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

Abstract The cholecystokinin‐2/gastrin receptor (CCK 2 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 2 R antagonist Z360/nastorazepide. As a proof of concept that CCK 2 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 2 R cell line (in the presence of agonist G17), with IC 50 values of 3.31, 4.11 and 10.4 nM for compounds containing PEG 4 , PEG 6 and PEG 12 , 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 7.4 values were determined for indium‐111‐ and gallium‐68‐labelled compounds, showing improved hydrophilicity compared to the reference compound.