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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
Author(s) -
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
Publication year - 2013
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201300331
Subject(s) - chemistry , dota , neurotensin , radioligand , in vivo , in vitro , receptor , amino acid , stereochemistry , neurotensin receptor , peptide , affinities , chelation , biochemistry , neuropeptide , microbiology and biotechnology , organic chemistry , biology
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 ).