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19 pages, 5036 KiB

Open AccessArticle

Semi-Rigid (Aminomethyl) Piperidine-Based Pentadentate Ligands for Mn(II) Complexation

by Jonathan Martinelli, Edoardo Callegari, Zsolt Baranyai, Alberto Fraccarollo, Maurizio Cossi and Lorenzo Tei

Molecules 2021, 26(19), 5993; https://doi.org/10.3390/molecules26195993 - 2 Oct 2021

Cited by 4 | Viewed by 2500

Abstract

Two pentadentate ligands built on the 2-aminomethylpiperidine structure and bearing two tertiary amino and three oxygen donors (three carboxylates in the case of AMPTA and two carboxylates and one phenolate for AMPDA-HB) were developed for Mn(II) complexation. Equilibrium studies on the ligands and [...] Read more.

Two pentadentate ligands built on the 2-aminomethylpiperidine structure and bearing two tertiary amino and three oxygen donors (three carboxylates in the case of AMPTA and two carboxylates and one phenolate for AMPDA-HB) were developed for Mn(II) complexation. Equilibrium studies on the ligands and the Mn(II) complexes were carried out using pH potentiometry, ¹H-NMR spectroscopy and UV-vis spectrophotometry. The Mn complexes that were formed by the two ligands were more stable than the Mn complexes of other pentadentate ligands but with a lower pMn than Mn(EDTA) and Mn(CDTA) (pMn for Mn(AMPTA) = 7.89 and for Mn(AMPDA-HB) = 7.07). ¹H and ¹⁷O-NMR relaxometric studies showed that the two Mn-complexes were q = 1 with a relaxivity value of 3.3 mM⁻¹ s⁻¹ for Mn(AMPTA) and 3.4 mM⁻¹ s⁻¹ for Mn(AMPDA-HB) at 20 MHz and 298 K. Finally, the geometries of the two complexes were optimized at the DFT level, finding an octahedral coordination environment around the Mn²⁺ ion, and MD simulations were performed to monitor the distance between the Mn²⁺ ion and the oxygen of the coordinated water molecule to estimate its residence time, which was in good agreement with that determined using the ¹⁷O NMR data. Full article

(This article belongs to the Special Issue Recent Advances on MRI Contrast Agents)

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26 pages, 30726 KiB

Open AccessArticle

Complexes of Bifunctional DO3A-N-(α-amino)propinate Ligands with Mg(II), Ca(II), Cu(II), Zn(II), and Lanthanide(III) Ions: Thermodynamic Stability, Formation and Dissociation Kinetics, and Solution Dynamic NMR Studies

by Zoltán Garda, Tamara Kócs, István Bányai, José A. Martins, Ferenc Krisztián Kálmán, Imre Tóth, Carlos F. G. C. Geraldes and Gyula Tircsó

Molecules 2021, 26(16), 4956; https://doi.org/10.3390/molecules26164956 - 16 Aug 2021

Cited by 2 | Viewed by 2481

Abstract

The thermodynamic, kinetic, and structural properties of Ln³⁺ complexes with the bifunctional DO3A-ACE⁴⁻ ligand and its amide derivative DO3A-BACE⁴⁻ (modelling the case where DO3A-ACE⁴⁻ ligand binds to vector molecules) have been studied in order to confirm the usefulness of [...] Read more.

The thermodynamic, kinetic, and structural properties of Ln³⁺ complexes with the bifunctional DO3A-ACE⁴⁻ ligand and its amide derivative DO3A-BACE⁴⁻ (modelling the case where DO3A-ACE⁴⁻ ligand binds to vector molecules) have been studied in order to confirm the usefulness of the corresponding Gd³⁺ complexes as relaxation labels of targeted MRI contrast agents. The stability constants of the Mg²⁺ and Ca²⁺ complexes of DO3A-ACE⁴⁻ and DO3A-BACE⁴⁻ complexes are lower than for DOTA⁴⁻ and DO3A³⁻, while the Zn²⁺ and Cu²⁺ complexes have similar and higher stability than for DOTA⁴⁻ and DO3A³⁻ complexes. The stability constants of the Ln(DO3A-BACE)⁻ complexes increase from Ce³⁺ to Gd³⁺ but remain practically constant for the late Ln³⁺ ions (represented by Yb³⁺). The stability constants of the Ln(DO3A-ACE)⁴⁻ and Ln(DO3A-BACE)⁴⁻ complexes are several orders of magnitude lower than those of the corresponding DOTA⁴⁻ and DO3A³⁻ complexes. The formation rate of Eu(DO3A-ACE)⁻ is one order of magnitude slower than for Eu(DOTA)⁻, due to the presence of the protonated amine group, which destabilizes the protonated intermediate complex. This protonated group causes the Ln(DO3A-ACE)⁻ complexes to dissociate several orders of magnitude faster than Ln(DOTA)⁻ and its absence in the Ln(DO3A-BACE)⁻ complexes results in inertness similar to Ln(DOTA)⁻ (as judged by the rate constants of acid assisted dissociation). The ¹H NMR spectra of the diamagnetic Y(DO3A-ACE)⁻ and Y(DO3A-BACE)⁻ reflect the slow dynamics at low temperatures of the intramolecular isomerization process between the SA pair of enantiomers, R-Λ(λλλλ) and S-Δ(δδδδ). The conformation of the C_α-substituted pendant arm is different in the two complexes, where the bulky substituent is further away from the macrocyclic ring in Y(DO3A-BACE)⁻ than the amino group in Y(DO3A-ACE)⁻ to minimize steric hindrance. The temperature dependence of the spectra reflects slower ring motions than pendant arms rearrangements in both complexes. Although losing some thermodynamic stability relative to Gd(DOTA)⁻, Gd(DO3A-BACE)⁻ is still quite inert, indicating the usefulness of the bifunctional DO3A-ACE⁴⁻ in the design of GBCAs and Ln³⁺-based tags for protein structural NMR analysis. Full article

