(S)-5-(p-nitrobenzyl)-PCTA, a promising bifunctional ligand with advantageous metal ion complexation kinetics

Abstract

A bifunctional version of PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid) that exhibits fast complexation kinetics with the trivalent lanthanide(III) ions was synthesized in reasonable yields starting from N,N',N''-tristosyl-(S)-2-(p-nitrobenzyl)-diethylenetriamine. pH-potentiometric studies showed that the basicities of p-nitrobenzyl-PCTA and the parent ligand PCTA were similar. The stability of M(NO(2)-Bn-PCTA) (M = Mg(2+), Ca(2+), Cu(2+), Zn(2+)) complexes was similar to that of the corresponding PCTA complexes, while the stability of Ln(3+) complexes of the bifunctional ligand is somewhat lower than that of PCTA chelates. The rate of complex formation of Ln(NO(2)-Bn-PCTA) complexes was found to be quite similar to that of PCTA, a ligand known to exhibit the fastest formation rates among all lanthanide macrocyclic ligand complexes studied to date. The acid-catalyzed decomplexation kinetic studies of the selected Ln(NO(2)-Bn-PCTA) complexes showed that the kinetic inertness of the complexes was comparable to that of Ln(DOTA) chelates making the bifunctional ligand NO(2)-Bn-PCTA suitable for labeling biological vectors with radioisotopes for nuclear medicine applications.

Figure 1

DTPA and DOTA and two bifunctional derivatives commonly used in nuclear medicine.

Figure 2

Structure of NETA, AAZTA, PCTA and NO₂-Bn-PCTA.

Figure 3

Absorbance changes in UV region during the formation of Ce(NO₂-Bn-PCTA) after mixing Ce³⁺ and the ligand at 10:1 metal to ligand concentration ratio at pH=4.20 (in 0.04 M DMP, I=1.0 M KCl and C_Lig=6×10⁻⁵ M), the curves represent the UV-spectrum of 1) 40 mM buffer, 2) 6×10⁻⁴ M CeCl₃ in DMP buffer, 3) 6×10⁻⁵ M ligand in DMP buffer, 4) immediately after mixing the Ce³⁺ with the ligand (“0” min), 5) after 2 min, 6) after 7 min, 7) after 12 min and 8) after 70 min (equilibrium).

Figure 4

Formation rates of Ce(NO₂-Bn-PCTA) (blue diamonds), Eu(NO₂-Bn-PCTA) (green triangles), Yb(NO₂-Bn-PCTA) (purple circles) and Yb(PCTA) (red circles) vs. OH⁻ ion concentration (I=1.0 M KCl, t=25 °C).

Figure 5

Dependence of the dissociation rate constants (k_d) on the H⁺ ion concentration in the dissociation of Ce(NO₂-Bn-PCTA) (blue diamonds), Eu(NO₂-Bn-PCTA) (green triangles), Yb(NO₂-Bn-PCTA) (purple circles) complexes at 25°C.

Scheme 1

Synthesis of the bifunctional ligand, NO₂-Bn-PCTA.