Radiolabeled analogs of neurotensin (8–13) containing multiple 1,2,3-triazoles as stable amide bond mimics in the backbone

Abstract

Radiometallated regulatory peptides are a promising class of radiopharmaceuticals for the diagnosis (imaging) and therapy of cancer in nuclear oncology. A limitation of such peptides employed as tumor-specific vectors is represented by their low stability in vivo. Stabilization of the peptides against proteolytic degradation by, e.g., structural modifications, can improve their tumor-targeting properties. We here report an application of our recently introduced peptide stabilization methodology, which involves the substitution of amide bonds in the backbone of peptides by metabolically stable 1,2,3-triazoles. Specifically, we replaced multiple amide bonds by the heterocyclic amide bond mimic in the binding sequence of neurotensin, NT(8-13), and studied in vitro the effect of the modifications on the biological properties of the peptidomimetics obtained (cell internalization, affinity towards the neurotensin receptor subtype 1, blood plasma stability, and log D). In the course of the work, a 177 Lu-labeled DOTA-NT(8-13) conjugate bearing two consecutively placed triazoles in its backbone with retained biological function was identified.Med. Chem. Commun. This journal is † The authors declare no competing interests. ‡ Electronic supplementary information (ESI) available: HPLC chromatograms and MS spectra of peptide conjugates NT 1c and 2c and the corresponding radiolabeled derivatives [ 177 Lu]-NT 1c and 2c. See

A mini review of the synthesis of poly-1,2,3-triazole-based functional materials

“…35 However, to further expand the applications of poly-1,2,3-triazoles in the areas of drug synthesis, ion recognition, chemicobiology, supramolecular chemistry and others, much work still remains. 11,36 The mini review presented here can hopefully serve as a guide to better design and fabrication of functional poly-1,2,3-triazoles for addressing the problems existing in scientic communities and real-world industries. Although a signicant advance has been achieved for synthesis and potential applications of poly-1,2,3-triazole-based functional materials in the past few decades, there still exist a number of challenges.…”

1,4-Disubstituted 1,2,3-Triazoles as Amide Bond Surrogates for the Stabilisation of Linear Peptides with Biological Activity

“…Subsequent investigations focused on the incorporation of multiple triazoles in the backbone of NT(8–13) [ 98 ]. Building on the results of the triazole scan discussed above, the triazolo-peptidomimetics NT11 and NT12 with a simultaneous substitution at PEG 4 -Arg 8 and Arg 8 -Arg 9 for the Ile 12 and Tle 12 analogue were synthesised and tested in vitro.…”

Radiopharmaceuticals for imaging and endoradiotherapy of neurotensin receptor‐positive tumors

“…47 In contrast to [ 177 Lu]Lu-NT 1c, which bears an additional triazole moiety at the N-terminus compared with [ 177 Lu] Lu-NT-VI (entry 5, Table 3) and has sustained affinity for NTS1, the introduction of a second triazole moiety into the backbone of NT IX led to a substantial decrease in receptor affinity, suggesting that employing multiple amide-to-triazole substitutions in molecules with biological function will require case-by-case studies regarding the preservation of receptor affinity. 48 To date, only a few studies have reported on the preclinical radiotherapeutic efficacy of 177 Lu-labeled NT peptide analogs. The first preclinical study on a 177 Lu- Table 3).…”

“…They systematically studied the influence of the triazole moiety in different positions of the amino acid sequence of the peptide, revealing that [ 177 Lu]Lu‐NT‐VI (entry 4, Table ) with a K d of 8.8 nM and its stabilized Tle 12 ‐for‐Ile 12 substituted analog ([ 177 Lu]Lu‐NT IX, entry 4, Table ) with a K d of 214 nM and a 98% 4‐hour stability in serum in vitro were interesting tracers for further developments of NT‐based radiotherapeutics . In contrast to [ 177 Lu]Lu‐NT 1c, which bears an additional triazole moiety at the N‐terminus compared with [ 177 Lu]Lu‐NT‐VI (entry 5, Table ) and has sustained affinity for NTS1, the introduction of a second triazole moiety into the backbone of NT IX led to a substantial decrease in receptor affinity, suggesting that employing multiple amide‐to‐triazole substitutions in molecules with biological function will require case‐by‐case studies regarding the preservation of receptor affinity …”