Cholecystokinin-2/gastrin receptor is known to be pathophysiologically involved in numerous types of tumour, in which it transmits signals from peptide hormones cholecystokinin and gastrin, which act upon it as growth factors. The diagnostic and therapeutic options for the mentioned malignancies are still scarce because of the lack of clinically successful drugs. CCK2R expresses on the membranes of tumour cells with higher density and incidence, which enables the use of nuclear medicine techniques for their visualisation (PET, SPECT) or radionuclide therapy.
Analogues of minigastrin, radiolabelled with indium-111 (111In) or lutecium-177 (177Lu), which belong to peptide receptor agonists, are currently being clinically evaluated. However, they possess some limitations associated with unfavourable pharmacokinetics and agonist-dependent adverse effects. We can avoid the latter with the use of antagonists, which have proven to be advantageous ligands on similar peptide receptor systems. One of the representatives of CCK2R antagonists is the molecule CLR1, which is a “lead” compound and comprises of a vector moiety (small molecule antagonist Z360), tripeptide linker and an acyclic chelator system, that restricts radiolabeling with therapeutic radionuclides. On the basis of lead molecule, we have carried out the structure-based drug design of similar compounds with novel linkers to optimize the length and possible interactions in the linker of CRL1. For this purpose we have systematically designed new spacers by combining amino acid and polyethylene glycol building blocks and gained results of the calculated score by molecular docking. Using the method of molecular docking we have predicted different types of interactions of these compounds with the receptor and defined the residues of the receptor, that are crucial for high docking score and compared them with the lead compound. Taking into account the visual observations and the value of the scoring function, we chose the most appropriate candidates and synthesized them combining the solid phase peptide synthesis with Fmoc protection and synthesis in solution. We purified the products, identified them with MS and HPLC and prepared them for the next step – radiolabelling.
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