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Article

[99mTc]Tc-DB1 Mimics with Different-Length PEG Spacers: Preclinical Comparison in GRPR-Positive Models

1
Molecular Radiopharmacy, INRASTES, NCSR “Demokritos”, 15341 Athens, Greece
2
Molecular Pharmacology, School of Medicine, University of Crete, Heraklion, 70013 Crete, 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.
Academic Editor: Svend Borup Jensen
Molecules 2020, 25(15), 3418; https://doi.org/10.3390/molecules25153418
Received: 5 July 2020 / Revised: 24 July 2020 / Accepted: 25 July 2020 / Published: 28 July 2020
(This article belongs to the Special Issue Past, Present, and Future of Radiochemical Synthesis)
Background: The frequent overexpression of gastrin-releasing peptide receptors (GRPRs) in human cancers provides the rationale for delivering clinically useful radionuclides to tumor sites using peptide carriers. Radiolabeled GRPR antagonists, besides being safer for human use, have often shown higher tumor uptake and faster background clearance than agonists. We herein compared the biological profiles of the GRPR-antagonist-based radiotracers [99mTc]Tc-[N4-PEGx-DPhe6,Leu-NHEt13]BBN(6-13) (N4: 6-(carboxy)-1,4,8,11-tetraazaundecane; PEG: polyethyleneglycol): (i) [99mTc]Tc-DB7 (x = 2), (ii) [99mTc]Tc-DB13 (x = 3), and (iii) [99mTc]Tc-DB14 (x = 4), in GRPR-positive cells and animal models. The impact of in situ neprilysin (NEP)-inhibition on in vivo stability and tumor uptake was also assessed by treatment of mice with phosphoramidon (PA). Methods: The GRPR affinity of DB7/DB13/DB14 was determined in PC-3 cell membranes, and cell binding of the respective [99mTc]Tc-radioligands was assessed in PC-3 cells. Each of [99mTc]Tc-DB7, [99mTc]Tc-DB13, and [99mTc]Tc-DB14 was injected into mice without or with PA coinjection and 5 min blood samples were analyzed by HPLC. Biodistribution was conducted at 4 h postinjection (pi) in severe combined immunodeficiency disease (SCID) mice bearing PC-3 xenografts without or with PA coinjection. Results: DB7, -13, and -14 displayed single-digit nanomolar affinities for GRPR. The uptake rates of [99mTc]Tc-DB7, [99mTc]Tc-DB13, and [99mTc]Tc-DB14 in PC-3 cells was comparable and consistent with a radioantagonist profile. The radiotracers were found to be ≈70% intact in mouse blood and >94% intact after coinjection of PA. Treatment of mice with PA enhanced tumor uptake. Conclusions: The present study showed that increase of PEG-spacer length in the [99mTc]Tc-DB7–[99mTc]Tc-DB13–[99mTc]Tc-DB14 series had little effect on GRPR affinity, specific uptake in PC-3 cells, in vivo stability, or tumor uptake. A significant change in in vivo stability and tumor uptake was observed only after treatment of mice with PA, without compromising the favorably low background radioactivity levels. View Full-Text
Keywords: gastrin-releasing peptide receptor targeting; [99mTc]Tc-radiotracer; tumor targeting; [99mTc]Tc-DB1 mimic; PEGx-spacer; neprilysin-inhibition; phosphoramidon gastrin-releasing peptide receptor targeting; [99mTc]Tc-radiotracer; tumor targeting; [99mTc]Tc-DB1 mimic; PEGx-spacer; neprilysin-inhibition; phosphoramidon
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MDPI and ACS Style

Kanellopoulos, P.; Lymperis, E.; Kaloudi, A.; de Jong, M.; Krenning, E.P.; Nock, B.A.; Maina, T. [99mTc]Tc-DB1 Mimics with Different-Length PEG Spacers: Preclinical Comparison in GRPR-Positive Models. Molecules 2020, 25, 3418. https://doi.org/10.3390/molecules25153418

AMA Style

Kanellopoulos P, Lymperis E, Kaloudi A, de Jong M, Krenning EP, Nock BA, Maina T. [99mTc]Tc-DB1 Mimics with Different-Length PEG Spacers: Preclinical Comparison in GRPR-Positive Models. Molecules. 2020; 25(15):3418. https://doi.org/10.3390/molecules25153418

Chicago/Turabian Style

Kanellopoulos, Panagiotis, Emmanouil Lymperis, Aikaterini Kaloudi, Marion de Jong, Eric P. Krenning, Berthold A. Nock, and Theodosia Maina. 2020. "[99mTc]Tc-DB1 Mimics with Different-Length PEG Spacers: Preclinical Comparison in GRPR-Positive Models" Molecules 25, no. 15: 3418. https://doi.org/10.3390/molecules25153418

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