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Design and Synthesis of 68Ga-Labeled Peptide-Based Heterodimers for Dual Targeting of NTS1 and GRPR
Sacha Bodin1,2, Santo Previti3,4, Emmanuelle Jestin5
1University of Bordeaux, CNRS, EPHE, INCIA UMR 5287, F-33400, Talence, France.
Abstract:
Tumor heterogeneity remains one of the main obstacles for cancer diagnosis and treatment. The simultaneous targeting of several cancer biomarkers is an appealing approach for improved diagnostic procedures. Neurotensin receptor 1 (NTS1) and Gastrin-Releasing Peptide Receptor (GRPR) are both G-protein coupled receptors with complementary profile of expression in several cancer types. This work proposes the design, the synthesis and the in vitro radiopharmaceutical characterization of three heterodimers, based on GRP/NT modified peptides, radiolabeled with gallium-68. Two NTS1/GRPR targeting pharmacophores containing linear hybrids that differ in the C-terminus were synthesized (i. e., JMV 7110 and JMV 7253). The branched analogue of the silicon-containing heterodimer JMV 7110, namely JMV 7266, was also synthesized. After radiolabeling with 68Ga, saturation binding studies performed on HT29 (NTS1 +/GRPR-) and PC3 (NTS1 +/GRPR+) cells demonstrated a significant loss in NTS1 and GRPR affinity compared to the reference monomers with the exception of the NTS1 affinity of [68Ga]Ga-JMV 7266 which was preserved. Considering cellular processing, NTS1-internalization at 1 h was the highest with [68Ga]Ga-JMV 7266 and was similar to the reference compound. Interestingly [68Ga]Ga-JMV 7266 demonstrated lower efflux than the other linear heterodimers but also than its NT reference compound. The branched structure of [68Ga]Ga-JMV 7266 seems beneficial for dual NTS1/GRPR targeting.
Insights
This study developed novel Gallium-68 dual-targeted radiopharmaceuticals for cancer diagnosis. The branched heterodimer JMV 7266 showed preserved Neurotensin receptor 1 affinity and improved cellular processing for dual NTS1/GRPR targeting.
Area of Science:
- Radiopharmaceutical chemistry
- Molecular imaging
- Cancer biomarker targeting
Background:
- Tumor heterogeneity poses challenges in cancer diagnosis and treatment.
- Targeting multiple cancer biomarkers simultaneously offers improved diagnostic potential.
- Neurotensin receptor 1 (NTS1) and Gastrin-Releasing Peptide Receptor (GRPR) are co-expressed in various cancers.
Purpose of the Study:
- To design, synthesize, and characterize novel Gallium-68 heterodimers for simultaneous NTS1 and GRPR targeting.
- To evaluate the in vitro performance of these radiopharmaceuticals for potential cancer imaging applications.
Main Methods:
- Synthesis of three heterodimers (JMV 7110, JMV 7253, JMV 7266) based on modified GRP/NT peptides.
- Radiolabeling of heterodimers with Gallium-68 (68Ga).
- In vitro saturation binding studies and cellular processing assays on cancer cell lines (HT29, PC3).
Main Results:
- Two linear heterodimers (JMV 7110, JMV 7253) and one branched analogue (JMV 7266) were synthesized.
- [68Ga]Ga-JMV 7266 demonstrated preserved NTS1 affinity and superior NTS1-internalization compared to linear analogues.
- JMV 7266 exhibited lower efflux, indicating improved retention in targeted cells.
Conclusions:
- The branched heterodimer JMV 7266 shows promise for dual NTS1/GRPR targeting.
- Its favorable binding affinity and cellular processing characteristics make it a potential candidate for advanced cancer diagnostics.
- This study highlights the benefit of branched structures in developing effective dual-targeting radiopharmaceuticals.
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