The increased expression of the
neurotensin (NT) receptor NTS1 by different
cancer cells, such as pancreatic
adenocarcinoma and ductal
breast cancer cells, as compared to normal epithelium, offers the opportunity to target these
tumors with radiolabeled
neurotensin analogues for diagnostic or therapeutic purposes. The aim of the present study was to design and synthesize new
neurotensin radioligands and to select a lead molecule with high in vivo
tumor selectivity for further development. Two series of
neurotensin analogues bearing
DTPA were tested: a series of
NT(8-13) analogues, with
DTPA coupled to the α-NH(2), sharing the same
peptide sequence with analogues previously developed for radiolabeling with
technetium or
rhenium, as well as an NT(6-13) series in which
DTPA was coupled to the ε-NH(2) of Lys(6). Changes were introduced to stabilize the bonds between Arg(8)-Arg(9), Pro(10)-Tyr(11), and Tyr(11)-Ile(12) to provide metabolic stability. Structure-activity studies of NT analogues have shown that the attachment of
DTPA induces an important loss of affinity unless the distance between the
chelator and the
NT(8-13) sequence, which binds to the NTS1 receptor, is increased. The doubly stabilized DTPA-NT-20.3 exhibits a high affinity and an elevated stability to enzymatic degradation. It shows specific
tumor uptake and high
tumor to blood, to liver, and to intestine activity uptake ratios and affords high-contrast planar and SPECT images in an animal model. The DTPA-NT-20.3
peptide is a promising candidate for imaging
neurotensin receptor-positive
tumors, such as pancreatic
adenocarcinoma and invasive ductal
breast cancer. Analogues carrying
DOTA are being developed for
yttrium-90 or
lutetium-177 labeling.