Improved in Vivo Stability of Actinium-225 Macrocyclic Complexes

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