Abstract
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.
Highlights
Recent advances in nuclear medicine include personalized treatment of cancer patients, whereby molecular probes are administered to deliver diagnostic or therapeutic radionuclides to cancer cells with high specificity
The synthesis and biological data for these analogs in neurotensin subtype 1 receptor (NTS1R)-expressing cells and animal models were previously reported [23,24], in the present study, we mainly focus on the impact of in situ NEP and/or angiotensin converting enzyme (ACE) inhibition on the in vivo stability and pharmacokinetic profile of these structurally related analogs
The impact of in-situ NEP and ACE inhibition on tumor targeting and pharmacokinetics of NT-based radioligands has been assessed for the first time employing three structurally related analogs, namely 99mTc-DT1 (99mTc-[N4-Gly7]NT(7-13)), 99mTc-DT5 (99mTc-[N4-βAla7,Dab9]NT(7-13)), and 99mTc-DT6 (99mTc-[N4-βAla7,Dab9,Tle12]]NT(7-13)), as examples
Summary
Recent advances in nuclear medicine include personalized treatment of cancer patients, whereby molecular probes are administered to deliver diagnostic or therapeutic radionuclides to cancer cells with high specificity. Therapy per se is operated by the peptide analog carrying the respective therapeutic radionuclide (a beta, 177Lu, 90Y, Auger electron, 111In, or an alpha emitter, 225Ac) to upload cytotoxic radiation doses selectively to tumor lesions [1,2,3,4,5]. The rationale of this integrated “theranostic” approach relies on the overexpression of the target biomolecule in cancer cells while healthy surrounding tissues remain devoid of target expression [6]. Several metal-chelators were coupled to its N-terminus, either directly or via different linkers, to accommodate a variety of clinical relevant radiometals [20,21,22,23,24,25,26,27,28,29]
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