Quantum-Mechanical Calculations on Energetics of Complexation
of Y(3+) with DOTA, a Model for Cancer Radiotherapy Chelators
(DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)

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Yun Hee Jang, Mario Blanco, Siddharth Dasgupta and William A. Goddard, III*

Materials and Process Simulation Center, Beckman Institute (139-74)
California Institute of Technology, Pasadena, California 91125

David A. Keire and John E. Shively

The Beckman Research Institute of the City of Hope
1450 E. Duarte Road, Duarte, California


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(3+).[1] However, incorporation of the Y(3+) into the DOTA conjugate is too slow.[2] In order 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 8-coordinate (four oxygens and 4 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.[3,4] Based on this mechanism we propose a modified chelate, DO3AlPr (1,4,7,10-tetraazacyclododecane-1,4,7-triraacetic acid-10-propionic acid), which we calculate to have a much faster rate of incorporation.

  1. Parker, D. Chem. Soc. Rev. 1990, 19, 271.

  2. Burai, L., et al. J. Chem. Soc., Dalton Trans. 1998, 243.

  3. Kumar, K.; Tweedle, M. F.; Inorg. Chem. 1993, 32, 4193.

  4. Wu, S. L.; Horrocks, Jr., W. D.; Inorg. Chem. 1995, 34, 3724.


Supported by NSF (CHE 95-22179 and ASC 92-100368)

Scheme 1. Radioimmunotherapy using bifunctional chelating agent: DOTA and newly-suggested DO3A1Pr.

(a) YH2(DOTA)+

(b) YH(DOTA)

(c) Y(DOTA)-
Figure 1. Optimized structures at different protonation states. Y3+ moves toward the DOTA cage spontaneously after deprotonation from ring nitrogen. The deprotonation is the rate-determining step.

(a) reactant

(b) TS: DOTA and DO3A1Pr

(c) product

6-membered ring
B3LYP//HF/LACVP*(kcal/mol) DOTA DO3A1Pr
Energy barrier(aq) 12.2 4.5
Activation Free Energy(aq) 8.4 3.9
Figure 2. The most favorable deprotonation pathway: Proton transfer from ring nitrogen to carboxylate oxygen of YH(DOTA) and YH(DO3A1Pr).