Complexes de Scandium : étude physico-chimique et évaluation des stabilités in vitro et in vivo pour des applications en médecine nucléaire

Among the different isotopes of Scandium that can be used in nuclear medicine may be mentioned the ⁴⁷Sc and ⁴⁴Sc. The first decays by emitting an electron associated with a 159 keV gamma can thus be used either for radiotherapy or TEMP imaging. The ⁴⁴Sc (3.97 h) decays in 94.27% in case by emitting a positron, with a γ photon energy equal to 1.157 MeV. This isotope is then an ideal candidate for applications in PET imaging. Currently, the Cyclotron of high energy and high intensity ARRONAX produce ⁴⁴Sc and co-produces the isomeric state the ⁴⁴mSc(2.44 d). The ⁴⁴mSc has properties (Eᵧ = 270 keV, 98.8%), which allows to consider its use as a potential in vivo generator. Previous work had demonstrated that the DOTA ligand is most suitable and stable for Sc. This thesis aims; make in evidence the feasibility of the in vivo ⁴⁴m/⁴⁴Sc generator. Initially a procedure was optimized and validated for the production of ⁴⁴m/⁴⁴Sc with a high specific activity and chemical purity. Radiolabeling of DOTA conjugated peptides was then developed and optimized. Theoretical and experimental studies have been performed in order to demonstrate the feasibility of ⁴⁴m/⁴⁴Sc as a potential in vivo generator. Finally, in vitro stability studies on radiolabeled ⁴⁴m / ⁴⁴Sc complexes were performed, followed by biodistribution studies and PET imaging.Parmi les différents isotopes du Scandium qui peuvent être utilisés en médecine nucléaire, on peut citer le ⁴⁷Sc et le ⁴⁴Sc. Le premier se désintègre en émettant un électron associé à un gamma de 159 keV et peut donc être utilisé soit pour faire de la radiothérapie, soit de l’imagerie TEMP. Le ⁴⁴Sc (3.97 h) se désintègre dans 94.27 % des cas en émettant un positron, accompagné d’un photon γ d’énergie égale à 1.157 MeV. Cet isotope est alors un candidat idéal pour des applications en imagerie TEP. Actuellement, le Cyclotron de haute énergie et haute intensité Arronax produit le ⁴⁴Sc et coproduit son état isomérique le ⁴⁴mSc (2.44 j). Le ⁴⁴mSc a des propriétés (Eᵧ=270 keV, 98.8 %) qui permet d’envisager son utilisation comme potentiel générateur in vivo. Les travaux précédents ont permis de montrer que le ligand DOTA est le plus adapté et le plus stable pour le Sc. Ce travail de thèse a pour but de mettre en évidence la faisabilité du générateur in vivo ⁴⁴m/⁴⁴Sc. Dans un premier temps une procédure a été optimisée et validée pour la production du ⁴⁴m/⁴⁴Sc avec une haute activité spécifique et pureté chimique. Le radiomarquage sur des peptides contenant du DOTA a été ensuite développé et optimisé. Des études théoriques et expérimentales ont été réalisées dans le but de démontrer la faisabilité du ⁴⁴m/⁴⁴Sc comme potentiel générateur in vivo. En fin des études de stabilité in vitro sur des complexes radiomarqués du ⁴⁴m/⁴⁴Sc suivi d’études de biodistribution et d’imagerie TEP ont été réalisées

Promising Scandium Radionuclides for Nuclear Medicine: A Review on the Production and Chemistry up to In Vivo Proofs of Concept

International audienceScandium radionuclides have been identified in the late 1990s as promising for nuclear medicine applications, but have been set aside for about 20 years. Among the different isotopes of scandium, 43Sc and 44Sc are interesting for positron emission tomography imaging, whereas 47Sc is interesting for therapy. The 44Sc/47Sc or 43Sc/47Sc pairs could be thus envisaged as true theranostic pairs. Another interesting aspect of scandium is that its chemistry is governed by the trivalent ion, Sc3+. When combined with its hardness and its size, it gives this element a lanthanide-like behavior. It is then also possible to use it in a theranostic approach in combination with 177Lu or other lanthanides. This article aims to review the progresses that have been made over the last decade on scandium isotope production and coordination chemistry. It also reviews the radiolabeling aspects and the first (pre) clinical studies performed

Scandium(III) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with 44 Sc from cyclotron and from a 44 Ti/ 44 Sc generator †

International audienceThe complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylene-phosphinic (DO3AP PrA and DO3AP ABn) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(III) complexes were determined by potentiometry combined with 45 Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc–DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(III) precludes stability constant determination of the Sc–DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless , as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with 44 Sc was performed using the radioisotope from two sources, a 44 Ti/ 44 Sc generator and 44m Sc/ 44 Sc from a cyclotron. The best radio-labelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(III) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of 44 Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the 44 Sc–DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine