Communication Dans Un Congrès Année : 2024

Dual 68Ga-labeled peptide-based radiopharmaceuticals to address tumor heterogeneity

Résumé

Despite the great efforts of the scientific community, tumor heterogeneity remains one of the main issues for cancer diagnosis and treatment. [1] Neurotensin receptor 1 (NTS1), Gastrin-Releasing Peptide Receptor (GRPR), and Prostate-Specific Membrane Antigen (PSMA) represent three promising targets for cancer imaging and therapy, with complementary profiles of expression in different types of tumors (i.e., breast and prostate cancer, to name a few). [2] Therefore, the development of heterodimers targeting two distinct receptors might address tumor heterogeneity. We herein report the synthesis, the radiolabeling, and biological investigation of four 68 Ga (a positron emitter for imaging)-labeled peptide-based heterodimers carrying the pharmacophores targeting either NTS1 and PMSA or NTS1 and GRPR. The branched NTS1/PSMA heterodimer ([68 Ga]Ga-JMV 7489) bearing showed affinity values towards PSMA 3-fold lower than other NT-PSMA heterodimers and similar to that of PSMA monomers. The affinity towards NTS1 was lower with respect to the known NT monomers. The novelty of heterodimers targeting NTS1 and GRPR will be here emphasized. The linear heterodimers JMV 7110 and JMV 7253, which differ by the presence of Leu or trimethylsilylalanine at the C-terminal fragment of NT, [3] were obtained through Solid-Phase Peptide Synthesis, whereas the branched analogue JMV 7266 was synthesized with a hybrid approach involving both SPPS and synthesis in batch. After radiolabeling with 68 Ga, saturation binding assays conducted on HT29 and PC3 cells showed sub-micromolar Kd values (130–190 nM range) at the NTS1 and GRPR. Cell processing studies showed rapid internalization which peaked at 60 min. Values within 33%–43% and 14%–19% towards NTS1-mediated internalization on HT29 cells and GRPR-mediated on PC3 cells, respectively, were observed. Moreover, the branched analogue [68 Ga]Ga-JMV 7266 demonstrated lower efflux than linear ligands, and was then investigated in vivo on HT29 tumor-bearing mice. Kidneys demonstrated intense signal associated with renal clearance, consistent with hydrophilicity. Unfortunately, tumor uptakes were modest, in line with its modest affinities. [68 Ga]Ga-JMV 7266 paves the way for further development of improved radiolabeled GRP/NT peptide-based heterodimers for molecular imaging and theragnostic purposes. References 1. Dagogo-Jack A, Shaw AT. Nat Rev Clin Oncol. 2018;15:81-94. 2. Morgat et al. J Nucl Med. 2014;55:1650-1657. 3. Fanelli R, Chastel A, Previti S, [...], Remond E, Morgat C, Cavelier F. Bioconjug Chem. 2020;31:2339-2349.

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Dates et versions

hal-04811498 , version 1 (29-11-2024)

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  • HAL Id : hal-04811498 , version 1

Citer

Santo Previti, Sacha Bodin, Emmanuelle Rémond, Emmanuelle Jestin, Clément Morgat, et al.. Dual 68Ga-labeled peptide-based radiopharmaceuticals to address tumor heterogeneity. 37th European Peptide Symposium (37th EPS) & 14th International Peptide Symposium (14th IPS), European Peptide Society (EPS), Aug 2024, Florence, Italy. pp.42. ⟨hal-04811498⟩
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