Preliminary evaluation of new bicyclic chelators for Ac-225 targeted α-therapy

225Ac is an α-particle emitting isotope studied in nuclear medicine for α-therapy applications. The isotopes generated by radioactive decay of 225Ac have different physico-chemical characteristics compared to the parent nuclide, that can lead to the release of the free isotopes during the in vivo application. One of the chelators most suitable for the stable complexation of 225Ac is the 4,13-diaza-18-crown-6 macrocycle functionalized with picolinic arms (Macropa).1 Unfortunately, one of the main problem of such ligand for the 225Ac radiolabelling is the possible release of 221Fr or 213Bi after radioactive decay of the parent radionuclide. In this work we synthetized the bis-alkyne ligand through the alkylation of the 4,13-diaza-18-crown-6 macrocycle with methyl 6-(chloromethyl)-4- (prop-2-yn-1-yloxy)picolinate as already reported in literature2. Two bis-azide-functionalized amines are then synthetized with different lengths with the aim to obtain a macrobicyclic structure able to create a cage around the isotopes preventing the release of both parent and daughter isotopes. The Cu(I) catalyzed Azide-Alkyne reaction has been carried out on the La(III) complex that is considered the non-radioactive surrogate of Actinium. The bicyclic La(III) complex has been characterized via 1H NMR and the its kinetic inertness evaluated in acidic conditions. After these preliminary studies, the amino groups on the closing molecules will be used for the bioconjugation of the radiopharmaceutical with biomolecules for targeting purposes.