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Bispidines as a new class of chelating agents for copper radionuclidesJuran, S.; Walther, M.; Stephan, H.; Steinbach, J.; Born, K.; Comba, P.; Kraus, W.; Emmerling, F.
The synthesis, characterization and evaluation of novel hexadentate bispidine derivatives containing pyridine and/or imidazole units as donor groups are presented. Bispidine ligands (bispidine = 3,7-diazabicyclo[3.3.1]-nonane) show unique complexation behaviour towards transition metals [1,2]. The high thermodynamic stability of the complexes of these structurally reinforced ligands with Cu(II) offers the possibility to apply such complexes for diagnostic (64Cu) and therapeutic (67Cu) purposes . Moreover the bispidine structure opens suitable chemical approaches to connect bio-molecules onto the skeleton, an important feature in view of the targeting of such complexes.
The ligands were prepared by two consecutive Mannich condensations according to the known procedure . Cyclic voltammetry (CV) measurements were recorded on a BAS 100B instrument with a standard three-electrode cell (glassy carbon electrode, AgNO3/Ag reference electrode, Pt wire with auxiliary electrode) at 25 °C in degassed water in an Ar atmosphere. Bispidines were labelled with 67Cu using 67CuCl2. To 200 µl of the ligand solution (10-4 M ligand in 0.05 M MES/NaOH buffer, pH = 5.4) 250 kBq of 67CuCl2 were added. 67Cu-labelling yields were studied by TLC using RP18 TLC plates which were developed in acetonitrile /water (0.1%TFA) = 4/1.
Results and Discussion:
CV measurements were performed in order to estimate the stability of the copper(II) bispidine complexes. Strongly negative redox potentials were found for all compounds investigated indicating the high stability of the Cu(II) complexes . Labelling experiments of the new bispidines with 67Cu and 64Cu indicate the rapid formation of radiocopper complexes under mild conditions in almost quantitatively yields.
The radiocopper complexes were found to be stable in the presence of a high excess of competing ligands, and showed a high in vitro stability in rat plasma up to 24 h. Studies on the bioconjugation of the bispidine 64Cu complexes are now in progress.
Roger Schibli (Paul Scherrer Institute, Villigen, Switzerland) is gratefully acknowledged for providing copper-67.
 P. Comba, W. Schiek, Coord. Chem. Rev. 2003, 238-239, 21-29.
 C. Bleiholder et al. Inorg. Chem. 2005, 44, 8145-8155.
 M. J. Welch, C. S. Redvanly, Eds., Handbook of Radiopharmaceuticals: Radiochemistry and Applications, J. Wiley & Sons, Chichester, 2003
17th International Symposium on Radiopharmaceutical Sciences, 30.04.-04.05.2007, Aachen, Deutschland
Abstract in refereed journal
Journal of Labelled Compounds and Radiopharmaceuticals 50(2007)Suppl. 1, S234
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