Radiopharmaceuticals are medicines used specifically for targeted therapy and diagnostics. They are labelled with radioactive isotopes, also known as radionuclides. As radionuclides on their own cannot selectively target desired tissues, they require a small vector molecule, connected to the radionuclide by a spacer, to act as the targeting moiety of the drug. These drugs are being developed because of their capability to selectively bind to receptors that are overexpressed in cancer tissue and therefore their ability to deliver radionuclides at desired sites.
The cholecystokinin-2/gastrin receptor (CCK2R) is one of many suitable targets for the use and development of radiopharmaceuticals as it is present in both greater density and frequency in cancerous tissue of the gut. The receptor is a G-protein coupled receptor (GPCR) which activates several signaling pathways as it’s endogenous ligand, gastrin, binds to it. This causes gut cell proliferation, migration, and remodeling. CCK2R antagonists represent a new and exciting group of potential drug candidates, which can be roughly divided into groups based on their chemical structure. This thesis focuses primarily on derivatives of 1,5-benzodiazepines.
During the course of this masters’ thesis, we prepared and optimized the synthesis of the most promising compound out of this group of drugs, Z-360 or nastorazepide. The basis for the synthesis was an already published procedure that we modified to fit our needs. We adapted the isolation procedures, reaction parameters, reagents, and solvents used to carry out the reactions. We describe in detail each stage of the entire preparation procedure. This can be used as a guideline for the synthesis of Z-360 derivatives. In the end we also recommend some modifications to the structure of nastorazepide in order to improve the compounds’ physio-chemical properties and binding affinity.
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