The effect on in situ inhibition of nep and/or ace on tumor targeting of a technetium-99m labeled biodegradable neurotensin (7-13) based radiotracer

Neurotensin subtype 1 receptor (NTS1R) is over expressed in various malignancies, such as lung, colon, breast and pancreatic cancer. In this work, we investigated the capability of technetium-99m labeled DT1 (N4-Gly7NT (7-13)) to target different malignancies in association with its stability in the blood stream. ^99mTc-DT1, like neurotensin, is fast degraded by NEP and ACE. Accordingly, the use of NEP (e.g. phosphoramidon (PA)/Entresto) and/or ACE (e.g. lisinopril (Lis)) inhibitors can increase its stability and tumor targeting capabilities. In this study, NTS1R-positive colon adenocarcinoma WiDr and pancreatic adenocarcinoma AsPC-1 cell-lines were used. The cell-association was assessed at 37 °C after 1 h incubation. The stability of the tracer was examined, 5 min post injection (pi) in healthy mice. Biodistribution was performed 4 h pi in male SCID mice bearing subcutaneous WiDr/AsPC-1 xenografts. The radiopeptide was administered intravenously in animals treated or not with Lis and/or PA/Entresto. ^99mTc-DT1 displayed high cell uptake both in WiDr (10.1±2.3%) and AsPC-1 (15.2±2.6%) cells, with the bulk of the radioactivity found internalized. In peripheral mouse blood the analog was degraded (1.8±0.8% intact), but applying the combination of Lis + PA/Entresto it remained intact up to 72.3±3.2%. A drastic increase in tumor targeting was observed in mice treated with the combination of Lis + PA/Entresto (9.60±3.62/7.05±0.8%IA/g for WiDr/AsPC-1 tumors) vs. untreated controls (≈1%IA/g). As previously suggested, the performance of biodegradable peptidic radiotracers, such as ^99mTc-DT1, can be greatly improved with the use of key-peptidase inhibitors. (author)