Pyridine-based lanthanide complexes combining MRI and NIR luminescence activities

A series of novel triazole derivative pyridine-based polyamino- polycarboxylate ligands has been synthesized for lanthanide complexation. This versatile platform of chelating agents combines advantageous properties for both magnetic resonance (MR) and optical imaging applications of the corresponding Gd ³⁺ and near-infrared luminescent lanthanide complexes. The thermodynamic stability constants of the Ln ³⁺ complexes, as assessed by pH potentiometric measurements, are in the range logK _LnL=17-19, with a high selectivity for lanthanides over Ca ²⁺, Cu ²⁺, and Zn ²⁺. The complexes are bishydrated, an important advantage to obtain high relaxivities for the Gd ³⁺ chelates. The water exchange of the Gd ³⁺ complexes (k _ex ²⁹⁸=7.7-9.3× 106 s ^-1) is faster than that of clinically used magnetic resonance imaging (MRI) contrast agents and proceeds through a dissociatively activated mechanism, as evidenced by the positive activation volumes (ΔV≠6 =7.2- 8.8 cm ³mol ^-1). The new triazole ligands allow a considerable shift towards lower excitation energies of the luminescent lanthanide complexes as compared to the parent pyridinic complex, which is a significant advantage in the perspective of biological applications. In addition, they provide increased epsilon values resulting in a larger number of emitted photons and better detection sensitivity. The most conjugated system PheTPy, bearing a phenyl-triazole pendant on the pyridine ring, is particularly promising as it displays the lowest excitation and triplet- state energies associated with good quantum yields for both Nd ³⁺ and Yb ³⁺ complexes. Cellular and in vivo toxicity studies in mice evidenced the non-toxicity and the safe use of such bishydrated complexes in animal experiments. Overall, these pyridinic ligands constitute a highly versatile platform for the simultaneous optimization of both MRI and optical properties of the Gd ³⁺ and the luminescent lanthanide complexes, respectively.