Alexandre Lecointre

Positively Charged Lanthanide Complexes with Cyclen-Based Ligands: Synthesis, Solid-State and Solution Structure, and Fluoride Interaction

The syntheses of a new cyclen-based ligand L(2) containing four N-[2-(2-hydroxyethoxy)ethyl]acetamide pendant arms and of its lanthanide(III) complexes [LnL(2)(H(2)O)]Cl(3) (Ln = La, Eu, Tb, Yb, or Lu) are reported, together with a comparison with some Ln(III) complexes of a previously reported analogue L(1) in which two opposite amide arms have been replaced by coordinating pyridyl units. The structure and dynamics of the La(III), Lu(III), and Yb(III) complexes in solution were studied by using multinuclear NMR investigations and density functional theory calculations. Luminescence lifetime measurements in H(2)O and D(2)O solutions of the [Ln(L(2))(H(2)O)](3+) complexes (Ln = Eu or Tb) were used to investigate the number of H(2)O molecules coordinated to the metal ion, pointing to the presence of an inner-sphere H(2)O molecule in a buffered aqueous solution. Fluoride binding to the latter complexes was investigated using a combination of absorption spectroscopy and steady-state and time-resolved luminescence spectroscopy, pointing to a surprisingly weak interaction in the case of L(2) (log K = 1.4 ± 0.1). In contrast to the results in solution, the X-ray crystal structure of the lanthanide complex showed the ninth coordination position occupied by a chloride anion. In the case of L(1), the X-ray structure of the [(EuL(1))(2)F] complex features a bridging fluoride donor with an uncommon linear Eu-F-Eu entity connecting two almost identical [Eu(L(1))](3+) units. Encapsulation of the F(-) anion within the two complexes is assisted by π-π stacking between the pyridyl rings of two complexes and C-H···F hydrogen-bonding interactions involving the anion and the pyridyl units.

Nonmacrocyclic Luminescent Lanthanide Complexes Stable in Biological Media

The synthesis of ligand L(P)H(8), based on a 2,6-bispyrazolyl-pyridine scaffold functionalized by iminobismethylenephosphonate functions, is described and its pK values were determined by a combination of pH-spectrophotometric titrations and potentiometry. The interaction of L(P) with Tb(3+) was investigated in water (0.01 M TRIS/HCl pH = 7.0) by means of UV-vis and fluorescence titration experiments and evidenced the formation of at least three species with 1:1; 1:2, and 2:1 M-L ratios, the 1:1 complex appearing as particularly stable under these conditions (log K(cond) > 8). Na(4)[LnL(P)H] complexes (Ln = Eu and Tb) were prepared and characterized by elemental analysis, IR spectroscopy, and electrospray mass spectrometry. Their photophysical properties were investigated in aqueous solutions, revealing an excellent shielding of the Ln cations from the solvent environment (no water molecules in the first coordination sphere), very long luminescence lifetimes (τ(H(2)(O)) = 1.50 and 3.28 ms, respectively, for Eu and Tb) and reasonable luminescent quantum yields (ϕ(H(2)(O)) = 2.4 and 37%, respectively, for Eu and Tb). Using fetal bovine serum as a model for biological media showed the Tb complex to remain luminescent in these conditions. The structure of the europium complex was studied by means of density functional theory (DFT) modeling, confirming the wrapping of the ligand around the cation, and the very good shielding of the coordinated Ln cation. The conditional stability constant for the formation of the Tb complex with L(P) was determined by competition experiments with EDTA and monitored by fluorescence spectroscopy (log K(TbL(P)cond) = 14.1 ± 0.3, 0.01 M TRIS/HCl, pH = 7.4) and was used to determine the thermodynamic constant (log K(TbL(P)) = 20.4 ± 0.4). A systematic comparison with ligand L(C), in which phosphonate functions are replaced by carboxylate ones, is made throughout the study, highlighting the large interest of the introduction of phosphonate moieties to obtain biologically stable luminescent lanthanide complexes.

Highly relaxing gadolinium based MRI contrast agents responsive to Mg2+ sensing

A Gd complex based on a polyphosphonated pyridyl ligand shows a very high stability in aqueous solution (log K(EuL) = 25.7), a high relaxivity (8.5 mM(-1) s(-1) at 25 °C and 20 MHz) and a marked and selective relaxivity enhancement (37%) in the presence of Mg(2+), opening interesting perspectives for the design of cation responsive contrast agents.

