Silicon-Containing Neurotensin Analogues as Radiopharmaceuticals for NTS 1 -Positive Tumors Imaging

Roberto Fanelli (1) , Adrien Chastel (2) , Santo Previti (3) , Elif Hindié (4) , Delphine Vimont (2) , Paolo Zanotti-Fregonara (2) , Philippe Fernandez (5) , Philippe Garrigue (6, 7) , Frédéric Lamare (2) , Romain Schollhammer (2) , Laure Balasse (6, 7) , Benjamin Guillet (6, 7) , Emmanuelle Rémond (6) , Clément Morgat (2) , Florine Cavelier (3)

1 ENSCM - Ecole Nationale Supérieure de Chimie de Montpellier
2 INCIA - Institut de Neurosciences cognitives et intégratives d'Aquitaine
3 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
4 Hôpital Haut-Lévêque [CHU Bordeaux]
5 LAMPEA - Laboratoire méditerranéen de préhistoire Europe-Afrique
6 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
7 CERIMED - Centre Européen de Recherche en Imagerie médicale

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 Ga-68-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, [Ga-68]Ga-JMV6659 exhibits high hydrophilicity (log D-7.4 = -3.41 +/- 0.14), affinity in the low nanomolar range toward NTS1 (K-d = 6.29 +/- 1.37 nM), good selectivity (K-d 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 ([Ga-68]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, [Ga-68]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. [Ga-68]Ga-JMV6659 was identified as a promising lead compound suitable for PET imaging of NTS1-expressing tumors.

Domaines: Biochimie, Biologie Moléculaire

Roberto Fanelli, Adrien Chastel, Santo Previti, Elif Hindié, Delphine Vimont, et al.. Silicon-Containing Neurotensin Analogues as Radiopharmaceuticals for NTS 1 -Positive Tumors Imaging. Bioconjugate Chemistry, 2020, 31 (10), pp.2339-2349. ⟨10.1021/acs.bioconjchem.0c00419⟩. ⟨hal-03169750⟩