A novel tetrabranched neurotensin(8-13) cyclam derivative: synthesis, 64Cu-labeling and biological evaluation.

Anika Röhrich, Ralf Bergmann, Anne Kretzschmann, Steffi Noll, Jörg Steinbach, Jens Pietzsch, Holger Stephan, Anika Röhrich, Ralf Bergmann, Anne Kretzschmann, Steffi Noll, Jörg Steinbach, Jens Pietzsch, Holger Stephan, Anika Röhrich, Ralf Bergmann, Anne Kretzschmann, Steffi Noll, Jörg Steinbach, Jens Pietzsch, Holger Stephan

Index: J. Inorg. Biochem. 105(6) , 821-32, (2011)

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Abstract

New macrocyclic 1,4,8,11-tetraazacyclotetradecane (cyclam) derivatives with 1, 2 and 4 neurotensin(8-13) units 4, 5 and 7 have been synthesized. Compounds 4 and 5 were prepared by the reaction of non-stabilized neurotensin(8-13) and cyclamtetrapropionic acid 2 using 1-ethyl-3-(3-dimethylaminocarbonyl)carbodiimide-hydrochloride and N-hydroxysulfosuccinimide. The tetrameric compound 7 was synthesized by Michael addition of neurotensin(8-13) acrylamide 6 and cyclam 1. The copper(II) complexation behavior of 4, 5 and 7 was investigated by UV/visible spectrophotometry and shows that the metal center resides inside the N4 chromophore with additional apical interactions established with pendant arms. The novel tetrabranched NT(8-13) cyclam 7 with nanomolar neurotensin receptor 1 binding affinity was efficiently radiolabeled with (64)Cu under mild conditions. (64)Cu⊂7 showed slow transchelation in the presence of a large amount of cyclam as competing ligand, while it completely remains intact in the presence of EDTA. The in vivo behavior of (64)Cu⊂7 was studied in rats and mice. The metabolic stability in rodent models was high with a half-life of intact (64)Cu⊂7 in plasma of 34 min in rats and 60 min in the mice, respectively. The binding affinity was high enough to demonstrate in vivo binding of (64)Cu⊂7 to NTR1 overexpressing HT-29 tumor xenotransplants in nude mice. Regarding elimination, (64)Cu⊂7 showed a substantial renal and reticuloendothelial accumulation. On the other hand, metabolization of the compound in vivo with a resulting metabolite-postulated to be the (64)Cu-cyclam-tetraarginine complex-also showed long retention in the circulating blood, preventing a better contrast of tumor imaging.Copyright © 2011 Elsevier Inc. All rights reserved.