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We investigated the coordination properties of original macrocyclic Ln3+ complexes comprising an imidazothiadiazole heterocycle. The thermodynamic stability of the Gd3+ complex was determined by a combination of potentiometric and photophysical measurements. The kinetic inertness was assessed in highly acidic media. The solution structure of the Ln3+ complex was unambiguously determined by a set of photophysical measurements and ¹H, 13C, 89Y NMR data in combination with DFT calculations, which proved coordination of the heterocycle to Ln3+. The ability of the imidazothiadiazole moiety to sensitize Tb3+ luminescence was investigated. Finally, the relaxation properties were investigated by recording ¹H nuclear magnetic relaxation dispersion (NMRD) profiles and 17O measurements. The water exchange rate is similar to that of GdDOTA as the less negative charge of the ligand is compensated for by the presence of a bulky heterocycle. Relaxivity is constant over a large range of pH values, demonstrating the favorable properties of the complex for imaging purposes. [ABSTRACT FROM AUTHOR]

We present the in vitro characterisation of a Gd3+-based contrast agent that responds to Zn2+ upon interaction with Human Serum Albumin. We show that the contradictory in vivo behaviour is related to Gd3+-accumulation in Zn-rich tissues. This highlights the importance of the biodistribution of such contrast agents. [ABSTRACT FROM AUTHOR]

Metal chelates targeted to amyloid peptides are widely explored as diagnostic tools or therapeutic agents. The attachment of a metal complex to amyloid recognition units typically leads to a decrease in peptide affinity. We show here that by separating a macrocyclic GdL chelate and a PiB targeting unit with a long hydrophobic C10 linker, it is possible to attain nanomolar affinities for both Aβ1‐40 (Kd=4.4 nm) and amylin (Kd=4.5 nm), implicated, respectively in Alzheimer's disease and diabetes. The Scatchard analysis of surface plasmon resonance data obtained for a series of amphiphilic, PiB derivative GdL complexes indicate that their Aβ1‐40 or amylin binding affinity varies with their concentration, thus micellar aggregation state. The GdL chelates also affect peptide aggregation kinetics, as probed by thioflavin‐T fluorescence assays. A 2D NMR study allowed identifying that the hydrophilic region of Aβ1‐40 is involved in the interaction between the monomer peptide and the Gd3+ complex. Finally, ex vivo biodistribution experiments were conducted in healthy mice by using 111In labeled analogues. Their pancreatic uptake, ∼3 %ID g−1, is promising to envisage amylin imaging in diabetic animals. [ABSTRACT FROM AUTHOR]

We propose quantitative assessment of zinc by combining nuclear and MR imaging. We use a cocktail of a Gd3+-complex providing a Zn2+-dependent MRI response and its 165Er3+ analogue allowing for concentration assessment. 165Er is readily obtained in a cyclotron and purified, which is indispensable for successful quantification of metal ions. [ABSTRACT FROM AUTHOR]

Background: Amyloidoses are characterized by the extracellular deposition of insoluble fibrillar proteinaceous aggregates highly organized into cross-β structure and referred to as amyloid fibrils. Nowadays, the diagnosis of these diseases remains tedious and involves multiple examinations while an early and accurate protein typing is crucial for the patients' treatment. Routinely used neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) using Pittsburgh compound B, [11C]PIB, provide structural information and allow to assess the amyloid burden, respectively, but cannot discriminate between different amyloid deposits. Therefore, the availability of efficient multimodal imaging nanoparticles targeting specific amyloid fibrils would provide a minimallyinvasive imaging tool useful for amyloidoses typing and early diagnosis. In the present study, we have functionalized gadolinium-based MRI nanoparticles (AGuIX) with peptides highly specific for Aβ amyloid fibrils, LPFFD and KLVFF. The capacity of such nanoparticles grafted with peptide to discriminate among different amyloid proteins, was tested with Aβ(1-42) fibrils and with mutated-(V30M) transthyretin (TTR) fibrils. Results: The results of surface plasmon resonance studies showed that both functionalized nanoparticles interact with Aβ(1-42) fibrils with equilibrium dissociation constant (Kd) values of 403 and 350 μM respectively, whilst they did not interact with V30M-TTR fibrils. Similar experiments, performed with PIB, displayed an interaction both with Aβ(1-42) fibrils and V30M-TTR fibrils, with Kd values of 6 and 10 μM respectively, confirming this agent as a general amyloid fibril marker. Thereafter, the ability of functionalized nanoparticle to target and bind selectively Aβ aggregates was further investigated by immunohistochemistry on AD like-neuropathology brain tissue. Pictures clearly indicated that KLVFF-grafted or LPFFD-grafted to AGuIX nanoparticle recognized and bound the Aβ amyloid plaque localized in the mouse hippocampus. Conclusion: These results constitute a first step for considering these functionalized nanoparticles as a valuable multimodal imaging tool to selectively discriminate and diagnose amyloidoses. [ABSTRACT FROM AUTHOR]

A series of novel pyridine-based Gd3+ complexes have been prepared and studied as potential MRI contrast agents for Zn2+ detection. By independent assessment of molecular parameters affecting relaxivity, we could interpret the relaxivity changes observed upon Zn2+ binding in terms of variations of the rotational motion. [ABSTRACT FROM AUTHOR]

