Projeto PRR

Sumário

Radiopharmaceuticals offer unique opportunities to explore a theranostic approach of cancer or infectious diseases, as one targeting biomolecule recognizing a specific molecular target can be labelled either with imaging and/or with therapeutic radionuclides, allowing patient-specific treatments with easier monitoring of the disease progression. Taking advantage of these favorable features, very encouraging results were obtained recently for peptides or peptidomimetics labeled with beta emitting radiometals, which led namely to the approval of [177Lu]Lu-DOTA-TATE (Lutathera) and [177Lu]Lu-PSMA-617 (PluvictoTM) by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of neuroendocrine tumors and prostate cancer, respectively. These encouraging developments opened new avenues for the use of less explored and emerging medical radiometals for the design of innovative target-specific radiopharmaceuticals. Towards this goal, a plethora of less explored radioactive metals or metalloids with nuclear properties adequate for imaging or therapy are now more available, spanning from PET (e.g., 44Sc, 64Cu or 89Zr) or SPECT (e.g., 111Ag or 155Tb) radionuclides to therapeutic radionuclides of the beta minus (e.g, 47Sc, 67Cu or 161Tb), alpha (e.g., 149Tb or 225Ac ) or Auger electron (e.g, 119Sb or 165Er) emitting types, comprising a variety of theranostic pairs/companions (e.g., 61Cu/64Cu/67Cu; 43Sc/44Sc/47Sc; 149Tb/152Tb/155Tb/161Tb).For radiometals, the synthesis of the radiopharmaceuticals relies on the formation of a coordination complex, using adequate bifunctional chelators able to bind d- and f-transition metal ions. Some of the available chelators, like 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), allow the stable coordination of a large range of radiometals, namely trivalent ones like 67/68Ga, 111In, or 177Lu. However, there is no universal chelator fitting all radiometals and therefore tailor-made chelators need to be designed for some, as is the case of 89Zr, copper radioisotopes and radioactinides, amongst others. Moreover, even for well-validated radiometals, already in clinical use like 177Lu, bifunctional chelators providing a fast coordination of the radiometal at physiological or lower temperature are still necessary for the labeling of thermosensitive molecules, such as antibodies and their fragments. All in all, fast and stable chelation of the different radiometals is a critical step in the synthesis of the respective radiopharmaceuticals. Stability end selectivity are two important criteria to guide the development of suitable chelators, together with their amenability to functionalization with targeting biomolecules. High kinetic and thermodynamic stability of the complex is crucial to maintain the radiometal associated with the targeting vector, either in vitro or in vitro . The selectivity might facilitate the achievement of high apparent molar activity by avoiding the chelation of possible metal contaminants.In this context, the auxiliary researcher to be recruited must be an inorganic or radiopharmaceutical chemist well-skilled in the study of metal-based compounds relevant for biomedical applications, and highly motivated to investigate theranostic radiopharmaceuticals suitable for the management of cancer and infectious diseases. His/her role will be focused mainly on the evaluation of the coordination capabilities of innovative chelators (e.g., hybrid chelators combining macrocyclic and acyclic units or metallophores) towards promising but less-explored radiometals, such as those mentioned above. This will comprise the development of appropriate methods to synthesize the devised chelators, followed by chemical speciation studies upon their interaction with the desired metal ions (using natural metals), evaluation of the corresponding coordination kinetics and detailed characterization of the thermodynamic solution behavior of the resulting metal complexes, based on potentiometric and spectroscopic techniques (e.g., UV-vis, NMR or EPR). For the most promising chelators (in terms of metal complex stability and chelation ability), the recruited auxiliary researcher will be also responsible for the synthesis and characterization of their complexes with the respective radiometals, which will comprise the proper optimization of the labeling conditions. Lastly, he/she should apply the best performing radiocomplexes in the labeling of selected biomolecules based on innovative bioconjugation strategies, aiming to develop novel radiopharmaceutical candidates for the theranostics of cancer or infectious diseases.