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

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.