Abstract
Purpose
Different attempts have been made to develop a suitable radioligand for targeting CCK-2 receptors in vivo, for staging of medullary thyroid carcinoma (MTC) and other receptor-expressing tumours. After initial successful clinical studies with [DTPA0,DGlu1]minigastrin (DTPA-MG0) radiolabelled with 111In and 90Y, our group developed a 99mTc-labelled radioligand, based on HYNIC-MG0. A major drawback observed with these derivatives is their high uptake by the kidneys. In this study we describe the preclinical evaluation of the optimised shortened peptide analogue, [HYNIC0,DGlu1,desGlu2–6]minigastrin (HYNIC-MG11).
Methods
99mTc labelling of HYNIC-MG11 was performed using tricine and EDDA as coligands. Stability experiments were carried out by reversed phase HPLC analysis in PBS, PBS/cysteine and plasma as well as rat liver and kidney homogenates. Receptor binding and cell uptake experiments were performed using AR4-2J rat pancreatic tumour cells. Animal biodistribution was studied in AR4-2J tumour-bearing nude mice.
Results
Radiolabelling was performed at high specific activities and radiochemical purity was >90%. 99mTc-EDDA-HYNIC-MG11 showed high affinity for the CCK-2 receptor and cell internalisation comparable to that of 99mTc-EDDA-HYNIC-MG0. Despite high stability in solution, a low metabolic stability in rat tissue homogenates was found. In a nude mouse tumour model, very low unspecific retention in most organs, rapid renal excretion with reduced renal retention and high tumour uptake were observed.
Conclusion
99mTc-EDDA-HYNIC-MG11 shows advantages over 99mTc-EDDA-HYNIC-MG0 in terms of lower kidney retention with unchanged uptake in tumours and CCK-2 receptor-positive tissue. However, the lower metabolic stability and impurities formed in the labelling process still leave room for further improvement.
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Acknowledgments
The authors want to thank all the members of the COST Action B12: “Radiotracers for In Vivo Assessment of Biological Function”, WG-3: “Radiolabeled Biologically Active Peptides” for fruitful discussions. We specifically thank Mr. Stephan Schwarz for his skilled technical assistance, Ms. Maria Saurer for her support in the cell culture and Prof. Georg Riccabona for his critical review of the manuscript.
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Parts of this study were presented at the Annual Congress of the European Association of Nuclear Medicine, Istanbul, Turkey, October 2005 and at the 7th International Symposium on Technetium in Chemistry and Nuclear Medicine, Bressanone, Italy, September 2006.
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von Guggenberg, E., Dietrich, H., Skvortsova, I. et al. 99mTc-labelled HYNIC-minigastrin with reduced kidney uptake for targeting of CCK-2 receptor-positive tumours. Eur J Nucl Med Mol Imaging 34, 1209–1218 (2007). https://doi.org/10.1007/s00259-006-0348-3
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DOI: https://doi.org/10.1007/s00259-006-0348-3