Neurotensin subtype 1 receptors (NTS1R) represent attractive molecular targets for directing radiolabeled neurotensin (NT) analogs to tumor lesions for diagnostic and therapeutic purposes. This approach has been largely undermined by the rapid in vivo degradation of linear NT-based radioligands. Herein, we aim to increase the tumor targeting of three99mTc-labeled NT analogs by the in-situ inhibition of two key proteases involved in their catabolism. DT1 ([N4- Gly7]NT(7-13)), DT5 ([N4-βAla7,Dab9]NT(7-13)), and DT6 ([N4-βAla7,Dab9,Tle12]]NT(7-13)) were labeled with99mTc. Their profiles were investigated in NTS1R-positive colon adenocarcinoma WiDr cells and mice treated or not with the neprilysin (NEP)-inhibitor phosphoramidon (PA) and/or the angiotensin converting enzyme (ACE)-inhibitor lisinopril (Lis). Structural modifications led to the partial stabilization of99mTc-DT6 in peripheral mice blood (55.1 ± 3.9% intact), whereas99mTc-DT1 and99mTc-DT5 were totally degraded within 5 min. Coinjection of PA and/or Lis significantly stabilized all three analogs, leading to a remarkable enhancement of tumor uptake for99mTc-DT1 and99mTc-DT5, but was less effective in the case of poorly internalizing99mTc-DT6. In conclusion, NEP and/or ACE inhibition represents a powerful tool to improve tumor targeting and the overall pharmacokinetics of NT-based radioligands, and warrants further validation in the field of NTS1R-targeted tumor imaging and therapy.

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Erasmus MC: University Medical Center Rotterdam

Kanellopoulos, P. (Panagiotis), Kaloudi, A, de Jong, M, Krenning, E.P, Nock, B.A, & Maina, T. (2020). Key-protease inhibition regimens promote tumor targeting of neurotensin radioligands. Pharmaceutics, 12(6), 1–16. doi:10.3390/pharmaceutics12060528