complexes formed as well as the radiopharmacologic properties of 64Cu-complexes are investigated and compared to CuII-TETA. Quite a few parameters (e.g. charge, configuration, lipophilicity) influence the kinetic inertness of the radiocopper complexes and thus may impair the pharmacokinetic properties.
All experiments point to a decrease of complex and in vivo stability with an increasing number of N-substituted propionic acid groups. Altogether, the cyclam mono- and dipropionic acids TE1P and trans-TE2P are ideally suited as chelating agents for 64CuII due to their fast complexation kinetics, their high kinetic inertness in the presence of superoxide dismutase (SOD) and human serum as well as their excellent biodistribution behavior. trans-TE2P has the possibility to use the non-chelating second propionate to introduce additional functions, such as solubilizing, fluorescent and targeting units.

References
1. T. J. Wadas, E. H. Wong, G. R. Weisman, C. J. Anderson, Chem. Rev. 110, 2858 (2010).
2. P. Comba, F. Emmerling, M. Jakob, W. Kraus, M. Kubeil, M. Morgen, J. Pietzsch, H. Stephan, Dalton Trans. 42, 6142 (2013).