Radiolabelled CCK 2 R Antagonists Containing PEG Linkers: Design, Synthesis and Evaluation

• Published in: ChemMedChem 2021-01, Vol.16 (1), p.155-163
• Main Authors: Novak, Doroteja, Tomašič, Tihomir, Krošelj, Marko, Javornik, Uroš, Plavec, Janez, Anderluh, Marko, Kolenc Peitl, Petra
• Format: Article
• Language: English
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202000392

The cholecystokinin-2/gastrin receptor (CCK R) is considered a suitable target for the development of radiolabelled antagonists, due to its overexpression in various tumours, but no such compounds are available in clinical use. Therefore, we designed novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated ligands based on CCK R antagonist Z360/nastorazepide. As a proof of concept that CCK R antagonistic activity can be retained by extending the Z360/nastorazepide structure using suitable linker, we present herein three compounds containing various PEG linkers synthesised on solid phase and in solution. The antagonistic properties were measured in a functional assay in the A431-CCK R cell line (in the presence of agonist G17), with IC values of 3.31, 4.11 and 10.4 nM for compounds containing PEG , PEG and PEG , respectively. All compounds were successfully radiolabelled with indium-111, lutetium-177 and gallium-68 (incorporation of radiometal >95 %). The gallium-68-labelled compounds were stable for up to 2 h (PBS, 37 °C). log D values were determined for indium-111- and gallium-68-labelled compounds, showing improved hydrophilicity compared to the reference compound.