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

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.