Radiolabelled CCK2R Antagonists Containing PEG Linkers: Design, Synthesis and Evaluation

The cholecystokinin‐2/gastrin receptor (CCK2R) 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‐tet...

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Bibliographic Details
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
Subjects:
CCK2R antagonists
Cholecystokinin
Gallium
gallium-68
Gastrin
Indium
indium-111
Lutetium
lutetium-177
radiolabelled antagonists
Solid phases
Tumors
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Summary:The cholecystokinin‐2/gastrin receptor (CCK2R) 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 CCK2R antagonist Z360/nastorazepide. As a proof of concept that CCK2R 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‐CCK2R cell line (in the presence of agonist G17), with IC50 values of 3.31, 4.11 and 10.4 nM for compounds containing PEG4, PEG6 and PEG12, 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 D7.4 values were determined for indium‐111‐ and gallium‐68‐labelled compounds, showing improved hydrophilicity compared to the reference compound. The overexpression of CCK2R in several tumours makes it a target of interest for the development of radiolabelled ligands. We have successfully radiolabelled a series of PEG‐containing CCK2R antagonists with either radiodiagnostic or therapeutic radionuclides. The favourable hydrophilicity, stability and retained antagonistic properties hold promise for potential progress into in vivo studies for this type of compound.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202000392