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Inorg Chem. 2003 Dec 29;42(26):8831-7.

Synthesis, characterization, and X-ray crystal structure of In(DOTA-AA) (AA = p-aminoanilide): a model for 111In-labeled DOTA-biomolecule conjugates.

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Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, USA.


This report describes the synthesis and structural characterization of the indium complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(p-aminoanilide) (DOTA-AA), a model compound for (111)In-labeled DOTA-biomolecule conjugates. In(DOTA-AA) was prepared by reacting DOTA-AA with 1 equiv of InCl(3) in 0.5 M ammonium acetate buffer (pH approximately 6). It was characterized by spectroscopic methods (IR, ES-MS, and (1)H NMR), elemental analysis, and X-ray crystallography. For comparison purposes, we also prepared the complex Y(DOTA-AA). ES-MS and (1)H NMR data are consistent with the proposed structure. HPLC analysis using a reversed phase method shows that the retention time of In(DOTA-AA) is approximately 2.0 min shorter than that of Y(DOTA-AA), demonstrating that In(DOTA-monoamide) is more hydrophilic than Y(DOTA-monoamide). In the solid state, In(DOTA-AA) has a twisted square antiprismatic coordination geometry with all eight donor atoms (N(4)O(4)) bonded to the In center. The average In-N and In-O distances are almost identical to those of Y-N and Y-O bonds found in Y(DOTA-d-Phe-NH(2)) even though the ionic radius of Y(3+) is much longer than that of In(3+). It seems that In(3+) does not fit the coordination cavity of DOTA-AA perfectly. The (1)H NMR data clearly demonstrated that In(DOTA-AA) becomes fluxional at room temperature, most likely due to dissociation of the acetamide-oxygen, rotation of acetate chelating arms, and inversion of ethylenic groups of the macrocyclic ring. Results from this study and our previous studies (Liu, S.; Pietryka, J.; Ellars C. E.; Edwards D. S. Bioconjugate Chem. 2002, 13, 902-913) suggest that the In(3+) complex of DOTA-monoamide in the solid state might be different from that in solution due to dissociation of the carbonyl-oxygen donor. Although Y(3+) and In(3+) complexes of DOTA-monoamide are both eight-coordinate in the solid state, the difference in their solution structures is most likely responsible for their difference in lipophilicity.

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