title: A novel tetrabranched neurotensin(8-13) cyclam derivative: synthesis, 64Cu-labeling and biological evaluation.
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.
authors.affiliation: Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Röhrich
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Anne
authors.initials: A
authors.lastname: Kretzschmann
authors.forename: Steffi
authors.initials: S
authors.lastname: Noll
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.forename: Holger
authors.initials: H
authors.lastname: Stephan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D006207:Half-Life; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D008024:Ligands; C560855:N,N',N',N-tetrakis((N-(arginyl-arginyl-prolyl-tyrosyl-isoleucyl-leucine)aminocarbonyl)ethyl)-1,4,8,11-tetraazacyclotetradecane; D010446:Peptide Fragments; C409806:neurotensin (9-13); C024560:cyclam; D009496:Neurotensin