Gadolinium(III) complexes of 1,4,7-triazacyclononane based picolinate ligands: simultaneous optimization of water exchange kinetics and electronic relaxation

The two new tripodal picolinate H₃ebpatcn (1-carboxyethyl-4,7-bis((6-carboxypyridin-2-yl)methyl)-1,4,7-triazacyclononane) and H₄pbpatcn (1-methylphosphonic-acid-4,7-bis((6-carboxypyridin-2-yl)methyl)-1,4,7-triazacyclononane) ligands based on the 1,4,7-triazacyclononane anchor were prepared and their lanthanide complexes were characterized by NMR, fluorescence and potentiometric studies. The [Gd(ebpatcn)(H₂O)] complex displays a relaxivity of r₁ = 4.68 mM⁻¹ s⁻¹ at 45 MHz and 298 K, whereas r₁ = 4.55 mM⁻¹ s⁻¹ was measured for [Gd(Hpbpatcn)(H₂O)] under the same conditions. The modified scaffold of the ligands with respect to the previously reported H₃bpatcn (1-(carboxymethyl)-4,7-bis[(6-carboxypyridin-2-yl)methyl]-1,4,7-triazacyclononane) leads to an optimization of the properties of these gadolinium complexes. The replacement of an acetate binding group of the H₃bpatcn ligand with a propionate group (H₃ebpatcn) or a phosphonate group (H₄pbpatcn) leads to a faster exchange rate of the coordinated water molecule in both mono-aquo gadolinium complexes. The resulting water exchange rate is optimized for the future design of high relaxivity macromolecular gadolinium based contrast agents with a value measured by O¹⁷ NMRD of k_ex = 34 × 10⁶ s⁻¹ for [Gd(Hpbpatcn)(H₂O)] falling in the range of optimum values of (30 to 50) × 10⁶ s⁻¹ predicted by the SBM theory. The water exchange rate k_ex²⁹⁸ = 86 × 10⁶ s⁻¹ of the complex [Gd(ebpatcn)(H₂O)] is the fastest reported in the literature for a neutral complex with only one inner-sphere water molecule. The relatively high stability of these modified gadolinium complexes (pGd = 14.1 for Gd(pbpatcn) and 13.1 for Gd(ebpatcn)) is similar to that of the [Gd(bpatcn)(H₂O)] complex (pGd = 13.6). The high luminescence efficiency is also retained for the terbium complex. However, whereas the longitudinal electronic spin relaxation time keeps a value for [Gd(ebpatcn)(H₂O)], which is long enough not to affect the relaxivity in macromolecular complexes (transient ZFS amplitude Δ² [10²⁰ rad² s⁻²] = 0.39), the O¹⁷ relaxation and the ¹H NMRD indicate a rather fast electron spin relaxation for the phosphonate containing complex (Δ² [10²⁰ rad² s⁻²]= 1.3).