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Highly Improved Metabolic Stability and Pharmacokinetics of Indium-111-DOTA-Gastrin Conjugates for Targeting of the Gastrin Receptor

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Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloška Cesta 7, SI-1000 Ljubljana, Slovenia
Division of Radiological Chemistry, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland
§ Department of Nuclear Medicine/PET Center, Zentralklinik Bad Berka, Bad Berka, Germany
Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, SI-1000 Ljubljana, Slovenia
Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, CH-3010 Berne, Switzerland
# Department of Nuclear Medicine, University of Freiburg, Hugstetterstrasse 55, 79106 Freiburg, Germany
Phone: ++49 761 270 7422. Fax: ++49 761 270 3930. E-mail: [email protected]
Cite this: J. Med. Chem. 2011, 54, 8, 2602–2609
Publication Date (Web):April 1, 2011
Copyright © 2011 American Chemical Society

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    The development of metabolically stable radiolabeled gastrin analogues with suitable pharmacokinetics is a topic of recent research activity. These imaging vectors are of interest because the gastrin/CCK2 receptor is highly overexpressed in different tumors such as medullary thyroid cancer, neuroendocrine tumors, and SCLC. The drawback of current targeting agents is either their metabolic instability or their high kidney uptake. We present the synthesis and in vitro and in vivo evaluation of 11 111In-labeled DOTA-conjugated peptides that differ by their spacer between the peptide and the chelate. We introduced uncharged but hydrophilic spacers such as oligoethyleneglycol, serine, and glutamine. The affinity of all radiopeptides was high with IC50 values between 0.5 and 4.8 nM. The improvement of human serum stability is 500-fold within this series of compounds. In addition the kidney uptake could be lowered distinctly and the tumor-to-kidney ratio improved almost 60-fold if compared with radiotracers having charged spacers such as glutamic acid.

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    Metabolite formation and disappearance rates for 111In-2; biodistribution data of 111In-6, 111In-10, and 111In-11; intracellular calcium mobilization induced in AR4-2J cells by minigastrin analogues; PET/CT scan of gastrin receptor positive liver metastases. This material is available free of charge via the Internet at

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