Cyclam with N-carbonxyethyl pendant arms as suitable radiocopper chelates

Cyclam (1,4,8,11-Tetraazacyclotetradecane) and its derivatives are powerful ligands for very stable complexes with (radio)copper(II) [1]. These chelators allow the functionalization 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-tetra(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane (TETA) is used for the development of copper-based target-specific radiopharmaceuticals, although dissociation and transchelation occur in biological systems. In contrast, radiolabeling of the pentadentate cyclam ligands with a different number of N-carboxyethyl groups have not been reported so far. As a consequence, their copper(II) complexes have been synthesized [2]. Herein, we present a comprehensive study, dealing with the influence of the pendant arm length on structural properties, radiolabelling conditions, in vitro and in vivo stability, and compare these results with cyclam ligands bearing N-carboxymethyl pendant arms e.g., Cu^II-TETA.
The different number of N-carboxyethyl pendant arms at the cyclam backbone strongly influences the structure and stability of the copper complexes. TE2P is ideally suited as a copper(II)-chelating agent due to its fast complexation with radiocopper, the high kinetic inertness towards SOD and human serum as well as the excellent biodistribution behaviour. The facile N-functionalization of TE2P with a specific peptide produces an imaging tool with improved pharmaceutical targeting.

References
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2. P. Comba, F. Emmerling, M. Jakob, W. Kraus, M. Kubeil, M. Morgen, J. Pietzsch, H.
Stephan, Dalton Trans. 42, 6142 (2013).