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

Sparr C, Purkayastha N, Yoshinari T, Seebach D, Maschauer S, Prante O, Hübner H, Gmeiner P, Kolesinska B, Cescato R, Waser B, Reubi JC (2013)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2013

Journal

Chemistry & Biodiversity Wiley-VCH Verlag / Wiley-Blackwell

Original Authors: Sparr C., Purkayastha N., Yoshinari T., Seebach D., Maschauer S., Prante O., Hubner H., Gmeiner P., Kolesinska B., Cescato R., Waser B., Reubi J.C.

Publisher: Wiley-VCH Verlag / Wiley-Blackwell

Book Volume: 10

Pages Range: 2101-2121

Journal Issue: 12

DOI: 10.1002/cbdv.201300331

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.

Authors with CRIS profile

Simone Maschauer Professur für Molekulare Bildgebung und Radiochemie Olaf Prante Professur für Molekulare Bildgebung und Radiochemie Harald Hübner Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Additional Organisation(s)

Emil-Fischer-Zentrum (Emil Fischer Center)

Involved external institutions

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

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: Download