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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.
- Source :
-
Chemistry & biodiversity [Chem Biodivers] 2013 Dec; Vol. 10 (12), pp. 2101-21. - Publication Year :
- 2013
-
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).<br /> (Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.)
- Subjects :
- Animals
Binding Sites
Contrast Media chemistry
Contrast Media metabolism
Coordination Complexes chemistry
Coordination Complexes metabolism
Crystallography, X-Ray
Gadolinium chemistry
HT29 Cells
Heterocyclic Compounds, 1-Ring chemistry
Humans
Mice
Mice, Nude
Molecular Docking Simulation
Neoplasms diagnostic imaging
Neurotensin analogs & derivatives
Positron-Emission Tomography
Protein Structure, Tertiary
Receptors, Neurotensin chemistry
Tissue Distribution
Transplantation, Heterologous
Heterocyclic Compounds, 1-Ring metabolism
Neurotensin metabolism
Receptors, Neurotensin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1612-1880
- Volume :
- 10
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Chemistry & biodiversity
- Publication Type :
- Academic Journal
- Accession number :
- 24327436
- Full Text :
- https://doi.org/10.1002/cbdv.201300331