Silicon-Containing Neurotensin Analogues as Radiopharmaceuticals for NTS1‑Positive Tumors Imaging

• Published in: Bioconjugate chemistry 2020-10, Vol.31 (10), p.2339-2349
• Main Authors: Fanelli, Roberto, Chastel, Adrien, Previti, Santo, Hindié, Elif, Vimont, Delphine, Zanotti-Fregonara, Paolo, Fernandez, Philippe, Garrigue, Philippe, Lamare, Frédéric, Schollhammer, Romain, Balasse, Laure, Guillet, Benjamin, Rémond, Emmanuelle, Morgat, Clément, Cavelier, Florine
• Format: Article
• Language: English
• Subjects: Amino acids; Blood plasma; Efflux; Half-life; Imaging; Injection; Internalization; Lead compounds; Neurotensin; Pharmaceuticals; Positron emission; Positron emission tomography; Radiation; Radiation dosage; Radioactive half-life; Radiochemistry; Radioisotopes; Selectivity; Silicon; Tomography; Tumors; Xenografts; Xenotransplantation
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.0c00419

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 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/K d 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.