Comprehensive Investigation of [Fe(EDTA)]--Functionalized Derivatives and their Supramolecular Adducts with Human Serum Albumin.

In recent years, the coordination chemistry of high-spin Fe(III) complexes has increasingly attracted interest due to their potential as effective alternatives to Gd(III)-based MRI contrast agents. This paper discusses the results from our study on Fe(III) complexes with two EDTA derivatives, each modified with either one (EDTA-BOM) or two (EDTA-BOM2) benzyloxymethylene (BOM) groups on the acetic arm(s). These pendant hydrophobic groups enable the complexes to form noncovalent adducts with human serum albumin (HSA), leading to an observed increase in relaxivity due to the reduction in molecular tumbling. Our research involved detailed relaxometric measurements and analyses of both 1H and 17O NMR data at varying temperatures and magnetic field strengths, which is conducted with and without the presence of a protein. A significant finding of this study is the effect of electronic relaxation time on the effectiveness of [Fe(EDTA-BOM)(H2O)]- and [Fe(EDTA-BOM2)(H2O)]- as diagnostic MRI probes. By integrating these relaxometric results with comprehensive thermodynamic, kinetic, and electrochemical data, we have thoroughly characterized how structural modifications to the EDTA base ligand influence the properties of the complexes.

Chiral Pyclen-Based Heptadentate Chelates as Highly Stable MRI Contrast Agents.

In recent years, pyclen-based complexes have attracted a great deal of interest as magnetic resonance imaging (MRI) contrast agents (CAs) and luminescent materials, as well as radiopharmaceuticals. Remarkably, gadopiclenol, a Gd(III) bishydrated complex featuring a pyclen-based heptadentate ligand, received approval as a novel contrast agent for clinical MRI application in 2022. To maximize stability and efficiency, two novel chiral pyclen-based chelators and their complexes were developed in this study. Gd-X-PCTA-2 showed significant enhancements in both thermodynamic and kinetic stabilities compared to those of the achiral parent derivative Gd-PCTA. 1H NMRD profiles reveal that both chiral gadolinium complexes (Gd-X-PCTA-1 and Gd-X-PCTA-2) have a higher relaxivity than Gd-PCTA, while variable-temperature 17O NMR studies show that the two inner-sphere water molecules have distinct residence times τMa and τMb. Furthermore, in vivo imaging demonstrates that Gd-X-PCTA-2 enhances the signal in the heart and kidneys of the mice, and the chiral Gd complexes exhibit the ability to distinguish between tumors and normal tissues in a 4T1 mouse model more efficiently than that of the clinical agent gadobutrol. Biodistribution studies show that Gd-PCTA and Gd-X-PCTA-2 are primarily cleared by a renal pathway, with 24 h residues of Gd-X-PCTA-2 in the liver and kidney being lower than those of Gd-PCTA.

Silica-based monoliths functionalized with DTPA for the removal of transition and lanthanide ions from aqueous solutions.

Transition and rare earth metals serve as indispensable raw materials across a broad spectrum of technological applications. However, their utilization is frequently linked to substantial waste production. Consequently, the recycling and recovery of these metals from end-of-life products or metal-contaminated aqueous environments hold significant importance within the framework of a circular economy. In our investigation, we employed synthetic mesoporous silica monoliths, synthesized via the sol-gel method and functionalized with chelating groups, for the efficient recovery of metal ions from aqueous matrices. The monoliths were characterized using a multi-technique approach and were tested in the recovery of paramagnetic Gd3+, Cu2+ and Co2+ ions from aqueous solutions, using 1H-NMR relaxometry to evaluate their uptake performance in real time and under simple conditions. Detailed information on the kinetics of the capture process was also highlighted. Finally, the possibility to regenerate the solid sorbents was evaluated.

α-Aryl substituted GdDOTA derivatives, the perfect contrast agents for MRI?

Enhancing the performance of Gd3+ chelates as relaxation agents for MRI has the potential to lower doses, improving safety and mitigating the environmental impact on our surface waters. More than three decades of research into manipulating the properties of Gd3+ have failed to develop a chelate that simultaneously optimizes all relevant parameters and affords maximal relaxivity. Introducing aryl substituents into the α-position of the pendant arms of a GdDOTA chelate affords chelates that, for the first time, simultaneously optimize all physico-chemical properties. Slowing tumbling by binding to human serum albumin affords a relaxivity of 110 ± 5 mM-1 s-1, close to the maximum possible. As discrete chelates, these α-aryl substituted GdDOTA chelates exhibit relaxivities that are 2-3 times higher than those of currently used agents, even at the higher fields (1.5 & 3.0 T) used in modern clinical MRI.

