Actinium-225 (Ac-225) is a promising radionuclide used in targeted alpha therapy (TAT). Although Ac-225 labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free Ac-225 can be released from the drugs and that such free Ac-225 is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of Ac-225 TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free Ac-225 and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free Ac-225 were examined in mice before an in vivo chelating study. The liver exhibited pronounced Ac-225 uptake, with an estimated human absorbed dose of 4.76 Sv(RBE5)/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced Ac-225 retention in the liver (22% and 30%, respectively). Significant Ac-225 reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free Ac-225. This feasibility study provides useful information for reducing undesirable radiation exposure from free Ac-225.
