Separation and equilibrium characterization of two diastereomeric multidentate ligand pairs for use as radiopharmaceuticals

Abstract

The multidentate ligand N,N'-ethylenebis[2-(o-hydroxyphenyl)- glycine] (EHPG) contains a mixture of racemic and meso forms of the ligand. Theoretical work has addressed the differences in the stabilities of the meso and racemic isomers, which until the current study have not been measured. In this study the commercial ligand has been separated into a racemic mixture and meso isomer, and potentiometric and spectrophotometric stability measurements have been made of each. Reported here for both forms at 25.0 °C and μ = 0.10 M (KC1) are ligand protonation constants as well as chelate protonation, stability, and hydrolysis constants with the divalent metal ions nickel(II), copper(II), and zinc(II) and the trivalent metal ions iron(III), gallium(III), and indium(III). In all cases rac-EHPG forms the more stable complexes. The greatest distinction between the diastereomers is found in their respective interactions with indium(III), where an unusual diprotonation of the racemic ligand occurs in a single step. Since the basicities of the two ligands are essentially the same (rac-EHPG, 38.0; meso-EHPG, 37.9), these ligands provide an interesting example whereby the differences observed in the stabilities of their complexes are due to differences in coordination geometry. A new synthetic analog of EHPG, N,N'-trimethylenebis[2-(2'- hydroxy-3',5'-dimethylphenyl)glycine] (TMPHPG), with significantly greater lipophilicity, has been synthesized. Possible limitations to the synthesis of some EHPG analogs via a Mannich-type reaction have been observed and are reported. Procedures employed in the separation of the TMPHPG diastereomers are presented. Unlike EHPG, the two diastereomeric forms of TMPHPG differ in ligand basicity. Hence the solution equilibria of these new ligands with iron(III), gallium(III), and indium(III) present differences due to both ligand basicity and coordination geometry. A comparison of the equilibrium distribution of metal ion between each form of EHPG and TMPHPG and the iron transport protein transferrin indicates that while the racemic and meso forms of each ligand may compete successfully in vivo for iron(III) and gallium(III), the indium(III) complexes are decidedly weaker and may be converted completely to the transferrin complexes, provided that the exchange kinetics are sufficiently rapid.