Marco Antonio Pometti

Ciclo: XXXIV

Data inizio: 01/01/2019

Curriculum: Biomediche e Precliniche

Borsa: UniCT - senza borsa

Titolo tesi: Development of new radiopharmaceuticals targeting the Cholecystokinin 2 receptor

Abstract: Radiopharmaceuticals are unique medicinal formulations containing radionuclides, that are used in various clinical areas for diagnosis and/or therapy, as a fundamental tool for nuclear medicine procedures. Such radionuclides are bound to a ligand, which selectively accumulates into a target tissue allowing either a precise imaging for accurate diagnosis or/and a focalized treatment. Cholecystokinin (CCK) 2 receptor (gastrin receptor; CCK2R) is a G-protein coupled receptor normally expressed in the central nervous system and in the gastric mucosa cells. It is a target studied in nuclear medicine as it is overexpressed in different tumor types like pancreatic, medullary thyroid, lung, breast, ovarian, GI tract and colon, but displays limited expression in normal tissue. In the last decade, several radiotracers have been developed to detect its expression using nuclear medicine techniques. Radiotracers based on analogues of endogenous peptides exhibited some issues, mainly due to their high kidneys retention. To overcome their limits, the development of radiotracers based on small molecules is one of the ways currently explored. Nastorazepide is a 1,5-benzodiazepine derivative whose selectivity for CCK2 receptor has been reported. Thus, a set of new radiopharmaceuticals based on the Nastorazepide vector were designed within the project “Isolpharm” of INFN, precursors were synthesized at department of pharmaceutical science of University of Padova, while the radiolabeling and the in vivo evaluation were carried out respectively at the Nuclear Medicine Department of Cannizzaro Hospital in Catania and the Center for Advanced Preclinical in vivo Research (CAPiR) of University of Catania. The first generation of Isolpharm radiopharmaceuticals bearing the chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was radiolabeled with Ga-68 with a radiochemical yield of 44% n.d.c and a radiochemical purity of 94%. Later, the new chelator 1,7-bis(2-(methylsulfanyl)ethyl)-4,10,diaceticacid-1,4,7,10-tetraazacyclododecane (DO2A2S) designed for softer radiometals, was radiolabeled with high yield (98%) with Cu-64 and its biodistribution on BALB/C mice was in vivo studied through micro-PET/CT scans at three different time point (1h, 4h and 24h p.i.) and ex-vivo through gamma measurements of organs and tissues. Moreover, the stability of the complex [64Cu][Cu(DO2A2S)] in blood and urine was evaluated through radiochemical analyses on samples taken before the sacrifices. The complex showed renal excretion in the first hours post injection and then accumulated mainly in the liver. The radioactivity circulating in blood was low and quite constant except for radioactive decay, whereas in urine decreased abruptly in the first hours post injection according to imaging data. The complex was stable in blood (95%), while in urine it was degraded (50%) already at 4 h p.i. Due to the encouraging results about the in vivo stability of the complex [64Cu][Cu(DO2A2S)], the synthesis of the second generation of Isolpharm radiopharmaceuticals is going on by conjugating DO2A2S to Nastorazepide through an appropriate linker for future radiolabeling with Cu-64 and preclinical studies on animal model of pathology.

Tutor: Parenti

Data Conseguimento Titolo: 23/11/2022

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Email: marco.pometti@gmail.com

Periodi all'estero- Sede e data: Si

Esperienze post-Dottorato ed attuale occupazione: Radiochimico presso azienda privata del settore sanitario