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Double targeting of NTS1 and GRPR receptors using 68Ga-labelled heterodimers
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International audience. Aim/Introduction: Neurotensin receptor-1 (NTS1) and gastrin-releasing peptide receptor GRPR (bombesin receptor-2, BB2) are interesting targets for nuclear oncology applications. In some tumors, these receptors exhibit complementary expression profiles considering the stage or the aggressiveness of tumors, such as in breast cancer, colorectal cancer or prostate carcinomas. Targeting both receptors in the same time with a single molecule could enhance the potential for imaging and therapy of such tumors. In this work we describe the in vitro and in vivo properties of [ 68 Ga]Ga-JMV7110, [ 68 Ga]Ga-JMV7253 and [68 Ga]Ga-JMV7266, the first heterodimers designed to target both NTS1 and GRPR. Materials and Methods: JMV7110 (DOTA-βAla-βAla-(D)Phe-Gln-Trp-Ala-Val-Gly-His-(3S,4S) Sta-Leu-βAla-βAla-Lys-Lys-Pro-Phe-Ile-Leu-OH), JMV7253 (DOTA-βAla-βAla-(D)Phe-Gln-Trp-Ala-Val-Gly-His-(3S,4S) Sta-Leu-βAla-βAla-Lys-Lys-Pro-Phe-Ile-TMSAla-OH) and JMV7266 (DOTA-βAla-Glu(βAla-βAla-(D)Phe-Gln-Trp-Ala-Val-Gly-His-(3S,4S)Sta-Leu-NH 2 )-βAla-Lys-Lys-Pro-Tyr-Ile-Leu-OH, branched compound) were prepared using solid-phase synthesis, purified and then radiolabelled with gallium-68. In vitro characterization was performed on human colorectal adenocarcinoma HT29 cell lines, expressing high levels of NTS1 and GRPR. Corresponding 68 Ga-monomers were used as controls. In vivo pharmacology was complemented by dynamic microPET/CT imaging on HT29-xenografted nude mice. Results: Radiolabelling heterodimers with 68 Ga was achieved with moderate yield (44.4 ± 6.3 %) and high apparent molar activity (> 15 GBq/μmol). The three compounds exhibited hydrophilic properties, suggesting renal clearance and low brain uptake, although hydrophilicity was somewhat reduced for [ 68 Ga]GaJMV7253 due to the adjunction of the non-natural amino acid trimethylsilylalanine (TMSAla). Saturation studies demonstrated moderate affinities for NTS1 and GRPR (Kd values 100-500 nM), which remain lower than the corresponding 68 Ga-monomers. JMV7266 branched structure correlated with better affinity compared with the two linear compounds. High levels of internalization were observed at 60 min, mediated by NTS1 (> 40 %) and GRPR (> 15 %) with very low membrane bindings (< 11 % via NTS1 and < 5% via GRPR). An early intense efflux was observed for [68 Ga]Ga-JMV7110 (> 80% at 5 min) and [ 68 Ga]Ga-JMV7253 but efflux was < 40% with [68 Ga]Ga-JMV7266. In vivo biodistribution studies on HT29-grafted mice showed moderate tumor uptake (0.44 ± 0.21% ID/g for [68 Ga]Ga-JMV7266 and 0.33 ± 0.11% ID/g for [ 68 Ga]Ga-JMV7110) 90 min post-injection. Kidneys showed the highest uptake at 90min (18.3 ± 9.6% ID/g and 19.4 ± 7.4% ID/g). Dynamic PET/CT data are under analysies. Conclusion: To our knowledge, the compounds presented in this work are the first radiolabelled heterodimers targeting both NTS1 and GRPR. Despite moderate affinities, [ 68 Ga]Ga-JMV7110 and [68 Ga]Ga-JMV7266 exhibited promising tumor uptake. References: None.
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