RSS-Feed abonnieren
DOI: 10.1055/s-0040-1708265
Ga-68 labeling of stable neurotensin(8-13) analogs via carbamoylated arginine residues gives NTS 1 R PET ligands with promising in vitro profile
Publikationsverlauf
Publikationsdatum:
08. April 2020 (online)
Ziel/Aim The neurotensin receptor 1 (NTS1 R) is considered an interesting target for cancer diagnosis and therapy as it is overexpressed in various tumors (e.g. colorectal and pancreatic carcinoma). Applying the concept of functionalized carbamoylated arginines (1), we aimed at the synthesis and in vitro characterization of stable Ga-68 labeled NTS1 R PET ligands derived from neurotensin(8–13) (NT(8–13)).
Methodik/Methods Analogs of NT(8–13) (sequence: Arg8-Arg9-Pro10-Tyr11-Ile12-Leu12) were prepared by solid-phase peptide synthesis. To stabilize the peptides against enzymatic degradation, Arg8 or Arg9 was replaced by Nα-methylated Arg and Ile12 by tert-butylglycine (2). Additionally, an amino-functionalized Nω-carbamoylated Arg was incorporated instead of Arg8 or Arg9. Conjugation of the peptides to DOTA and insertion of Ga3+ (100 °C, 10 min) gave the potential PET ligands UR-LS029 and UR-LS051. NTS1 R affinities were determined by radioligand competition binding at HT-29 cells using [3 H]UR-MK300 (1). The PET ligands [68 Ga]UR-LS029 and [68 Ga]UR-LS051 (synthesis see contribution by Moosbauer et al.) were characterized with respect to stability in human plasma (37 °C) by HPLC, logD (shake flask assay) and by autoradiography at cryo-sections of HT-29 xenografts.
Ergebnisse/Results UR-LS029 and UR-LS051 showed high NTS1 R affinities (Ki < 16 nM). [68 Ga]UR-LS029 and [68 Ga]UR-LS051 (logD: −2.6 and −3.2, respectively) exhibited high radiochemical purities (> 99 %), proved to be stable in plasma over 3 h (> 98 % intact tracer), and allowed the detection of NTS1 Rs in HT-29 xenografts.
Schlussfolgerungen/Conclusions Incorporation of functionalized Nω-carbamoylated arginines in backbone stabilized NT(8–13) analogs gave access to stable Ga-68 labeled NTS1 R PET ligands. The in vitro results justify in vivo studies, e.g. in tumor bearing nude mice.
#
-
Literatur/References
- 1 Keller M. et al. J. Med. Chem. 2016; , 59: 1925-1945.
- 2 Schindler L. et al. ACS Med. Chem. Lett. 2019; , 10 , 960-965.
-
Literatur/References
- 1 Keller M. et al. J. Med. Chem. 2016; , 59: 1925-1945.
- 2 Schindler L. et al. ACS Med. Chem. Lett. 2019; , 10 , 960-965.