Gd³⁺ Complexes for MRI Detection of Zn²⁺ in the Presence of Human Serum Albumin: Structure–Activity Relationships

Zn2+-responsive magnetic resonance imaging (MRI) contrast agents are typically composed of a Gd chelate conjugated to a Zn2+-binding moiety via a linker. They allow for Zn2+ detection in the presence of human serum albumin (HSA). In order to decipher the key parameters that drive their Zn2+-dependent MRI response, we designed a pyridine-based ligand, PyAmC2mDPA, and compared the properties of GdPyAmC2mDPA to those of analogue complexes with varying Gd core, Zn-binding moiety, or linker sizes. The stability constants determined by pH potentiometry showed the good selectivity of PyAmC2mDPA for Gd3+ (log KGd = 16.27) versus Zn2+ (log KZn = 13.58), proving that our modified Zn2+-binding DPA moiety prevents the formation of previously observed dimeric species. Paramagnetic relaxation enhancement measurements indicated at least three sites that are available for GdPyAmC2mDPA binding on HSA, as well as a 2-fold affinity increase when Zn2+ is present (KD = 170 μM versus KDZn = 60 μM). Fluorescence competition experiments provided evidence of the higher affinity for site II vs site I, as well as the importance of both the Zn-binding part and the Gd core in generating enhanced HSA affinity in the presence of Zn2+. Finally, an analysis of nuclear magnetic relaxation dispersion (NMRD) data suggested a significantly increased rigidity for the Zn2+-bound system, which is responsible for the Zn2+-dependent relaxivity response

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 <b>L²</b> containing four <i>N</i>-[2-(2-hydroxyethoxy)­ethyl]­acetamide pendant arms and of its lanthanide­(III) complexes [Ln<b>L²</b>(H₂O)]­Cl₃ (Ln = La, Eu, Tb, Yb, or Lu) are reported, together with a comparison with some Ln^III complexes of a previously reported analogue <b>L¹</b> in which two opposite amide arms have been replaced by coordinating pyridyl units.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 H₂O and D₂O solutions of the [Ln­(<b>L²</b>)­(H₂O)]³⁺ complexes (Ln = Eu or Tb) were used to investigate the number of H₂O molecules coordinated to the metal ion, pointing to the presence of an inner-sphere H₂O 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 <b>L²</b> (log <i>K</i> = 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 <b>L¹</b>, the X-ray structure of the [(Eu<b>L¹</b>)₂F] complex features a bridging fluoride donor with an uncommon linear Eu–F–Eu entity connecting two almost identical [Eu­(<b>L¹</b>)]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

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 <b>L²</b> containing four <i>N</i>-[2-(2-hydroxyethoxy)­ethyl]­acetamide pendant arms and of its lanthanide­(III) complexes [Ln<b>L²</b>(H₂O)]­Cl₃ (Ln = La, Eu, Tb, Yb, or Lu) are reported, together with a comparison with some Ln^III complexes of a previously reported analogue <b>L¹</b> 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 H₂O and D₂O solutions of the [Ln­(<b>L²</b>)­(H₂O)]³⁺ complexes (Ln = Eu or Tb) were used to investigate the number of H₂O molecules coordinated to the metal ion, pointing to the presence of an inner-sphere H₂O 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 <b>L²</b> (log <i>K</i> = 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 <b>L¹</b>, the X-ray structure of the [(Eu<b>L¹</b>)₂F] complex features a bridging fluoride donor with an uncommon linear Eu–F–Eu entity connecting two almost identical [Eu­(<b>L¹</b>)]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

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 <b>L²</b> containing four <i>N</i>-[2-(2-hydroxyethoxy)­ethyl]­acetamide pendant arms and of its lanthanide­(III) complexes [Ln<b>L²</b>(H₂O)]­Cl₃ (Ln = La, Eu, Tb, Yb, or Lu) are reported, together with a comparison with some Ln^III complexes of a previously reported analogue <b>L¹</b> 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 H₂O and D₂O solutions of the [Ln­(<b>L²</b>)­(H₂O)]³⁺ complexes (Ln = Eu or Tb) were used to investigate the number of H₂O molecules coordinated to the metal ion, pointing to the presence of an inner-sphere H₂O 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 <b>L²</b> (log <i>K</i> = 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 <b>L¹</b>, the X-ray structure of the [(Eu<b>L¹</b>)₂F] complex features a bridging fluoride donor with an uncommon linear Eu–F–Eu entity connecting two almost identical [Eu­(<b>L¹</b>)]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

PiB-Conjugated, Metal-Based Imaging Probes: Multimodal Approaches for the Visualization of β‑Amyloid Plaques

In an effort toward the visualization of β-amyloid plaques by in vivo imaging techniques, we have conjugated an optimized derivative of the Pittsburgh compound B (PiB), a well-established marker of Aβ plaques, to DO3A-monoamide that is capable of forming stable, noncharged complexes with different trivalent metal ions including Gd³⁺ for MRI and ¹¹¹In³⁺ for SPECT applications. Proton relaxivity measurements evidenced binding of Gd­(DO3A-PiB) to the amyloid peptide Aβ_1–40 and to human serum albumin, resulting in a two- and four-fold relaxivity increase, respectively. Ex vivo immunohistochemical studies showed that the DO3A-PiB complexes selectively target Aβ plaques on Alzheimer’s disease human brain tissue. Ex vivo biodistribution data obtained for the ¹¹¹In-analogue pointed to a moderate blood–brain barrier (BBB) penetration in adult male Swiss mice (without amyloid deposits) with 0.36% ID/g in the cortex at 2 min postinjection