N-Terminal Stabilization of Radiolabeled Neurotensin Analogues for Improved Tumor Uptake

Abstract

Peptide-based radiopharmaceuticals targeting neurotensin-receptor-1 (NTS₁) are mainly stabilized using chemical modifications at the NT[8–13] sequence, thus increasing the stability and the uptake of the corresponding radionuclide-macrocycle-linker-bioconjugate. We postulate that the introduction of the linker at the N-term part induces additional cleavage sites that can be further stabilized to achieve a prolonged uptake. Double (JMV 7259 and JMV 7222) and triple-stabilized neurotensin analogues (JMV 7258 and JMV 7490) were synthesized, radiolabeled, and evaluated on HT-29 cells (NTS₁⁺). Nanomolar NTS₁-affinity and high internalization rates were observed for all of the radiopharmaceuticals. Efflux was lower for radiolabeled JMV 7490. Consequently, [¹¹¹In]In-JMV 7490 showed uptake of 5.86 ± 0.86 and 3.65 ± 0.29% ID/g of tissue in HT-29 xenografts at 1 and 4 h, respectively. We have successfully shown that high and persistent uptake of NTS₁-positive tumor cells is achievable by stabilization of the N-term part. Efflux also appears to be a critical parameter for the successful targeting of NTS₁ using radiopharmaceuticals.