A promising cancer therapy involves the use of the macrocyclic polyaminoacetate DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) attached to a tumor-targeting antibody complexed with the beta emitter Y-90(3+). However, incorporation of the Y-90 into the DOTA conjugate is too slow. To identify the origins of this problem, we used ab initio quantum chemistry methods (B3LYP/LACVP* and HF/LACVP*) to-predict structures and energetics. We find that the initial complex YH2(DOTA)(+) is 4-coordinate (the four equivalent carboxylate oxygens), which transforms to YH(DOTA) (5-coordinate with one ring N and four carboxylate oxygens), and finally to Y(DOTA)(-), which is g-coordinate (four oxygens and four nitrogens). The rate-determining step is the conversion of YH(DOTA) to Y(DOTA)(-), which we calculate to have an activation free energy (aqueous phase) of 8.4 kcal/mol, in agreement with experimental results (8.1-9.3 kcal/mol) for various metals to DOTA [Kumar, K.; Tweedle, M. F. Inorg. Chem. 1993, 32, 4193-4199; Wu, S,L.; Horrocks, W. D., Jr. Inorg. Chem. 1995, 34; 3724-3732]. On the basis of this mechanism we propose a modified chelate, DO3AlPr, which we calculate to have a much faster rate of incorporation.