N-Terminal Stabilization of Radiolabeled Neurotensin Analogues for Improved Tumor Uptake

Peptide-based radiopharmaceuticals targeting neurotensin-receptor-1 (NTS<sub>1</sub>) are mainly stabilized using chemical modifications at the NT[8-13] sequence, thus increasing the stability and the uptake of the corresponding radionuclide-macrocycle-linker-bioconjugate. We postulate that the introduction of the linker at the <i>N</i>-term part induces additional cleavage sites that can be further stabilized to achieve a prolonged uptake. Double (JMV 7259 and JMV 7222) and triple-stabilized neurotensin analogues (JMV 7258 and JMV 7490) were synthesized, radiolabeled, and evaluated on HT-29 cells (NTS<sub>1</sub><sup>+</sup>). Nanomolar NTS<sub>1</sub>-affinity and high internalization rates were observed for all of the radiopharmaceuticals. Efflux was lower for radiolabeled JMV 7490. Consequently, [<sup>111</sup>In]In-JMV 7490 showed uptake of 5.86 ± 0.86 and 3.65 ± 0.29% ID/g of tissue in HT-29 xenografts at 1 and 4 h, respectively. We have successfully shown that high and persistent uptake of NTS<sub>1</sub>-positive tumor cells is achievable by stabilization of the N-term part. Efflux also appears to be a critical parameter for the successful targeting of NTS<sub>1</sub> using radiopharmaceuticals.

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Journal
Journal of Medicinal Chemistry
Published
2025-03-20
DOI
https://doi.org/10.1021/acs.jmedchem.4c02844
Primary Topic
Neuropeptides and Animal Physiology
Type
article
Field-Weighted Citation Impact
0.00

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article

N-Terminal Stabilization of Radiolabeled Neurotensin Analogues for Improved Tumor Uptake

Sacha Bodin, Vincent Nail, Elif Hindié, Santo Previti et al.
Journal of Medicinal Chemistry
Neuropeptides and Animal Physiology
article

N-Terminal Stabilization of Radiolabeled Neurotensin Analogues for Improved Tumor Uptake

Sacha Bodin, Vincent Nail, Elif Hindié, Santo Previti, Liaquat Ali, Clément Morgat, Florine Cavelier, F. Lamare, Delphine Vimont, Simone U. Dalm, Laure Balasse, Tyrillshall S. T. Damiana, Benjamin Guillet, Emmanuelle Rémond
article en

Abstract

Peptide-based radiopharmaceuticals targeting neurotensin-receptor-1 (NTS<sub>1</sub>) are mainly stabilized using chemical modifications at the NT[8-13] sequence, thus increasing the stability and the uptake of the corresponding radionuclide-macrocycle-linker-bioconjugate. We postulate that the introduction of the linker at the <i>N</i>-term part induces additional cleavage sites that can be further stabilized to achieve a prolonged uptake. Double (JMV 7259 and JMV 7222) and triple-stabilized neurotensin analogues (JMV 7258 and JMV 7490) were synthesized, radiolabeled, and evaluated on HT-29 cells (NTS<sub>1</sub><sup>+</sup>). Nanomolar NTS<sub>1</sub>-affinity and high internalization rates were observed for all of the radiopharmaceuticals. Efflux was lower for radiolabeled JMV 7490. Consequently, [<sup>111</sup>In]In-JMV 7490 showed uptake of 5.86 ± 0.86 and 3.65 ± 0.29% ID/g of tissue in HT-29 xenografts at 1 and 4 h, respectively. We have successfully shown that high and persistent uptake of NTS<sub>1</sub>-positive tumor cells is achievable by stabilization of the N-term part. Efflux also appears to be a critical parameter for the successful targeting of NTS<sub>1</sub> using radiopharmaceuticals.

Journal of Medicinal ChemistryVol. 68(7)
École Nationale Supérieure de Chimie de Montpellier (FR), Centre National de la Recherche Scientifique (FR), Université de Bordeaux (FR), Inserm (FR), École Pratique des Hautes Études (FR), Institut Universitaire de France (FR), Université de Montpellier (FR), Aix-Marseille Université (FR), Erasmus MC (NL), Centre Hospitalier Universitaire de Bordeaux (FR), Institut de Neurosciences Cognitives et Intégratives d’Aquitaine (FR), Imagerie Médicale et Radiothérapie Drôme Ardèche (FR), Institut des Biomolécules Max Mousseron (FR)
Institut National Du Cancer
Openalex Percentile: Top 94%
Neuropeptides and Animal Physiology
DOISourceOpenAlex
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