(This article belongs to the Special Issue Recent Advances on MRI Contrast Agents)

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17 pages, 6142 KiB

Open AccessArticle

Lanthanide DO3A-Complexes Bearing Peptide Substrates: The Effect of Peptidic Side Chains on Metal Coordination and Relaxivity

by Sophie Laine, Jean-François Morfin, Mathieu Galibert, Vincent Aucagne, Célia S. Bonnet and Éva Tóth

Molecules 2021, 26(8), 2176; https://doi.org/10.3390/molecules26082176 - 9 Apr 2021

Cited by 4 | Viewed by 2398

Abstract

Two DO3A-type ligands conjugated to substrates of urokinase (L3) and caspase-3 (L4) via a propyl-amide linker were synthesized and their lanthanide(III) (Ln³⁺) complexes studied. A model compound without peptide substrate (L2) and an amine derivative ligand mimicking the state after enzymatic [...] Read more.

Two DO3A-type ligands conjugated to substrates of urokinase (L3) and caspase-3 (L4) via a propyl-amide linker were synthesized and their lanthanide(III) (Ln³⁺) complexes studied. A model compound without peptide substrate (L2) and an amine derivative ligand mimicking the state after enzymatic cleavage (L1) were also prepared. Proton Nuclear Magnetic Relaxation Dispersion (NMRD) profiles recorded on the gadolinium(III) (Gd³⁺) complexes, complemented with the assessment of hydration numbers via luminescence lifetime measurements on the Eu³⁺ analogues, allowed us to characterize the lanthanide coordination sphere in the chelates. These data suggest that the potential donor groups of the peptide side chains (carboxylate, amine) interfere in metal coordination, leading to non-hydrated LnL3 and LnL4 complexes. Nevertheless, GdL3 and GdL4 retain a relatively high relaxivity due to an important second-sphere contribution generated by the strongly hydrophilic peptide chain. Weak PARACEST effects are detected for the amine-derivative EuL1 and NdL1 chelates. Unfortunately, the GdL3 and GdL4 complexes are not significantly converted by the enzymes. The lack of enzymatic recognition of these complexes can likely be explained by the participation of donor groups from the peptide side chain in metal coordination. Full article

(This article belongs to the Special Issue Recent Advances on MRI Contrast Agents)

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20 pages, 17440 KiB

Open AccessArticle

Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference

by Ferenc K. Kálmán, Viktória Nagy, Rocío Uzal-Varela, Paulo Pérez-Lourido, David Esteban-Gómez, Zoltán Garda, Kristof Pota, Roland Mezei, Agnès Pallier, Éva Tóth, Carlos Platas-Iglesias and Gyula Tircsó

Molecules 2021, 26(6), 1524; https://doi.org/10.3390/molecules26061524 - 10 Mar 2021

Cited by 8 | Viewed by 3799

Abstract

We report two macrocyclic ligands based on a 1,7-diaza-12-crown-4 platform functionalized with acetate (tO2DO2A²⁻) or piperidineacetamide (tO2DO2AM^Pip) pendant arms and a detailed characterization of the corresponding Mn(II) complexes. The X−ray structure of [Mn(tO2DO2A [...] Read more.

