20.500.12556/RUL-130078 1,5-benzodiazepinski antagonisti holecistokininskega-2/gastrinskega receptorja kot vektorske molekule v razvoju radiofarmakov 1,5-benzodiazepine cholecystokinin-2/gastrin receptor antagonists as vector moieties in the development of radiopharmaceuticals Radiofarmaki so zdravila označena z radioaktivnim izotopom in služijo za tarčno terapijo ali diagnostiko. Posebna oblika radiofarmakov so vektorske molekule, ki imajo preko distančnika nase pritrjeno radioaktivno zvrst, in se selektivno vežejo na željene receptorje, ki jih določene celice (npr. določene vrst rakavih celic) prekomerno izražajo. Holecistokininski-2/gastrinski receptor (CCK2R) je ena izmed možnih tarč za uporabo radiofarmakov, saj se izraža v večji gostoti in frekvenci na malignih tkivih v gastrointestinalnem traktu (GIT). Gre za z receptor sklopljen s proteinom G (GPCR), ki po vezavi endogenega liganda, gastrina, sproži kaskado signalnih poti, ki vodijo tudi do proliferacije, migracije in remodelacije celic GIT. Antagonisti CCK2R predstavljajo obetavno področje razvoja novih zdravilnih učinkovin za različne indikacije. Trenutno znane spojine s takšnim delovanjem lahko glede na njihovo kemijsko strukturo razdelimo v več skupin, od katerih smo se v okviru naloge posvetili derivatom 1,5-benzodiazepinov. V okviru magistrske naloge smo pripravili in optimizirali sintezo najbolj obetavne spojine s tega področja, Z-360 ali nastorazepida. Kot osnovo za sintezo smo v literaturi poiskali že znan postopek, ki smo ga nato modificirali. Večinoma je šlo za prilagoditve postopkov izolacije, spremembe reakcijskih pogojev, zamenjavo reagentov in topil, s katerimi smo izvajali reakcije. Opisujemo posamezne stopnje sinteznega postopka, kar bo lahko v pomoč pri sintezi spojin podobnih Z-360. Predlagamo tudi strukturne modifikacije omenjene spojine z namenom izboljšanja njenih fizikalno-kemijskih lastnosti in afinitete vezave. 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. CCK2R holecistokinin gastrin Z-360 1 5-benzodiazepini CCK2R cholecystokinin gastrin Z-360 1 5-benzodiazepines true false false Slovenski jezik Angleški jezik Magistrsko delo/naloga 2021-09-10 08:45:05 2021-09-10 08:45:07 2022-09-09 04:14:41 0000-00-00 00:00:00 2021 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 83310 3314.pdf 3314.pdf 1 5BB65DCC88469E7D9E0D535D862FA8DC c576d24435542c100f69b01e640b413a8f80a06729f20b4616705be1367405f3 62fc6095-1202-11ec-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=147133 Fakulteta za farmacijo 0 0 0