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

Journal article
(Original article)


Publication Details

Author(s): Sparr C, Purkayastha N, Yoshinari T, Seebach D, Maschauer S, Prante O, Hübner H, Gmeiner P, Kolesinska B, Cescato R, Waser B, Reubi JC
Journal: Chemistry & Biodiversity
Publisher: Wiley-VCH Verlag / Wiley-Blackwell
Publication year: 2013
Volume: 10
Journal issue: 12
Pages range: 2101-2121
ISSN: 1612-1872
Language: English


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 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 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 Ga complexes shows that they are rapidly cleaved in the animals (Fig. 5). Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.



FAU Authors / FAU Editors

Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Maschauer, Simone PD Dr.
Professur für Molekulare Bildgebung und Radiochemie
Prante, Olaf Prof. Dr.
Professur für Molekulare Bildgebung und Radiochemie


Additional Organisation
Emil-Fischer-Zentrum (Emil Fischer Center)


External institutions with authors

Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich
Universität Bern
University of Lodz / Uniwersytet Łódzki


How to cite

APA:
Sparr, C., Purkayastha, N., Yoshinari, T., Seebach, D., Maschauer, S., Prante, O.,... Reubi, J.C. (2013). 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. Chemistry & Biodiversity, 10(12), 2101-2121. https://dx.doi.org/10.1002/cbdv.201300331

MLA:
Sparr, Christof, et al. "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." Chemistry & Biodiversity 10.12 (2013): 2101-2121.

BibTeX: 

Last updated on 2018-16-07 at 08:23