EHDTA: a green approach to efficient Ln3+-chelators.

The rich coordination chemistry of lanthanoid ions (Ln3+) is currently exploited in a vast and continuously expanding array of applications. Chelating agents are central in the development of Ln3+-complexes and in tuning their physical and chemical properties. Most chelators for Ln3+-complexation are derived from the macrocyclic DOTA or from linear DTPA platforms, both of which arise from fossil-based starting materials. Herein, we report a green and efficient approach to a chelating agent (EHDTA), derived from cheap and largely available furfurylamine. The oxygenated heterocycle of the latter is converted to a stereochemically defined and rigid heptadentate chelator, which shows good affinity towards Ln3+ ions. A combination of NMR, relaxometric, potentiometric and spectrophotometric techniques allows us to shed light on the interesting coordination chemistry of Ln3+-EHDTA complexes, unveiling a promising ligand for the chelation of this important family of metal ions.

Endeavor toward Redox-Responsive Transition Metal Contrast Agents Based on the Cross-Bridge Cyclam Platform.

We present the synthesis and characterization of a series of Mn(III), Co(III), and Ni(II) complexes with cross-bridge cyclam derivatives (CB-cyclam = 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) containing acetamide or acetic acid pendant arms. The X-ray structures of [Ni(CB-TE2AM)]Cl2·2H2O and [Mn(CB-TE1AM)(OH)](PF6)2 evidence the octahedral coordination of the ligands around the Ni(II) and Mn(III) metal ions, with a terminal hydroxide ligand being coordinated to Mn(III). Cyclic voltammetry studies on solutions of the [Mn(CB-TE1AM)(OH)]2+ and [Mn(CB-TE1A)(OH)]+ complexes (0.15 M NaCl) show an intricate redox behavior with waves due to the MnIII/MnIV and MnII/MnIII pairs. The Co(III) and Ni(II) complexes with CB-TE2A and CB-TE2AM show quasi-reversible features due to the CoIII/CoII or NiII/NiIII pairs. The [Co(CB-TE2AM)]3+ complex is readily reduced by dithionite in aqueous solution, as evidenced by 1H NMR studies, but does not react with ascorbate. The [Mn(CB-TE1A)(OH)]+ complex is however reduced very quickly by ascorbate following a simple kinetic scheme (k0 = k1[AH-], where [AH-] is the ascorbate concentration and k1 = 628 ± 7 M-1 s-1). The reduction of the Mn(III) complex to Mn(II) by ascorbate provokes complex dissociation, as demonstrated by 1H nuclear magnetic relaxation dispersion studies. The [Ni(CB-TE2AM)]2+ complex shows significant chemical exchange saturation transfer effects upon saturation of the amide proton signals at 71 and 3 ppm with respect to the bulk water signal.

Effect of hydration equilibria on the relaxometric properties of Gd(III) complexes: new insights into old systems.

We present a detailed relaxometric and computational investigation of three Gd(III) complexes that exist in solution as an equilibrium of two species with a different number of coordinated water molecules: [Gd(H2O)q]3+ (q = 8, 9), [Gd(EDTA)(H2O)q]- and [Gd(CDTA)(H2O)q]- (q = 2, 3). 1H nuclear magnetic relaxation dispersion (NMRD) data were recorded from aqueous solutions of these complexes using a wide Larmor frequency range (0.01-500 MHz). These data were complemented with 17O transverse relaxation rates and chemical shifts recorded at different temperatures. The simultaneous fit of the NMRD and 17O NMR data was guided by computational studies performed at the DFT and CASSCF/NEVPT2 levels, which provided information on Gd⋯H distances, 17O hyperfine coupling constants and the zero-field splitting (ZFS) energy, which affects electronic relaxation. The hydration equilibrium did not have a very important effect in the fits of the experimental data for [Gd(H2O)q]3+ and [Gd(CDTA)(H2O)q]-, as the hydration equilibrium is largely shifted to the species with the lowest hydration number (q = 8 and 2, respectively). The quality of the analysis improves however considerably for [Gd(EDTA)(H2O)q]- upon considering the effect of the hydration equilibrium. As a result, this study provides for the first time an analysis of the relaxation properties of this important model system, as well as accurate parameters for [Gd(H2O)q]3+ and [Gd(CDTA)(H2O)q]-.

Novel Nanogels Loaded with Mn(II) Chelates as Effective and Biologically Stable MRI Probes.

