Radioisotopes of the lanthanides (Ln) and actinides (An) are being extensively investigated for their application in diagnosis and systemic radiotherapy in nuclear medicine. Radioisotopes of terbium have applications in imaging and radiotherapy. In particular, Tb-161 has shown superior radiotoxicity compared to Lu-177 in recent studies. Alpha-emitting actinide radioisotopes, Ac-225 and Th-227, have demonstrated exceptional therapeutic efficacy when tethered to targeting vectors. To date, most radiopharmaceuticals based on Ln and An radioisotopes use DOTA as the chelating agent for the radiometal. Whilst DOTA forms highly stable complexes with these radiometals, radiolabelling/complex formation often requires high temperatures, which are not compatible with many biological agents – for example, antibodies for use in systemic radioimmunotherapies. We have designed and synthesised a library of hybrid chelators based on macrocyclic cyclen or cyclam groups, each bearing four coordinating hydroxypyridinone motifs, enabling complexation of large Ln and An ions, for application in nuclear medicine. These chelators have the potential to allow highly selective, sensitive biological molecules to be radiolabelled under mild conditions, for development of novel Ln and An radiopharmaceuticals. We will test radiolabelling of these new chelators with Tb-161, Ac-225 and Th-227, and assess the stability of new radiometalled chelators in serum. We will synthesise bifunctional derivatives and PSMA-targeted bioconjugates of the best performing chelators, and radiolabel these with Tb-161, Ac-225 and/or Th-227. Finally, we will show proof-of-principle of the utility of these new chelator platforms, by testing the new radiolabelled derivatives in vitro and in vivo, in prostate cancer models.