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We explore the potential of fluorine‐containing small Mn2+ chelates as alternatives to perfluorinated nanoparticles, widely used as 19F MRI probes. In MnL1, the cyclohexanediamine skeleton and two piperidine rings, involving each a metal‐coordinating amide group and an appended CF3 moiety, provide high rigidity to the complex. This allows for good control of the Mn−F distance (rMnF=8.2±0.2 Å determined from 19F relaxation data), as well as for high kinetic inertness (a dissociation half‐life of 1285 h is estimated for physiological conditions). The paramagnetic Mn2+ leads to a ~150‐fold acceleration of the longitudinal 19F relaxation, with moderate line‐broadening effect, resulting in T2/T1 ratios of 0.8 (9.4 T). Owing to its inner sphere water molecule, MnL1 is a good 1H relaxation agent as well (r1=5.36 mM−1 s−1 at 298 K, 20 MHz). MnL1 could be readily visualized in 19F MRI by using fast acquisition techniques, both in phantom images and living mice following intramuscular injection, with remarkable signal‐to‐noise ratios and short acquisition times. While applications in targeted imaging or cell therapy monitoring require further optimisation of the molecular structure, these results argue for the potential of such small, monohydrated and fluorinated Mn2+ complexes for combined 19F and 1H MRI detection. [ABSTRACT FROM AUTHOR]

Lanthanide complexes of DO3A‐derivative ligands bearing a pyridine‐carbamate (L1) or pyridine‐amine (L2) arm have potential interest in the design of enzymatically activated imaging probes. Solid‐state X‐ray structures for CeL1 and YbL2 both demonstrate twisted square antiprismatic geometry, with the metal ion in a nine‐ or an eight‐coordinate environment, respectively. As assessed by pH‐potentiometry, in solution lanthanide ions form more stable complexes with the nonadentate L1 than with the octadentate L2 ligand (logKML=18.7–21.1 vs. 16.7–18.6, respectively), while stability constants are similar for L1 and L2 chelates of Mg2+, Ca2+, Zn2+ or Cu2+. The kinetic inertness of GdL1 is exceptionally high, with an estimated dissociation half‐life of ~108 h at pH 7.4, while LnL2 (Ln=Ce, Gd, Yb) complexes have 3–4 orders of magnitude faster dissociation, related to the presence of the protonatable, non‐coordinating amine function. The water exchange rate determined for the monohydrated GdL2 (kex298=1.3×106 s−1) shows a threefold decrease with respect to GdDOTA, as a consequence of a reduction in the negative charge and in the steric crowding around the water binding site, both important in dissociatively activated water exchange processes. [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]

In line with our research to find inert Mn(ii) complexes as contrast agents for magnetic resonance imaging, we have studied the aromatic-ring rigidified EDTA-analogue o-phenylenediamine-N,N,N′,N′-tetraacetic acid (PhDTA). The protonation constants (KHi) of PhDTA and stability constants of complexes formed between this open-chain ligand and several different biogenic metal ions (Ca2+, Mg2+, Zn2+, Cu2+, Mn2+) have been determined in 0.15 M NaCl at 25 °C and compared with the values reported in the literature previously. The protonation constants are lower than those of the corresponding cis- and trans-CDTA complexes, which might be attributed to the electron withdrawing effect of the phenylene group. The lower total basicity of the ligand leads to lower stability constants for all the examined metal complexes. On the contrary, we have found that the conditional stability constants of [Mn(PhDTA)]2− and [Mn(trans-CDTA)]2− are approximately the same, as both complexes are completely formed at pH 5 and their pM values are also comparable. The relaxivity of [Mn(PhDTA)]2− is nearly identical (r1 = 3.72 mM−1 s−1) to that determined previously for the [Mn(trans-CDTA)]2− complex (r1 = 3.62 mM−1 s−1), and its pH-dependence confirms the equilibrium model used for the fitting of the titration data. The results of the kinetic studies of the metal exchange reactions reveal that the [Mn(PhDTA)]2− complex possesses a slightly better dissociation kinetics profile than that of [Mn(trans-CDTA)]2−, which has been tested in vivo recently (including human injections). The half-life of the dissociation of the complex near physiological pH at 25 °C is 19 hours. By using the rate constant calculated for the dissociation (pH = 7.4, cCu2+ = 10 μM) and the half-life of excretion (1.6 hour), the ratio of the dissociated complex is estimated to represent 8% of the injected dose. DFT studies reveal that the metal coordination environment of [Mn(PhDTA)]2− is very similar to that of [Mn(EDTA)]2−, both containing an inner-sphere water molecule. Cyclic voltammetry studies indicate that [Mn(PhDTA)]2− is slightly more resistant towards oxidation to the Mn3+ complex than the EDTA analogue. [ABSTRACT FROM AUTHOR]

