Towards Targeted Alpha Therapy with Actinium 225: Chelators for Mild Condition Radiolabeling and Targeting PSMA – a Proof of Concept Study

Currently, targeted alpha therapy is one of the most investigated topics in radiopharmaceutical cancer management. Especially, the alpha emitter ²²⁵ Ac provides excellent nuclear properties and is gaining increasing popularity for the treatment of various tumor entities. We herein report on the synthesis of two universal ²²⁵Ac-chelators for mild condition radiolabeling and binding sites to conjugate biomolecules via the copper-mediated click chemistry. A convenient radiolabeling procedure was investigated as well as the complex stability proved for both chelators and two PSMA-targeting model radioconjugates. Studies regarding affinity and cell survival were per-formed on LNCaP cells followed by biodistribution studies, which were performed using LNCaP tumor-bearing mice. High efficiency radiolabeling for all conjugates was demonstrated. Cell binding studies revealed a fourfold lower cell affinity for the PSMA conjugate with one targeting vector compared to the conjugate owing two targeting vectors. Additionally, these differences were verified by in vitro cell survival evaluation and biodistribution studies, both showing a higher therapeutic efficiency for the same dose on a cellular leve, a higher tumor up-take (15%ID/g) and a rapid whole body clearance after 24 hours. The synthesized chelators will overcome obstacles of lacking stability and worse labeling needs regarding ²²⁵Ac complexation using the DOTA chelator. Moreover, the universal functionalization expands the coverage of these chelators in combination with any sensitive bio(macro)molecule, thus improving treat-ment of any addressable tumor target.