Highly stable acyclic bifunctional chelator for 64Cu PET imaging

Abstract Ligand L1, based on a pyridine scaffold, functionalized by two bis(methane phosphonate)aminomethyl groups, was shown to display a very high affinity towards Cu(II) (log KCuL=22.7) and selectivity over Ni(II), Co(II), Zn(II) and Ga(III) (Δ log KML>4) as shown by the values of the stability constants obtained from potentiometric measurements. Insights into the coordination mode of the ligand around Cu(II) cation were obtained by UV-Vis absorption and EPR spectroscopies as well as density functional theory (DFT) calculations (B3LYP model) performed in aqueous solution. The results point to a pentacoordination pattern of the metal ion in the fully deprotonated [CuL1]6− species. Considering the beneficial thermodynamic parameters of this ligand, kinetic experiments were run to follow the formation of the copper(II) complexes, indicating a very rapid formation of the complex, appropriat e for 64Cu complexation. As L1 represents a particularly interesting target within the frame of 64Cu PET imaging, a synthetic protocol was developed to introduce a labeling function on the pyridyl moiety of L1, thereby affording L2, a potential bifunctional chelator (BFC) for PET imaging.

Activated phosphonated trifunctional chelates for highly sensitive lanthanide-based FRET immunoassays applied to total prostate specific antigen detection.

The first example of an activated phosphonated trifunctional chelate (TFC) is presented, which combines a non-macrocyclic coordination site for lanthanide coordination based on two aminobis-methylphosphonate coordinating arms, a central bispyrazolylpyridyl antenna and an N-hydroxysuccinimide ester in para position of the central pyridine as an activated function for the labeling of biomaterial. The synthesis of the TFC is presented together with photo-physical studies of the related Tb and Eu complexes. Excited state lifetime measurements in H2O and D2O confirmed an excellent shielding of the cation from water molecules with a hydration number of zero. The Tb complex provides a high photoluminescence (PL) quantum yield of 24% in aqueous solutions (0.01 M Tris-HCl, pH 7.4) and a very long luminescence lifetime of 2.6 ms. The activated ligand was conjugated to different biological compounds such as streptavidin, and a monoclonal antibody against total prostate specific antigen (TPSA). In combination with AlexaFluor647 (AF647) and crosslinked allophycocyanin (XL665) antibody (ABs) conjugates, homogeneous time-resolved Fluorescence Resonance Energy Transfer (FRET) immunoassays of TPSA were performed in serum samples. The Tb donor-dye acceptor FRET pairs provided large Förster distances of 5.3 nm (AF647) and 7.1 nm (XL665). A detailed time-resolved FRET analysis of Tb donor and dye acceptor PL decays revealed average donor-acceptor distances of 4.2 nm (AF647) and 6.3 nm (XL665) within the sandwich immunocomplex and FRET efficiencies of 0.79 and 0.68, respectively. Very low detection limits of 1.4 ng mL(-1) (43 pM) and 2.4 ng mL(-1) (74 pM) TPSA were determined using a KRYPTOR fluorescence immunoanalyzer. These results demonstrate the applicability of our novel Tb-bioconjugates for highly sensitive clinical diagnostics.

Formation of Mono- and Polynuclear Luminescent Lanthanide Complexes based on the Coordination of Preorganized Phosphonated Pyridines

A series of polynuclear assemblies based on ligand L (1,4,7-tris[hydrogen (6-methylpyridin-2-yl)phosphonate]-1,4,7-triazacyclononane) has been developed. The coordination properties of ligand L with LnIII (Ln = La, Eu, Tb, Yb, Lu) have been studied in water (pH = 7.0) and in D2O (pD = 7.0) by UV-absorption spectrometry, spectrofluorimetry, 1H and 31P NMR, DOSY, ESI-mass spectrometry, and X-ray diffraction. This nonadentate ligand forms highly stable mononuclear complexes in water and provides a very efficient shielding of the Ln cations, as emphasized by the very good luminescence properties of the Yb complex in D2O, especially regarding its lifetime (τD2O = 10.2 μs) and quantum yield (ϕD2O = 0.42%). In the presence of excess LnIII cation, polynuclar complexes of [(LnL)2Ln x] stoichiometry (x = 1 and x = 2) are observed in solution. In the solid state, a dinuclear complex of La could be isolated and structurally characterized by X-ray diffraction, unraveling the presence of strong hydrogen bonding interactions between a La(H2O)93+ cation and the [LaL]3- complex.