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, Christof; Purkayastha, Nirupam; Yoshinari, Tomohiro; Seebach, Dieter; Maschauer, Simone; Prante, Olaf; Hübner, Harald; Gmeiner, Peter; Kolesinska, Beata; Cescato, Renzo; Waser, Beatrice; Reubi, Jean-Claude (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), pp. 2101-2121. Verlag Helvetica Chimica Acta 10.1002/cbdv.201300331

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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).

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Pathology
UniBE Contributor:	Waser, Beatrice, Reubi-Kattenbusch, Jean-Claude
Subjects:	500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health
ISSN:	1612-1872
Publisher:	Verlag Helvetica Chimica Acta
Language:	English
Submitter:	Andrea Arnold
Date Deposited:	02 Apr 2014 15:45
Last Modified:	05 Dec 2022 14:31
Publisher DOI:	10.1002/cbdv.201300331
PubMed ID:	24327436
Uncontrolled Keywords:	Neurotensin(8 – 13), Receptor binding, Biodistribution, Amino acids, Animal experiments, Docking, virtual
URI:	https://boris.unibe.ch/id/eprint/46329