Here it is described nanogels (NG) based on a chitosan matrix, which are covalently stabilized by a bisamide derivative of Mn-t-CDTA (t-CDTA = trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid). the Mn(II) complex acts both as a contrast medium and as a cross-linking agent. These nanogels are proposed as an alternative to the less stable paramagnetic nanogels obtained by electrostatic interactions between the polymeric matrix and paramagnetic Gd(III) chelates. The present novel nanogels show: i) relaxivity values seven times higher than that of typical monohydrated Mn(II) chelates at the clinical fields, thanks to the combination of a restricted mobility of the complex with a fast exchange of the metal-bound water molecule; ii) high stability of the formulation over time at pH 5 and under physiological conditions, thus excluding metal leaking or particles aggregation; iii) good extravasation and accumulation, with a maximum contrast achieved at 24 h post-injection in mice bearing subcutaneous breast cancer tumor; iv) high T1 contrast (1 T) in the tumor 24 h post-injection. These improved properties pave the way for the use of these paramagnetic nanogels as promising magnetic resonance imaging (MRI) probes for in vitro and in vivo preclinical applications.

Characterization of the Fe(III)-Tiron System in Solution through an Integrated Approach Combining NMR Relaxometric, Thermodynamic, Kinetic, and Computational Data.

The Fe(III)-Tiron system (Tiron = 4,5-dihydroxy-1,3-benzenedisulfonate) was investigated using a combination of 1H and 17O NMR relaxometric studies at variable field and temperature and theoretical calculations at the DFT and NEVPT2 levels. These studies require a detailed knowledge of the speciation in aqueous solution at different pH values. This was achieved using potentiometric and spectrophotometric titrations, which afforded the thermodynamic equilibrium constants characterizing the Fe(III)-Tiron system. A careful control of the pH of the solution and the metal-to-ligand stoichiometric ratio allowed the relaxometric characterization of [Fe(Tiron)3]9-, [Fe(Tiron)2(H2O)2]5-, and [Fe(Tiron)(H2O)4]- complexes. The 1H nuclear magnetic relaxation dispersion (NMRD) profiles of [Fe(Tiron)3]9- and [Fe(Tiron)2(H2O)2]5- complexes evidence a significant second-sphere contribution to relaxivity. A complementary 17O NMR study provided access to the exchange rates of the coordinated water molecules in [Fe(Tiron)2(H2O)2]5- and [Fe(Tiron)(H2O)4]- complexes. Analyses of the NMRD profiles and NEVPT2 calculations indicate that electronic relaxation is significantly affected by the geometry of the Fe3+ coordination environment. Dissociation kinetic studies indicated that the [Fe(Tiron)3]9- complex is relatively inert due to the slow release of one of the Tiron ligands, while the [Fe(Tiron)2(H2O)2]5- complex is considerably more labile.

High spin Fe(III)-doped nanostructures as T1 MR imaging probes.

Magnetic Resonance Imaging (MRI) T1 contrast agents based on Fe(III) as an alternative to Gd-based compounds have been under intense scrutiny in the last 6-8 years and a number of nanostructures have been designed and proposed for in vivo diagnostic and theranostic applications. Excluding the large family of superparamagnetic iron oxides widely used as T2 -MR imaging agents that will not be covered by this review, a considerable number and type of nanoparticles (NPs) have been employed, ranging from amphiphilic polymer-based NPs, NPs containing polyphenolic binding units such as melanin-like or polycatechols, mixed metals such as Fe/Gd or Fe/Au NPs and perfluorocarbon nanoemulsions. Iron(III) exhibits several favorable magnetic properties, high biocompatibility and improved toxicity profile that place it as the paramagnetic ion of choice for the next generation of nanosized MRI and theranostic contrast agents. An analysis of the examples reported in the last decade will show the opportunities for relaxivity and MR-contrast enhancement optimization that could bring Fe(III)-doped NPs to really compete with Gd(III)-based nanosystems. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Peptide-Based Hydrogels and Nanogels Containing Gd(III) Complexes as T1 Relaxation Agents.