Front Cover: Concentration-Dependent Interactions of Amphiphilic PiB Derivative Metal Complexes with Amyloid Peptides A and Amylin (Chem. Eur. J. 6/2021) Keywords: amylin; amyloid peptide; A ; metal complex; micellar aggregation EN amylin amyloid peptide A metal complex micellar aggregation 1860 1860 1 01/29/21 20210126 NES 210126 B Metal chelates targeted to amyloid peptides b are widely explored as diagnostic tools or therapeutic agents. Amylin, amyloid peptide, A , metal complex, micellar aggregation. [Extracted from the article]

We investigated the coordination properties of original macrocyclic Ln 3+ complexes comprising an imidazothiadiazole heterocycle. The thermodynamic stability of the Gd 3+ complex was determined by a combination of potentiometric and photophysical measurements. The kinetic inertness was assessed in highly acidic media. The solution structure of the Ln 3+ complex was unambiguously determined by a set of photophysical measurements and 1 H, 13 C, 89 Y NMR data in combination with DFT calculations, which proved coordination of the heterocycle to Ln 3+ . The ability of the imidazothiadiazole moiety to sensitize Tb 3+ luminescence was investigated. Finally, the relaxation properties were investigated by recording 1 H nuclear magnetic relaxation dispersion (NMRD) profiles and 17 O measurements. The water exchange rate is similar to that of GdDOTA as the less negative charge of the ligand is compensated for by the presence of a bulky heterocycle. Relaxivity is constant over a large range of pH values, demonstrating the favorable properties of the complex for imaging purposes.

Zn 2+ -responsive magnetic resonance imaging (MRI) contrast agents are typically composed of a Gd chelate conjugated to a Zn 2+ -binding moiety via a linker. They allow for Zn 2+ detection in the presence of human serum albumin (HSA). In order to decipher the key parameters that drive their Zn 2+ -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 Gd 3+ (log K Gd = 16.27) versus Zn 2+ (log K Zn = 13.58), proving that our modified Zn 2+ -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 Zn 2+ is present ( K D = 170 μM versus K DZn = 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 Zn 2+ . Finally, an analysis of nuclear magnetic relaxation dispersion (NMRD) data suggested a significantly increased rigidity for the Zn 2+ -bound system, which is responsible for the Zn 2+ -dependent relaxivity response.

Invited for the cover of this issue are Jean-François Morfin and Éva Tóth at the CNRS in Orléans, and their collaborators from University of Debrecen, University of Coimbra and Université de Toulouse. The image depicts that when an amphiphilic compound is intravenously injected, monomer, pre-micellar and micellar forms can co-exist in the blood and have different affinities for amyloid peptides. Read the full text of the article at 10.1002/chem.202004000., (© 2021 Wiley-VCH GmbH.)

Many smart magnetic resonance imaging (MRI) probes provide response to a biomarker based on modulation of their rotational correlation time. The magnitude of such MRI signal changes is highly dependent on the magnetic field and the response decreases dramatically at high fields (>2 T). To overcome the loss of efficiency of responsive probes at high field, with fast-field cycling magnetic resonance imaging (FFC-MRI) we exploit field-dependent information rather than the absolute difference in the relaxation rate measured in the absence and in the presence of the biomarker at a given imaging field. We report here the application of fast field-cycling techniques combined with the use of a molecular probe for the detection of Zn 2+ to achieve 166 % MRI signal enhancement at 3 T, whereas the same agent provides no detectable response using conventional MRI. This approach can be generalized to any biomarker provided the detection is based on variation of the rotational motion of the probe., (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

We propose quantitative assessment of zinc by combining nuclear and MR imaging. We use a cocktail of a Gd3+-complex providing a Zn2+-dependent MRI response and its 165Er3+ analogue allowing for concentration assessment. 165Er is readily obtained in a cyclotron and purified, which is indispensable for successful quantification of metal ions.

Metal complexes are increasingly explored as imaging probes in amyloid peptide related pathologies. We report the first detailed study on the mechanism of interaction between a metal complex and both the monomer and the aggregated form of Aβ1-40 peptide. We have studied lanthanide(III) chelates of two PiB-derivative ligands (PiB=Pittsburgh compound B), L(1) and L(2), differing in the length of the spacer between the metal-complexing DO3A macrocycle (DO3A=1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) and the peptide-recognition PiB moiety. Surface plasmon resonance (SPR) and saturation transfer difference (STD) NMR spectroscopy revealed that they both bind to aggregated Aβ1-40 (KD =67-160 μM), primarily through the benzothiazole unit. HSQC NMR spectroscopy on the (15) N-labeled, monomer Aβ1-40 peptide indicates nonsignificant interaction with monomeric Aβ. Time-dependent circular dichroism (CD), dynamic light scattering (DLS), and TEM investigations of the secondary structure and of the aggregation of Aβ1-40 in the presence of increasing amounts of the metal complexes provide coherent data showing that, despite their structural similarity, the two complexes affect Aβ fibril formation distinctly. Whereas GdL(1), at higher concentrations, stabilizes β-sheets, GdL(2) prevents aggregation by promoting α-helical structures. These results give insight into the behavior of amyloid-targeted metal complexes in general and contribute to a more rational design of metal-based diagnostic and therapeutic agents for amyloid- associated pathologies., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A series of novel pyridine-based Gd(3+) complexes have been prepared and studied as potential MRI contrast agents for Zn(2+) detection. By independent assessment of molecular parameters affecting relaxivity, we could interpret the relaxivity changes observed upon Zn(2+) binding in terms of variations of the rotational motion., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)