We report two macrocyclic ligands based on a 1,7-diaza-12-crown-4 platform functionalized with acetate (tO2DO2A²⁻) or piperidineacetamide (tO2DO2AM^Pip) pendant arms and a detailed characterization of the corresponding Mn(II) complexes. The X−ray structure of [Mn(tO2DO2A)(H₂O)]·2H₂O shows that the metal ion is coordinated by six donor atoms of the macrocyclic ligand and one water molecule, to result in seven-coordination. The Cu(II) analogue presents a distorted octahedral coordination environment. The protonation constants of the ligands and the stability constants of the complexes formed with Mn(II) and other biologically relevant metal ions (Mg(II), Ca(II), Cu(II) and Zn(II)) were determined using potentiometric titrations (I = 0.15 M NaCl, T = 25 °C). The conditional stabilities of Mn(II) complexes at pH 7.4 are comparable to those reported for the cyclen-based tDO2A²⁻ ligand. The dissociation of the Mn(II) chelates were investigated by evaluating the rate constants of metal exchange reactions with Cu(II) under acidic conditions (I = 0.15 M NaCl, T = 25 °C). Dissociation of the [Mn(tO2DO2A)(H₂O)] complex occurs through both proton− and metal−assisted pathways, while the [Mn(tO2DO2AM^Pip)(H₂O)] analogue dissociates through spontaneous and proton-assisted mechanisms. The Mn(II) complex of tO2DO2A²⁻ is remarkably inert with respect to its dissociation, while the amide analogue is significantly more labile. The presence of a water molecule coordinated to Mn(II) imparts relatively high relaxivities to the complexes. The parameters determining this key property were investigated using ¹⁷O NMR (Nuclear Magnetic Resonance) transverse relaxation rates and ¹H nuclear magnetic relaxation dispersion (NMRD) profiles. Full article

(This article belongs to the Special Issue Recent Advances on MRI Contrast Agents)

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11 pages, 1949 KiB

Open AccessArticle

Macrocyclic Chelates Bridged by a Diaza-Crown Ether: Towards Multinuclear Bimodal Molecular Imaging Probes

by Gaoji Wang and Goran Angelovski

Molecules 2020, 25(21), 5019; https://doi.org/10.3390/molecules25215019 - 29 Oct 2020

Cited by 1 | Viewed by 2337

Abstract

Bridged polymacrocyclic ligands featured by structurally different cages offer the possibility of coordinating multiple trivalent lanthanide ions, giving rise to the exploitation of their different physicochemical properties, e.g., multimodal detection for molecular imaging purposes. Intrigued by the complementary properties of optical and MR-based [...] Read more.

Bridged polymacrocyclic ligands featured by structurally different cages offer the possibility of coordinating multiple trivalent lanthanide ions, giving rise to the exploitation of their different physicochemical properties, e.g., multimodal detection for molecular imaging purposes. Intrigued by the complementary properties of optical and MR-based image capturing modalities, we report the synthesis and characterization of the polymetallic Ln(III)-based chelate comprised of two DOTA-amide-based ligands (DOTA—1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) bridged via 1,10-diaza-18-crown-6 (DA18C6) motif. The DOTA-amide moieties and the DA18C6 were used to chelate two Eu(III) ions and one Tb(III) ion, respectively, resulting in a multinuclear heterometallic complex Eu₂LTb. The bimetallic complex without Tb(III), Eu₂L, displayed a strong paramagnetic chemical exchange saturation transfer (paraCEST) effect. Notably, the luminescence spectra of Eu₂LTb featured mixed emission including the characteristic bands of Eu(III) and Tb(III). The advantageous features of the complex Eu₂LTb opens new possibilities for the future design of bimodal probes and their potential applicability in CEST MR and optical imaging. Full article

(This article belongs to the Special Issue Recent Advances on MRI Contrast Agents)

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17 pages, 3979 KiB

Open AccessArticle

Functionalization of Magnetic Nanoparticles by Folate as Potential MRI Contrast Agent for Breast Cancer Diagnostics

by Hamid Heydari Sheikh Hossein, Iraj Jabbari, Atefeh Zarepour, Ali Zarrabi, Milad Ashrafizadeh, Afrooz Taherian and Pooyan Makvandi

Molecules 2020, 25(18), 4053; https://doi.org/10.3390/molecules25184053 - 4 Sep 2020

Cited by 27 | Viewed by 4221

Abstract

In recent years, the intrinsic magnetic properties of magnetic nanoparticles (MNPs) have made them one of the most promising candidates for magnetic resonance imaging (MRI). This study aims to evaluate the effect of different coating agents (with and without targeting agents) on the [...] Read more.

