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Article

Key-Protease Inhibition Regimens Promote Tumor Targeting of Neurotensin Radioligands

1
Molecular Radiopharmacy, INRASTES, NCSR “Demokritos”, 15341 Athens, Greece
2
Molecular Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Greece
3
Department of Radiology & Nuclear Medicine Erasmus MC, 3015 CN Rotterdam, The Netherlands
4
Cyclotron Rotterdam BV, Erasmus MC, 3015 CE Rotterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(6), 528; https://doi.org/10.3390/pharmaceutics12060528
Received: 11 May 2020 / Revised: 5 June 2020 / Accepted: 6 June 2020 / Published: 9 June 2020
(This article belongs to the Section Drug Targeting and Design)
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 three 99mTc-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 with 99mTc. 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 of 99mTc-DT6 in peripheral mice blood (55.1 ± 3.9% intact), whereas 99mTc-DT1 and 99mTc-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 for 99mTc-DT1 and 99mTc-DT5, but was less effective in the case of poorly internalizing 99mTc-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. View Full-Text
Keywords: neurotensin; neurotensin subtype 1 receptor; 99mTc-radiotracer; tumor targeting; protease-inhibition; neprilysin-inhibitor; angiotensin-converting enzyme-inhibitor neurotensin; neurotensin subtype 1 receptor; 99mTc-radiotracer; tumor targeting; protease-inhibition; neprilysin-inhibitor; angiotensin-converting enzyme-inhibitor
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MDPI and ACS Style

Kanellopoulos, P.; Kaloudi, A.; de Jong, M.; Krenning, E.P.; Nock, B.A.; Maina, T. Key-Protease Inhibition Regimens Promote Tumor Targeting of Neurotensin Radioligands. Pharmaceutics 2020, 12, 528. https://doi.org/10.3390/pharmaceutics12060528

AMA Style

Kanellopoulos P, Kaloudi A, de Jong M, Krenning EP, Nock BA, Maina T. Key-Protease Inhibition Regimens Promote Tumor Targeting of Neurotensin Radioligands. Pharmaceutics. 2020; 12(6):528. https://doi.org/10.3390/pharmaceutics12060528

Chicago/Turabian Style

Kanellopoulos, Panagiotis, Aikaterini Kaloudi, Marion de Jong, Eric P. Krenning, Berthold A. Nock, and Theodosia Maina. 2020. "Key-Protease Inhibition Regimens Promote Tumor Targeting of Neurotensin Radioligands" Pharmaceutics 12, no. 6: 528. https://doi.org/10.3390/pharmaceutics12060528

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