The kinetic inertness of Mn2+ complexes is an important parameter for the in vivo safety of potential MRI contrast agents. Rigidifying the ligand structure typically leads to reinforced kinetic inertness. In this context, we studied the Mn2+ complexes of three linear poly(amino carboxylate) ligands containing a pyridine moiety in their skeleton and bearing four (L1, L2) or three carboxylates (L3). The thermodynamic stability constants of the complexes formed with Mn2+, Ca2+, Mg2+, Zn2+ and Cu2+ have been determined using pH-potentiometry, 1H relaxometry and UV/Vis spectrophotometry and are close to those of the EDTA analogues. In contrast, and despite the presence of the pyridine in the ligand backbone, the dissociation rates of the complexes are several orders of magnitude higher than that of [Mn(EDTA)]2−, resulting from a very efficient dissociation pathway catalyzed by the direct attack of Cu2+ or Cu(OH)+. Due to the fewer carboxylate functions, ligand L3 is less favorable for metal-assisted dissociation and provides higher kinetic inertness for its Mn2+ chelate than the L1 and L2 analogues. The water exchange of the monohydrated MnL3 complex has been studied in a variable temperature 17O NMR study. The exchange rate is very high, k298ex = 2.8 × 109 s−1, which is among the highest values reported for a Mn2+ complex. The NMRD profiles are typical of small molecular weight Mn2+ chelates (r1p = 2.44 mM−1 s−1 at 25 °C and 20 MHz). [ABSTRACT FROM AUTHOR]