In recent years, the intrinsic magnetic properties of magnetic nanoparticles (MNPs) have made them one of the most promising candidates for magnetic resonance imaging (MRI). This study aims to evaluate the effect of different coating agents (with and without targeting agents) on the magnetic property of MNPs. In detail, iron oxide nanoparticles (IONPs) were prepared by the polyol method. The nanoparticles were then divided into two groups, one of which was coated with silica (SiO₂) and hyperbranched polyglycerol (HPG) (SPION@SiO₂@HPG); the other was covered by HPG alone (SPION@HPG). In the following section, folic acid (FA), as a targeting agent, was attached on the surface of nanoparticles. Physicochemical properties of nanostructures were characterized using Fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), and a vibrating sample magnetometer (VSM). TEM results showed that SPION@HPG was monodispersed with the average size of about 20 nm, while SPION@SiO₂@HPG had a size of about 25 nm. Moreover, HPG coated nanoparticles had much lower magnetic saturation than the silica coated ones. The MR signal intensity of the nanostructures showed a relation between increasing the nanoparticle concentrations inside the MCF-7 cells and decreasing the signal related to the T₂ relaxation time. The comparison of coating showed that SPION@SiO₂@HPG (with/without a targeting agent) had significantly higher r₂ value in comparison to Fe₃O₄@HPG. Based on the results of this study, the Fe₃O₄@SiO₂@HPG-FA nanoparticles have shown the best magnetic properties, and can be considered promising contrast agents for magnetic resonance imaging applications. Full article

(This article belongs to the Special Issue Recent Advances on MRI Contrast Agents)

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20 pages, 2506 KiB

Open AccessArticle

Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups

by Didar Asik, Rachel Smolinski, Samira M. Abozeid, Travis B. Mitchell, Steven G. Turowski, Joseph A. Spernyak and Janet R. Morrow

Molecules 2020, 25(10), 2291; https://doi.org/10.3390/molecules25102291 - 13 May 2020

Cited by 31 | Viewed by 6004

Abstract

Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to [...] Read more.

Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to large changes in MRI contrast enhancement in mice. Two new Fe(III) complexes, one with a third coordinating hydroxypropyl pendant, Fe(L2), and one with an anionic non-coordinating sulfonate group, Fe(L1)(OH₂), are compared. Both complexes have a deprotonated hydroxyl group at neutral pH and electrode potentials representative of a stabilized trivalent iron center. The r₁ relaxivity of the Fe(L1)(OH₂) complex is double that of the saturated complex, Fe(L2), at 4.7 T, 37 °C in buffered solutions. However, variable-temperature ¹⁷O-NMR experiments show that the inner-sphere water of Fe(L1)(OH₂) does not exchange rapidly with bulk water under these conditions. The pendant sulfonate group in Fe(L1)(OH₂) confers high solubility to the complex in comparison to Fe(L2) or previously studied analogues with benzyl groups. Dynamic MRI studies of the two complexes showed major differences in their pharmacokinetics clearance rates compared to an analogue containing a benzyl ancillary group. Rapid blood clearance and poor binding to serum albumin identify Fe(L1)(OH₂) for development as an extracellular fluid contrast agent. Full article

(This article belongs to the Special Issue Recent Advances on MRI Contrast Agents)

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Review

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19 pages, 1272 KiB

Open AccessReview

How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo

by Quyen N. Do, Robert E. Lenkinski, Gyula Tircso and Zoltan Kovacs

Molecules 2022, 27(1), 58; https://doi.org/10.3390/molecules27010058 - 23 Dec 2021

Cited by 13 | Viewed by 5114

Abstract

The extracellular class of gadolinium-based contrast agents (GBCAs) is an essential tool for clinical diagnosis and disease management. In order to better understand the issues associated with GBCA administration and gadolinium retention and deposition in the human brain, the chemical properties of GBCAs [...] Read more.

The extracellular class of gadolinium-based contrast agents (GBCAs) is an essential tool for clinical diagnosis and disease management. In order to better understand the issues associated with GBCA administration and gadolinium retention and deposition in the human brain, the chemical properties of GBCAs such as relative thermodynamic and kinetic stabilities and their likelihood of forming gadolinium deposits in vivo will be reviewed. The chemical form of gadolinium causing the hyperintensity is an open question. On the basis of estimates of total gadolinium concentration present, it is highly unlikely that the intact chelate is causing the T₁ hyperintensities observed in the human brain. Although it is possible that there is a water-soluble form of gadolinium that has high relaxitvity present, our experience indicates that the insoluble gadolinium-based agents/salts could have high relaxivities on the surface of the solid due to higher water access. This review assesses the safety of GBCAs from a chemical point of view based on their thermodynamic and kinetic properties, discusses how these properties influence in vivo behavior, and highlights some clinical implications regarding the development of future imaging agents. Full article

(This article belongs to the Special Issue Recent Advances on MRI Contrast Agents)

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