title: Syntheses, receptor bindings, in vitro and in vivo stabilities and biodistributions of DOTA-neurotensin(8-13) derivatives containing β-amino acid residues - a lesson about the importance of animal experiments.
abstract: Neurotensin(8-13) (NTS(8-13)) analogs with C- and/or N-terminal β-amino acid residues and three DOTA derivatives thereof have been synthesized (i.e., 1-6). A virtual docking experiment showed almost perfect fit of one of the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives, 6a, into a crystallographically identified receptor NTSR1 (Fig.1). The affinities for the receptors of the NTS analogs and derivatives are low, when determined with cell-membrane homogenates, while, with NTSR1-exhibiting cancer tissues, affinities in the single-digit nanomolar range can be observed (Table 2). Most of the β-amino acid-containing NTS(8-13) analogs (Table 1 and Fig.2), including the (68) Ga complexes of the DOTA-substituted ones (6; Figs.2 and 5), are stable for ca. 1 h in human serum and plasma, and in murine plasma. The biodistributions of two (68) Ga complexes (of 6a and 6b) in HT29 tumor-bearing nude mice, in the absence and in the presence of a blocking compound, after 10, 30, and 60 min (Figs. 3 and 4) lead to the conclusion that the amount of specifically bound radioligand is rather low. This was confirmed by PET-imaging experiments with the tumor-bearing mice (Fig.6). Comparison of the in vitro plasma stability (after 1 h) with the ex vivo blood content (after 10-15 min) of the two (68) Ga complexes shows that they are rapidly cleaved in the animals (Fig.5).
authors: Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH-Zürich, Hönggerberg HCI, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, (phone: +41-44-632-2990; fax: +41-44-632-1144).
authors: Christof
authors: C
authors: Sparr
authors: Nirupam
authors: N
authors: Purkayastha
authors: Tomohiro
authors: T
authors: Yoshinari
authors: Dieter
authors: D
authors: Seebach
authors: Simone
authors: S
authors: Maschauer
authors: Olaf
authors: O
authors: Prante
authors: Harald
authors: H
authors: Hübner
authors: Peter
authors: P
authors: Gmeiner
authors: Beata
authors: B
authors: Kolesinska
authors: Renzo
authors: R
authors: Cescato
authors: Beatrice
authors: B
authors: Waser
authors: Jean Claude
authors: JC
authors: Reubi
mesh_terms: D000818:Animals; D001665:Binding Sites; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D005682:Gadolinium / Q000737:chemistry; D019073:HT29 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000000981:diagnostic imaging; D009496:Neurotensin / Q000031:analogs & derivatives / Q000378:metabolism*; D049268:Positron-Emission Tomography; D017434:Protein Structure, Tertiary; D018028:Receptors, Neurotensin / Q000737:chemistry / Q000378:metabolism*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D003287:Contrast Media; D056831:Coordination Complexes; D006573:Heterocyclic Compounds, 1-Ring; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D009496:Neurotensin; D005682:Gadolinium
keywords: Amino acids; Animal experiments; Biodistribution; Docking, virtual; Neurotensin(8 - 13); Receptor binding