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Molecular Imaging and Biology
Published in: Molecular Imaging and Biology 6/2018

Open Access 01-12-2018 | Research Article

In Vivo Stabilized SB3, an Attractive GRPR Antagonist, for Pre- and Intra-Operative Imaging for Prostate Cancer

Authors: Ingrid L. Bakker, Sandra T. van Tiel, Joost Haeck, Gabriela N. Doeswijk, Erik de Blois, Marcel Segbers, Theodosia Maina, Berthold A. Nock, Marion de Jong, Simone U. Dalm

Published in: Molecular Imaging and Biology | Issue 6/2018

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Abstract

Purpose

The gastrin-releasing peptide receptor (GRPR), overexpressed on various tumor types, is an attractive target for receptor-mediated imaging and therapy. Another interesting approach would be the use of GRPR radioligands for pre-operative imaging and subsequent radio-guided surgery, with the goal to improve surgical outcome. GRPR radioligands were successfully implemented in clinical studies, especially Sarabesin 3 (SB3) is an appealing GRPR antagonist with high receptor affinity. Gallium-68 labeled SB3 has good in vivo stability, after labeling with Indium-111; however, the molecule shows poor in vivo stability, which negatively impacts tumor-targeting capacity. A novel approach to increase in vivo stability of radiopeptides is by co-administration of the neutral endopeptidase (NEP) inhibitor, phosphoramidon (PA). We studied in vivo stability and biodistribution of [111In]SB3 without/with (−/+) PA in mice. Furthermore, SPECT/MRI on a novel, state-of-the-art platform was performed.

Procedures

GRPR affinity of SB3 was determined on PC295 xenograft sections using [125I]Tyr4-bombesin with tracer only or with increasing concentrations of SB3. For in vivo stability, mice were injected with 200/2000 pmol [111In]SB3 −/+ 300 μg PA. Blood was collected and analyzed. Biodistribution and SPECT/MRI studies were performed at 1, 4, and 24 h postinjection (p.i.) of 2.5 MBq/200 pmol or 25 MBq/200 pmol [111In]SB3 −/+ 300 μg PA in PC-3-xenografted mice.

Results

SB3 showed high affinity for GRPR (IC50 3.5 nM). Co-administration of PA resulted in twice higher intact peptide in vivo vs [111In]SB3 alone. Biodistribution studies at 1, 4, and 24 h p.i. show higher tumor uptake values with PA co-administration (19.7 ± 3.5 vs 10.2 ± 1.5, 17.6 ± 5.1 vs 8.3 ± 1.1, 6.5 ± 3.3 vs 3.1 ± 1.9 % ID/g tissue (P < 0.0001)). Tumor imaging with SPECT/MRI clearly improved after co-injection of PA.

Conclusions

Co-administration of PA increased in vivo tumor targeting capacity of [111In]SB3, making this an attractive combination for GRPR-targeted tumor imaging.
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Metadata
Title
In Vivo Stabilized SB3, an Attractive GRPR Antagonist, for Pre- and Intra-Operative Imaging for Prostate Cancer
Authors
Ingrid L. Bakker
Sandra T. van Tiel
Joost Haeck
Gabriela N. Doeswijk
Erik de Blois
Marcel Segbers
Theodosia Maina
Berthold A. Nock
Marion de Jong
Simone U. Dalm
Publication date
01-12-2018
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 6/2018
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-018-1185-z

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