N-Terminal Stabilization of Radiolabeled Neurotensin Analogues for Improved Tumor Uptake
J. Med. Chem.. 2025-03-20; 68(7): 7280-7290
DOI: 10.1021/acs.jmedchem.4c02844
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https://www.bordeaux-neurocampus.fr/11692
Bodin S(1)(2), Damiana TST(3), Previti S(4), Balasse L(5)(6), Ali L(2), Rémond
E(4), Nail V(5)(6), Lamare F(1)(2), Hindié E(1)(2)(7), Guillet B(5)(6), Vimont
D(2), Dalm SU(3), Cavelier F(4), Morgat C(1)(2).
Author information:
(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.
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.
DOI: 10.1021/acs.jmedchem.4c02844
PMID: 40111113 [Indexed for MEDLINE]