New peptide-based hydrogels incorporating Gd(III) chelates with different hydration states, molecular structures and overall negative charges ([Gd(BOPTA)]2−), [Gd(DTPA)]2−, and ([Gd(AAZTA)]−) were prepared and characterized. N-terminal Fmoc- or acetyl-derivatized hexapeptides (K1, K2 and K3) containing five aliphatic amino acids (differently ordered Gly, Ala, Val, Leu and Ile) and a charged lysine at the amidated C-terminal were used for the formation of the hydrogels. Particular attention was paid to the investigation of the morphological and rheological properties of the nanoparticles, in addition to the assessment of the ability (relaxivity) of the confined complexes to accelerate the longitudinal relaxation rate of the water protons localized in the polymeric network. The relaxivity values at high magnetic fields (>0.5 T) of the paramagnetic hydrogels appear to be more than five times higher than those of isolated chelates in an aqueous solution, reaching a value of 25 mmol−1 s−1 for Fmoc-K2+[Gd(BOPTA)]2− at 0.5 T and 310 K. Furthermore, an interesting trend of decrease of relaxivity with increasing the degree of rigidity of the hydrogel was observed. The type of interactions between the various complexes and the polymeric network also plays a key role in influencing the relaxivity values of the final materials. Nanogels were also obtained from the submicronization of the hydrogel containing [Gd(BOPTA)]2− chelate. Circular dichroism, dynamic light scattering and relaxometric investigations on these nanoparticles revealed the formation of nanogels endowed with higher relaxivities (r1 = 41 mM−1 s−1 at 0.5 T MHz and 310 K) than the corresponding hydrogels.

Derivatives of GdAAZTA Conjugated to Amino Acids: A Multinuclear and Multifrequency NMR Study.

The GdAAZTA (AAZTA = 6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid) complex represents a platform of great interest for the design of innovative MRI probes due to its remarkable magnetic properties, thermodynamic stability, kinetic inertness, and high chemical versatility. Here, we detail the synthesis and characterization of new derivatives functionalized with four amino acids with different molecular weights and charges: l-serine, l-cysteine, l-lysine, and l-glutamic acid. The main reason for conjugating these moieties to the ligand AAZTA is the in-depth study of the chemical properties in aqueous solution of model compounds that mimic complex structures based on polypeptide fragments used in molecular imaging applications. The analysis of the 1H NMR spectra of the corresponding Eu(III)-complexes indicates the presence of a single isomeric species in solution, and measurements of the luminescence lifetimes show that functionalization with amino acid residues maintains the hydration state of the parent complex unaltered (q = 2). The relaxometric properties of the Gd(III) chelates were analyzed by multinuclear and multifrequency NMR techniques to evaluate the molecular parameters that determine their performance as MRI probes. The relaxivity values of all of the novel chelates are higher than that of GdAAZTA over the entire range of applied magnetic fields because of the slower rotational dynamics. Data obtained in reconstituted human serum indicate the occurrence of weak interactions with the proteins, which result in larger relaxivity values at the typical imaging fields. Finally, all of the new complexes are characterized by excellent chemical stability in biological matrices over time, by the absence of transmetallation processes, or the formation of ternary complexes with oxyanions of biological relevance. In particular, the kinetic stability of the new complexes, measured by monitoring the release of Gd3+ in the presence of a large excess of Zn2+, is ca. two orders of magnitude higher than that of the clinical MRI contrast agent GdDTPA.

High Relaxivity with No Coordinated Waters: A Seemingly Paradoxical Behavior of [Gd(DOTP)]5- Embedded in Nanogels.

Nanogels (NGs) obtained by electrostatic interactions between chitosan and hyaluronic acid and comprising paramagnetic Gd chelates are gaining increasing attention for their potential application in magnetic resonance bioimaging. Herein, the macrocyclic complexes [Gd(DOTP)]5-, lacking metal-bound water molecules (q = 0), were confined or used as a cross-linker in this type of NG. Unlike the typical behavior of Gd complexes with q = 0, a remarkable relaxivity value of 78.0 mM-1 s-1 was measured at 20 MHz and 298 K, nearly 20 times greater than that found for the free complex. A careful analysis of the relaxation data emphasizes the fundamental role of second sphere water molecules with strong and long-lived hydrogen bonding interactions with the complex. Finally, PEGylated derivatives of nanoparticles were used for the first in vivo magnetic resonance imaging study of this type of NG, revealing a fast renal excretion of paramagnetic complexes after their release from the NGs.

Surprising Complexity of the [Gd(AAZTA)(H2O)2]- Chelate Revealed by NMR in the Frequency and Time Domains.

