Silicon-Containing Neurotensin Analogues as Radiopharmaceuticals for NTS1-Positive Tumors Imaging
- Roberto FanelliRoberto FanelliInstitut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université de Montpellier, ENSCM, Place Eugène Bataillon, Montpellier 34095 Cedex 5, FranceMore by Roberto Fanelli
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- Adrien ChastelAdrien ChastelUniversity of Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux F-33000, FranceNuclear Medicine Department, University Hospital of Bordeaux, Bordeaux F-33000, FranceMore by Adrien Chastel
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- Santo PrevitiSanto PrevitiInstitut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université de Montpellier, ENSCM, Place Eugène Bataillon, Montpellier 34095 Cedex 5, FranceMore by Santo Previti
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- Elif HindiéElif HindiéUniversity of Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux F-33000, FranceNuclear Medicine Department, University Hospital of Bordeaux, Bordeaux F-33000, FranceMore by Elif Hindié
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- Delphine VimontDelphine VimontUniversity of Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux F-33000, FranceMore by Delphine Vimont
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- Paolo Zanotti-FregonaraPaolo Zanotti-FregonaraHouston Methodist Research Institute, Houston, Texas 77030, United StatesMore by Paolo Zanotti-Fregonara
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- Philippe FernandezPhilippe FernandezUniversity of Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux F-33000, FranceNuclear Medicine Department, University Hospital of Bordeaux, Bordeaux F-33000, FranceMore by Philippe Fernandez
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- Philippe GarriguePhilippe GarrigueAix-Marseille University, INSERM, Institut National de la Recherche Agronomique, Centre de Recherche en Cardiovasculaire et Nutrition, Marseille 13385, FranceAix-Marseille University, Centre Européen de Recherche en Imagerie Médicale, Marseille 13005, FranceMore by Philippe Garrigue
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- Frédéric LamareFrédéric LamareUniversity of Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux F-33000, FranceNuclear Medicine Department, University Hospital of Bordeaux, Bordeaux F-33000, FranceMore by Frédéric Lamare
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- Romain SchollhammerRomain SchollhammerUniversity of Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux F-33000, FranceNuclear Medicine Department, University Hospital of Bordeaux, Bordeaux F-33000, FranceMore by Romain Schollhammer
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- Laure BalasseLaure BalasseAix-Marseille University, INSERM, Institut National de la Recherche Agronomique, Centre de Recherche en Cardiovasculaire et Nutrition, Marseille 13385, FranceMore by Laure Balasse
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- Benjamin GuilletBenjamin GuilletAix-Marseille University, INSERM, Institut National de la Recherche Agronomique, Centre de Recherche en Cardiovasculaire et Nutrition, Marseille 13385, FranceAix-Marseille University, Centre Européen de Recherche en Imagerie Médicale, Marseille 13005, FranceMore by Benjamin Guillet
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- Emmanuelle RémondEmmanuelle RémondInstitut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université de Montpellier, ENSCM, Place Eugène Bataillon, Montpellier 34095 Cedex 5, FranceMore by Emmanuelle Rémond
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- Clément Morgat*Clément Morgat*Email: [email protected]University of Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux F-33000, FranceNuclear Medicine Department, University Hospital of Bordeaux, Bordeaux F-33000, FranceMore by Clément Morgat
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- Florine Cavelier*Florine Cavelier*Email: [email protected]Institut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université de Montpellier, ENSCM, Place Eugène Bataillon, Montpellier 34095 Cedex 5, FranceMore by Florine Cavelier
Abstract
Several independent studies have demonstrated the overexpression of NTS1 in various malignancies, which make this receptor of interest for imaging and therapy. To date, radiolabeled neurotensin analogues suffer from low plasmatic stability and thus insufficient availability for high uptake in tumors. We report the development of 68Ga-radiolabeled neurotensin analogues with improved radiopharmaceutical properties through the introduction of the silicon-containing amino acid trimethylsilylalanine (TMSAla). Among the series of novel radiolabeled neurotensin analogues, [68Ga]Ga-JMV6659 exhibits high hydrophilicity (log D7.4 = −3.41 ± 0.14), affinity in the low nanomolar range toward NTS1 (Kd = 6.29 ± 1.37 nM), good selectivity (Kd NTS1/Kd NTS2 = 35.9), and high NTS1-mediated internalization. It has lower efflux and prolonged plasmatic half-life in human plasma as compared to the reference compound ([68Ga]Ga-JMV6661 bearing the minimum active fragment of neurotensin and the same linker and chelate as other analogues). In nude mice bearing HT-29 xenograft, [68Ga]Ga-JMV6659 uptake reached 7.8 ± 0.54 %ID/g 2 h post injection. Uptake was decreased to 1.38 ± 0.71 %ID/g with injection of excess of non-radioactive neurotensin. Radiation dose as extrapolated to human was estimated as 2.35 ± 0.6 mSv for a standard injected activity of 100MBq. [68Ga]Ga-JMV6659 was identified as a promising lead compound suitable for PET imaging of NTS1-expressing tumors.
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