Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2011 Aug;38(8):1410-6.
doi: 10.1007/s00259-011-1806-0. Epub 2011 Apr 2.

Comparative biodistribution of 12 ¹¹¹In-labelled gastrin/CCK2 receptor-targeting peptides

Peter Laverman  1 , Lieke Joosten, Annemarie Eek, Susan Roosenburg, Petra Kolenc Peitl, Theodosia Maina, Helmut Mäcke, Luigi Aloj, Elisabeth von Guggenberg, Jane K Sosabowski, Marion de Jong, Jean-Claude Reubi, Wim J G Oyen, Otto C Boerman
Affiliations
Comparative Study

Comparative biodistribution of 12 ¹¹¹In-labelled gastrin/CCK2 receptor-targeting peptides

Peter Laverman et al. Eur J Nucl Med Mol Imaging. 2011 Aug.

Abstract

Purpose: Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in various tumours such as medullary thyroid carcinomas and small-cell lung cancers. Due to this high expression, CCK-2 receptors might be suitable targets for radionuclide imaging and/or radionuclide therapy. Several CCK-2 receptor-binding radiopeptides have been developed and some have been tested in patients. Here we aimed to compare the in vivo tumour targeting properties of 12 (111)In-labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated gastrin/CCK2 receptor-binding peptides.

Methods: Two CCK8-based peptides and ten gastrin-based peptide analogues were tested. All peptides were conjugated with DOTA and labelled with (111)In. Biodistribution studies were performed in mice with subcutaneous CCK2/gastrin receptor-expressing tumours and with receptor-negative tumours contralaterally. Biodistribution was studied by counting dissected tissues at 1 and 4 h after injection.

Results: Both the CCK analogues displayed relatively low tumour uptake (approximately 2.5%ID/g) as compared to minigastrin analogues. Two linear minigastrin peptides (MG0 and sargastrin) displayed moderate tumour uptake at both 1 and 4 h after injection, but also very high kidney uptake (both higher than 48%ID/g). The linear MG11, lacking the penta-Glu sequence, showed lower tumour uptake and also low kidney uptake. Varying the N-terminal Glu residues in the minigastrin analogues led to improved tumour targeting properties, with PP-F11 displaying the optimal biodistribution. Besides the monomeric linear peptides, a cyclized peptide and a divalent peptide were tested.

Conclusion: Based on these studies, optimal peptides for peptide receptor radionuclide targeting of CCK2/gastrin receptor-expressing tumours were the linear minigastrin analogue with six D-Glu residues (PP-F11), the divalent analogue MGD5 and the cyclic peptide cyclo-MG1. These peptides combined high tumour uptake with low kidney retention, and may therefore be good candidates for future clinical studies.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Tissue distribution of 111In-labelled peptides in mice (n = 5/group) with subcutaneous A431-CCK2R and A431 negative control tumours at 1 and 4 h p.i. Uptake of radioactivity is expressed as percentage of the injected dose per gram (%ID/g). Kidney uptake of MG0 and sargastrin (centre) is truncated to allow comparison with other peptides. Error bars represent standard deviation
Fig. 1
Fig. 1
Tissue distribution of 111In-labelled peptides in mice (n = 5/group) with subcutaneous A431-CCK2R and A431 negative control tumours at 1 and 4 h p.i. Uptake of radioactivity is expressed as percentage of the injected dose per gram (%ID/g). Kidney uptake of MG0 and sargastrin (centre) is truncated to allow comparison with other peptides. Error bars represent standard deviation
Fig. 2
Fig. 2
Tumour-to-blood and tumour-to-kidney ratios of 111In-labelled peptides in A431-CCK2R tumours in mice (n = 5/group) at 1 and 4 h p.i
See this image and copyright information in PMC

References

    1. Reubi JC, Schaer JC, Waser B. Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors. Cancer Res. 1997;57(7):1377–1386. - PubMed
    1. Smeets RL, Fouraux MA, van Emst-de Vries SE, De Pont JJ, Willems PH. Protein kinase C-mediated inhibition of transmembrane signalling through CCK(A) and CCK(B) receptors. Br J Pharmacol. 1998;123(6):1189–1197. doi: 10.1038/sj.bjp.0701713. - DOI - PMC - PubMed
    1. Aloj L, Caraco C, Panico M, Zannetti A, Del Vecchio S, Tesauro D, et al. In vitro and in vivo evaluation of In-111-DTPAGlu-G-CCK8 for cholecystokinin-B receptor imaging. J Nucl Med. 2004;45(3):485–494. - PubMed
    1. Laverman P, Behe M, Oyen WJ, Willems PH, Corstens FH, Behr TM, et al. Two technetium-99m-labeled cholecystokinin-8 (CCK8) peptides for scintigraphic imaging of CCK receptors. Bioconjug Chem. 2004;15(3):561–568. doi: 10.1021/bc034208w. - DOI - PubMed
    1. Roosenburg S, Laverman P, Joosten L, Eek A, Oyen WJ, De JM, et al. Stabilized 111In-labeled sCCK8 analogues for targeting CCK2-receptor positive tumors: synthesis and evaluation. Bioconjug Chem. 2010;21(4):663–670. doi: 10.1021/bc900465y. - DOI - PubMed

Publication types