Improved in vivo stability of actinium-225 macrocyclic complexes

The favorable nuclear properties of actinium-225 (Ac-225) have led to proposal of this isotope for use in radioimmunotherapy. In an effort to reduce the toxicity of free Ac-225, a series of ligands were evaluated for stability in vivo. Loss of Ac-225 from acyclic chelating agents resulted in high liver uptake and poor whole body clearance. The macrocyclic ligands c-DOTA, PEPA, and HEHA were evaluated, and Ac-225-HEHA showed exceptional stability in vivo. Ac-225 chelated with EDTA, DTPA, DOTA, or PEPA permitted substantial accumulation of the radionuclide to the Liver, while the Ac-225-HEHA complex was essentially excreted within minutes of administration. The preparation of the ligands and radiolabeled complexes and the biodistribution results will be discussed.