In this study we present the results of the equilibrium, dissociation kinetics, DFT and X-ray crystallographic studies performed on the complexes of metal ions of biomedical importance (Mn2+, Cu2+ and Gd3+) formed with octadentate ligands based on a cyclen platform incorporating two picolinate pendant arms (dodpa2− and Medodpa2−). The stability constants of the complexes were accessed by multiple methods (pH-potentiometry, direct and competition UV-vis spectrophotometry and 1H-relaxometry). The stability constants of the complexes formed with dodpa2− and Medodpa2− do not differ significantly (e.g. log K[Mn(dodpa)] = 17.40 vs. log K[Mn(Medodpa)] = 17.46, log K[Cu(dodpa)] = 24.34–25.17 vs. log K[Cu(Medodpa)] = 24.74 and log K[Gd(dodpa)]+ = 17.27 vs. log K[Gd(Medodpa)]+ = 17.59), which indicates that the steric hindrance brought by the methyl groups has no significant effect on the stability of the complexes. The stability constants of the Mn2+ complexes formed with the cyclen dipicolinates were found to be ca. 3 log K units higher than those determined for the complex of the cyclen monopicolinate (dompa−), which indicates that the second picolinate moiety attached to the backbone of the macrocycle is very likely coordinated to the Mn2+ ion. However, the stability of the [Cu(dodpa)] and [Cu(Medodpa)] complexes agrees well with the stability constant of [Cu(dompa)]+, in line with the hexadentate coordination around the metal ion observed in the X-ray structure of [Cu(Medodpa)]. The [Gd(dodpa)]+ and [Gd(Medodpa)]+ complexes display a fairly high kinetic inertness, as the rate constants of acid catalysed dissociation (k1 = 2.5(4) × 10−3 and 8.3(4) × 10−4 M−1 s−1 for [Gd(dodpa)]+ and [Gd(Medodpa)]+, respectively) are smaller than the value reported for [Gd(do3a)] (k1 = 2.5 × 10−2 M−1 s−1). The [Mn(dodpa)] complex was found to be more inert than [Mn(Medodpa)]. The results of the diffusion-ordered NMR spectroscopy (DOSY) and DFT calculations of diamagnetic [La(dodpa)]+ and [Lu(dodpa)]+ complexes indicate the formation of a trinuclear entity of the La complex in aqueous solution. [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 explore the potential of fluorine-containing small Mn 2+ chelates as alternatives to perfluorinated nanoparticles, widely used as 19 F MRI probes. In MnL1, the cyclohexanediamine skeleton and two piperidine rings, involving each a metal-coordinating amide group and an appended CF 3 moiety, provide high rigidity to the complex. This allows for good control of the Mn-F distance (r MnF =8.2±0.2 Å determined from 19 F relaxation data), as well as for high kinetic inertness (a dissociation half-life of 1285 h is estimated for physiological conditions). The paramagnetic Mn 2+ leads to a ~150-fold acceleration of the longitudinal 19 F relaxation, with moderate line-broadening effect, resulting in T 2 /T 1 ratios of 0.8 (9.4 T). Owing to its inner sphere water molecule, MnL1 is a good 1 H relaxation agent as well (r 1 =5.36 mM -1  s -1 at 298 K, 20 MHz). MnL1 could be readily visualized in 19 F MRI by using fast acquisition techniques, both in phantom images and living mice following intramuscular injection, with remarkable signal-to-noise ratios and short acquisition times. While applications in targeted imaging or cell therapy monitoring require further optimisation of the molecular structure, these results argue for the potential of such small, monohydrated and fluorinated Mn 2+ complexes for combined 19 F and 1 H MRI detection., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The stability constants of lanthanide complexes with the potentially octadentate ligand CHX OCTAPA 4- , which contains a rigid 1,2-diaminocyclohexane scaffold functionalized with two acetate and two picolinate pendant arms, reveal the formation of stable complexes [log K LaL = 17.82(1) and log K YbL = 19.65(1)]. Luminescence studies on the Eu 3+ and Tb 3+ analogues evidenced rather high emission quantum yields of 3.4 and 11%, respectively. The emission lifetimes recorded in H 2 O and D 2 O solutions indicate the presence of a water molecule coordinated to the metal ion. 1 H nuclear magnetic relaxation dispersion profiles and 17 O NMR chemical shift and relaxation measurements point to a rather low water exchange rate of the coordinated water molecule ( k ex 298 = 1.58 × 10 6 s -1 ) and relatively high relaxivities of 5.6 and 4.5 mM -1 s -1 at 20 MHz and 25 and 37 °C, respectively. Density functional theory calculations and analysis of the paramagnetic shifts induced by Yb 3+ indicate that the complexes adopt an unprecedented cis geometry with the two picolinate groups situated on the same side of the coordination sphere. Dissociation kinetics experiments were conducted by investigating the exchange reactions of LuL occurring with Cu 2+ . The results confirmed the beneficial effect of the rigid cyclohexyl group on the inertness of the Lu 3+ complex. Complex dissociation occurs following proton- and metal-assisted pathways. The latter is relatively efficient at neutral pH, thanks to the formation of a heterodinuclear hydroxo complex.

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.)

A highly rigid open-chain octadentate ligand (H4 cddadpa) containing a diaminocylohexane unit to replace the ethylenediamine bridge of 6,6'-[(ethane-1,2 diylbis{(carboxymethyl)azanediyl})bis(methylene)]dipicolinic acid (H4 octapa) was synthesized. This structural modification improves the thermodynamic stability of the Gd(3+) complex slightly (log KGdL =20.68 vs. 20.23 for [Gd(octapa)](-) ) while other MRI-relevant parameters remain unaffected (one coordinated water molecule; relaxivity r1 =5.73 mm(-1)  s(-1) at 20 MHz and 295 K). Kinetic inertness is improved by the rigidifying effect of the diaminocylohexane unit in the ligand skeleton (half-life of dissociation for physiological conditions is 6 orders of magnitude higher for [Gd(cddadpa)](-) (t1/2 =1.49×10(5)  h) than for [Gd(octapa)](-) . The kinetic inertness of this novel chelate is superior by 2-3 orders of magnitude compared to non-macrocyclic MRI contrast agents approved for clinical use., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)