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

  • J Med Chem. 2025 Apr 10;68(7):7280-7290. doi: 10.1021/acs.jmedchem.4c02844.
Sacha Bodin  1  2 ,  Tyrillshall S T Damiana  3 ,  Santo Previti  4 ,  Laure Balasse  5  6 ,  Lina Ali  2 ,  Emmanuelle Rémond  4 ,  Vincent Nail  5  6 ,  Frédéric Lamare  1  2 ,  Elif Hindié  1  2  7 ,  Benjamin Guillet  5  6 ,  Delphine Vimont  2 ,  Simone U Dalm  3 ,  Florine Cavelier  4 ,  Clément Morgat  1  2
Affiliations
  • 1. Department of Nuclear Medicine & Radiopharmacy, CHU de Bordeaux, F-33000 Bordeaux, France.
  • 2. CNRS, EPHE, INCIA, UMR 5287, University of Bordeaux, F-33000 Bordeaux, France.
  • 3. Department of Radiology & Nuclear Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands.
  • 4. Institut des Biomolécules Max Mousseron, IBMM, UMR 5247, CNRS, Université de Montpellier, ENSCM, 1919 route de Mende, 34293 Montpellier Cedex 5, France.
  • 5. INSERM, Institut National de la Recherche Agronomique, Centre de Recherche en Cardiovasculaire et Nutrition, Aix-Marseille University, 13385 Marseille, France.
  • 6. Centre Européen de Recherche en Imagerie Médicale, Aix-Marseille University, 13005 Marseille, France.
  • 7. Institut Universitaire de France, IUF, F-75000 Paris, France.
PMID: 40111113 DOI: 10.1021/acs.jmedchem.4c02844
Abstract

Peptide-based radiopharmaceuticals targeting neurotensin-receptor-1 (NTS1) 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 N-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 (NTS1+). Nanomolar NTS1-affinity and high internalization rates were observed for all of the radiopharmaceuticals. Efflux was lower for radiolabeled JMV 7490. Consequently, [111In]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 NTS1-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 NTS1 using radiopharmaceuticals.

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