Localization of 99mTc-GRP Analogs in GRPR-Expressing Tumors: Effects of Peptide Length and Neprilysin Inhibition on Biological Responses.

Kaloudi, Aikaterini; Lymperis, Emmanouil; Kanellopoulos, Panagiotis; Waser, Beatrice; de Jong, Marion; Krenning, Eric P; Reubi, Jean Claude; Nock, Berthold A; Maina, Theodosia (2019). Localization of 99mTc-GRP Analogs in GRPR-Expressing Tumors: Effects of Peptide Length and Neprilysin Inhibition on Biological Responses. Pharmaceuticals, 12(1) MDPI 10.3390/ph12010042

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The overexpression of gastrin-releasing peptide receptors (GRPRs) in frequently occurring human tumors has provided the opportunity to use bombesin (BBN) analogs as radionuclide carriers to cancer sites for diagnostic and therapeutic purposes. We have been alternatively exploring human GRP motifs of higher GRPR selectivity compared to frog BBN sequences aiming to improve pharmacokinetic profiles. In the present study, we compared two differently truncated human endogenous GRP motifs: GRP(14⁻27) and GRP(18⁻27). An acyclic tetraamine was coupled at the N-terminus to allow for stable binding of the SPECT radionuclide Tc. Their biological profiles were compared in PC-3 cells and in mice without or with coinjection of phosphoramidon (PA) to induce transient neprilysin (NEP) inhibition in vivo. The two Tc-N₄-GRP(14/18⁻27) radioligands displayed similar biological behavior in mice. Coinjection of PA exerted a profound effect on in vivo stability and translated into notably improved radiolabel localization in PC-3 experimental tumors. Hence, this study has shown that promising Tc-radiotracers for SPECT imaging may indeed derive from human GRP sequences. Radiotracer bioavailability was found to be of major significance. It could be improved during in situ NEP inhibition resulting in drastically enhanced uptake in GRPR-expressing lesions.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Reubi-Kattenbusch, Jean-Claude

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1424-8247

Publisher:

MDPI

Language:

English

Submitter:

Christa Hagert

Date Deposited:

20 Aug 2019 14:04

Last Modified:

03 Dec 2019 14:40

Publisher DOI:

10.3390/ph12010042

PubMed ID:

30897789

Uncontrolled Keywords:

99mTc-radioligand bombesin gastrin-releasing peptide gastrin-releasing peptide receptor metabolic stability neprilysin-inhibition phosphoramidon tumor targeting

BORIS DOI:

10.7892/boris.132177

URI:

https://boris.unibe.ch/id/eprint/132177

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