Towards bioinspired dendritic ligands for imaging and therapeutic purposes

Metalloradiopharmaceuticals of the metallic radionuclides ^64/67Cu, ^99mTc, ^186/188Re and ⁹⁰Y are often used for diagnostic and therapeutic purposes.¹ Ligand multimers derived from radionuclide chelating macrocycles are attractive candidates for applications in oncologic diagnostics and endoradiotherapy. In this perspective, cyclam and its derivatives form very stable complexes in particular with transition and rare earth metal ions as the radionuclides mentioned above.² Recently, we could show that a star-like cyclam ligand appended with four PEG-arms rapidly forms stable copper(II) complexes.³

Currently, we are focusing our attention on the development of dendritic ligands having both enhanced complex stability and improved bio-availability. Branched ligands possessing biomolecules such as sugar and peptide moieties may show both unique cell uptake behaviour and specific ligand-receptor interaction. In this nexus, we built up ligands I and II with a cyclam core. D-glucose, 2-acetamido-2-deoxy-D-glucose and the hexapeptide (Arg-Arg-Pro-Tyr-Ile-Leu-OH) have been chosen as biomolecules.

The interaction of the sugar-containing ligands I with concanavalin A has been studied using isothermal titration microcalorimetry in order to characterize protein-ligand interaction. The results clearly indicate a cluster glycoside effect.

The preparation of asymmetric branched ligands possessing peptide moieties is currently in progress. Using this synthetic concept, it appears possible to adjust the solubility properties, the binding behaviour, and the biodistribution of these bioinspired ligands. The corresponding radiocopper complexes would allow the non-invasive in vivo imaging and therapeutic application.

1 X. Liang and P. Sadler, Chem. Soc. Rev., 2004, 33, 246.
2 R. M. Izatt, K. Pawlak, J. S. Bradshaw and R. L. Bruening, Chem. Rev., 1991, 91, 1721.
3 H. Stephan, G. Geipel, D. Appelhans, G. Bernhard, D. Tabuani, H. Komber and B. Voit, Tetrahedron Lett. 2005, 46, 3209.