Panagiotis Kanellopoulos1,2, Aikaterini Kaloudi1, Maritina Rouchota3, George Loudos3, Marion de Jong4, Eric P Krenning5, Berthold A Nock1, Theodosia Maina1. 1. Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", 15341 Athens, Greece. 2. Molecular Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Greece. 3. BIOEMTECH, Lefkippos Attica Technology Park NCSR "Demokritos", 15310 Athens, Greece. 4. Department of Radiology & Nuclear Medicine Erasmus MC, 3015 CN Rotterdam, The Netherlands. 5. Cyclotron Rotterdam BV, Erasmus MC, 3015 CE Rotterdam, The Netherlands.
Abstract
BACKGROUND: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides. METHODS: The metabolic stability of [99mTc]Tc-DB4 (DB4, N4-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH2) and [111In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCK2R)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls. RESULTS: LBQ657/Entresto treatment induced marked stabilization of [99mTc] Tc-DB4 and [111In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [99mTc]Tc-DB4 uptake of 7.13 ± 1.76%IA/g in PC-3 tumors increased to 16.17 ± 0.71/17.50 ± 3.70%IA/g (LBQ657/Entresto) and the [111In]In-SG4 uptake of 3.07 ± 0.87%IA/g in A431-CCK2R(+) tumors to 8.11 ± 1.45/9.61 ± 1.70%IA/g. Findings were visualized by SPECT/CT. CONCLUSIONS: This study has shown the efficacy of Entresto to notably improve the profile of [99mTc]Tc-DB4 and [111In]In-SG4 in mice, paving the way for clinical translation of this approach.
BACKGROUND: Peptide radioligands may serve as pan class="Chemical">radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides. METHODS: The metabolic stability of [99mTc]Tc-DB4 (DB4, N4-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH2) and [111In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCK2R)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls. RESULTS:LBQ657/Entresto treatment induced marked stabilization of [99mTc] Tc-DB4 and [111In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [99mTc]Tc-DB4 uptake of 7.13 ± 1.76%IA/g in PC-3tumors increased to 16.17 ± 0.71/17.50 ± 3.70%IA/g (LBQ657/Entresto) and the [111In]In-SG4 uptake of 3.07 ± 0.87%IA/g in A431-CCK2R(+) tumors to 8.11 ± 1.45/9.61 ± 1.70%IA/g. Findings were visualized by SPECT/CT. CONCLUSIONS: This study has shown the efficacy of Entresto to notably improve the profile of [99mTc]Tc-DB4 and [111In]In-SG4 in mice, paving the way for clinical translation of this approach.
Entities:
Keywords:
Entresto; LBQ657; [111In]In-SG4; [99mTc]Tc-DB4; cholecystokinin subtype 2 receptor; gastrin-releasing peptide receptor; in vivo stability; neprilysin inhibition; peptide radioligand; single photon emission computed tomography; tumor-targeting
Authors: Emmanouil Lymperis; Aikaterini Kaloudi; Werner Sallegger; Ingrid L Bakker; Eric P Krenning; Marion de Jong; Theodosia Maina; Berthold A Nock Journal: Bioconjug Chem Date: 2018-04-30 Impact factor: 4.774
Authors: W A van der Zwan; T Brabander; B L R Kam; J J M Teunissen; R A Feelders; J Hofland; E P Krenning; W W de Herder Journal: Eur J Nucl Med Mol Imaging Date: 2018-09-28 Impact factor: 9.236
Authors: Berthold A Nock; Panagiotis Kanellopoulos; Oleg G Chepurny; Maritina Rouchota; George Loudos; George G Holz; Eric P Krenning; Theodosia Maina Journal: Pharmaceutics Date: 2022-03-18 Impact factor: 6.321