Synthesis, Characterization, and Structures of Indium In(DTPA-BA2) and Yttrium Y(DTPA-BA2)(CH3OH) Complexes (BA = Benzylamine): Models for 111In- and 90Y-Labeled DTPA-Biomolecule Conjugates

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Abstract
To explore structural differences in In3+, Y3+, and Lu3+ chelates, we prepared M(DTPA-BA2) complexes (M = In, Y, and Lu; DTPA-BA2 = N,N‘ ‘-bis(benzylcarbamoylmethyl)diethylenetriamine-N,N‘,N‘ ‘-triacetic acid) by reacting the trisodium salt of DTPA-BA2 with 1 equiv of metal chloride or nitrate. All three complexes have been characterized by elemental analysis, HPLC, IR, ES-MS, and NMR (1H and 13C) methods. ES-MS spectral and elemental analysis data are consistent with the proposed formula for M(DTPA-BA2) (M = In, Y, and Lu) and have been confirmed by the X-ray crystal structures of both In(DTPA-BA2)·2H2O and Y(DTPA-BA2)(CH3OH) complexes. By a reversed-phase HPLC method, it was found that In(DTPA-BA2) is more hydrophilic than M(DTPA-BA2) (M = Y and Lu), most likely due to the dissociation of the two carbonyl oxygen donors in solution. The X-ray crystal structure of In(DTPA-BA2) revealed a rare example of an eight-coordinated In3+ complex with DTPA-BA2 bonding to the In3+ in a distorted square antiprism coordination geometry. Both benzylamine groups are in the trans position relative to the acetate-chelating arm that is attached to the central N atom. The Y3+ in Y(DTPA-BA2)(CH3OH) is nine-coordinated with an octadentate DTPA-BA2 and a methanol oxygen. The coordination geometry is best described as a tricapped trigonal prism. One benzylamine group is trans and the other cis to the acetate-chelating arm that is attached to the central N atom. All three M(DTPA-BA2) complexes (M = In, Y, and Lu) exist as at least three isomers in solution (∼10 mM), as shown by the presence of 6−8 overlapped 1H NMR signals from the methylene hydrogens of the benzylamine groups. The coordinated DTPA-BA2 remains rigid even at temperatures >85 °C. The exchange rate between different isomers in M(DTPA-BA2) (M = In, Y, and Lu) is relatively slow at high concentrations (>1.0 mM), but it is fast due to the partial dissociation and rapid interconversion of different isomers at lower concentrations (∼10 μM). It is not surprising that M(DTPA-BA2) complexes (M = In, Y, and Lu) appear as a single peak in their respective HPLC chromatogram.

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