99mTc-labelled HYNIC-minigastrin with reduced kidney uptake for targeting of CCK-2 receptor-positive tumours
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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).
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.
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.
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.
KeywordsTechnetium-99m Minigastrin CCK-2 receptors Medullary thyroid carcinoma Peptide
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.
- 8.Behe M, Becker W, Gotthardt M, Angerstein C, Behr TM. Improved kinetic stability of DTPA-DGlu as compared with conventional monofunctional DTPA in chelating indium and yttrium: preclinical and initial clinical evaluation of radiometal labelled minigastrin derivatives. Eur J Nucl Med Mol Imaging 2003;30:1140–6.CrossRefPubMedGoogle Scholar
- 13.Gotthart M, Grass J, Schipper ML, Höffken H, Schlieck A, Schurrat T, et al. Scintigraphy with In-111-DTPA-D-Glu1-minigastrin and In-111-DTPA-D-Phe1-octreotide in patients with gastrointestinal neuroendocrine tumors: results of the first 60 patients. Eur J Nucl Med Mol Imaging 2003;30:S181.CrossRefGoogle Scholar
- 22.Breeman WAP, de Blois E, van Gameren A, Melis M, Fröberg A, de Jong M, et al. Aspects of CCK-2 Receptor-Targeting with 111In-DOTA-MG. In: Mazzi U, editor. Technetium, rhenium and other materials in chemistry and nuclear medicine 7. Padova: SG Editoriali; 2006. p 231–2.Google Scholar
- 23.Behe M, Reubi J, Nock B, Mäcke H, Breeman WAP, Bernard HF, et al. Evaluation of a DOTA-minigastrin derivative for therapy and diagnosis for CCK-2 receptor positive tumours. Eur J Nucl Med Mol Imaging 2005;32:S78.Google Scholar