Typically, Ln(III) complexes are isostructural along the series, which enables studying one particular metal chelate to derive the structural features of the others. This is not the case for [Ln(AAZTA)(H2O)x]- (x = 1, 2) systems, where structural variations along the series cause changes in the hydration number of the different metal complexes, and in particular the loss of one of the two metal-coordinated water molecules between Ho and Er. Herein, we present a 1H field-cycling relaxometry and 17O NMR study that enables accessing the different exchange dynamics processes involving the two water molecules bound to the metal center in the [Gd(AAZTA)(H2O)2]- complex. The resulting picture shows one Gd-bound water molecule with an exchange rate ∼6 times faster than that of the other, due to a longer metal-water distance, in accordance with density functional theory (DFT) calculations. The substitution of the more labile water molecule with a fluoride anion in a diamagnetic-isostructural analogue of the Gd-complex, [Y(AAZTA)(H2O)2]-, allows us to follow the chemical exchange process by high-resolution NMR and to describe its thermodynamic behavior. Taken together, the variety of tools offered by NMR (including high-resolution 1H, 19F NMR as a function of temperature, 1H longitudinal relaxation rates vs B0, and 17O transverse relaxation rates vs T) provides a complete description of the structure and exchange dynamics of these Ln-complexes along the series.

Rigid versions of PDTA4- incorporating a 1,3-diaminocyclobutyl spacer for Mn2+ complexation: stability, water exchange dynamics and relaxivity.

Rigid derivatives of the acyclic ligand PDTA4- (H4PDTA = propylenediamine-N,N,N',N'-tetraacetic acid) were prepared by functionalization of a 1,3-diaminocyclobutyl spacer. The new ligands contain either four acetate groups attached to the central scaffold (H4L1) or incorporate pyridyl (H2L2) or propylamide (H2L3) units replacing two of the carboxylate groups. The ligand protonation constants and the stability constants of their Mn2+ complexes were determined using potentiometric and spectrophotometric titrations. The stability of the [Mn(L1)]2- complex was found to be significantly higher than that of the flexible [Mn(PDTA)]2- derivative (log KMnL = 10.78 and 10.01, respectively). A detailed study of the 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles and 17O NMR measurements evidence that the [Mn(L1)]2- and [Mn(L2)] complexes display a hydration equilibrium in solution involving a seven-coordinate species with an inner-sphere water molecule and a six-coordinate species that lacks a coordinated water molecule. As a result the 1H relaxivities of these complexes are somewhat lower than that of [Mn(EDTA)]2- and related systems. The introduction of propylamide groups in [Mn(L3)] shifts the hydration equilibrium to the seven-coordinate species, which results in a 1H relaxivity (r1p = 3.7 mM-1 s-1 at 22 MHz and 25 °C) exceeding that of [Mn(EDTA)]2- (r1p = 3.3 mM-1 s-1 at 22 MHz and 25 °C). The parameters that control the relaxivities in this family of complexes were determined by simultaneous fitting of the experimental 1H NMRD and 17O NMR data (transverse relaxation rates and chemical shifts), with the aid of computational studies performed at the DFT and CASSCF/NEVPT2 levels. These studies provide detailed insight of the parameters that control the efficiency of these relaxation agents at the molecular level.

Understanding the Effect of the Electron Spin Relaxation on the Relaxivities of Mn(II) Complexes with Triazacyclononane Derivatives.

Investigating the relaxation of water 1H nuclei induced by paramagnetic Mn(II) complexes is important to understand the mechanisms that control the efficiency of contrast agents used in diagnostic magnetic resonance imaging (MRI). Herein, a series of potentially hexadentate triazacyclononane (TACN) derivatives containing different pendant arms were designed to explore the relaxation of the electron spin in the corresponding Mn(II) complexes by using a combination of 1H NMR relaxometry and theoretical calculations. These ligands include 1,4,7-triazacyclononane-1,4,7-triacetic acid (H3NOTA) and three derivatives in which an acetate group is replaced by sulfonamide (H3NO2ASAm), amide (H2NO2AM), or pyridyl (H2NO2APy) pendants. The analogue of H3NOTA containing three propionate pendant arms (H3NOTPrA) was also investigated. The X-ray structure of the derivative containing two acetate groups and a sulfonamide pendant arm [Mn(NO2ASAm)]- evidenced six-coordination of the ligand to the metal ion, with the coordination polyhedron being close to a trigonal prism. The relaxivities of all complexes at 20 MHz and 25 °C (1.1-1.3 mM-1 s-1) are typical of systems that lack water molecules coordinated to the metal ion. The nuclear magnetic relaxation profiles evidence significant differences in the relaxivities of the complexes at low fields (<1 MHz), which are associated with different spin relaxation rates. The zero field splitting (ZFS) parameters calculated by using DFT and CASSCF methods show that electronic relaxation is relatively insensitive to the nature of the donor atoms. However, the twist angle of the two tripodal faces that delineate the coordination polyhedron, defined by the N atoms of the TACN unit (lower face) and the donor atoms of the pendant arms (upper face), has an important effect in the ZFS parameters. A twist angle close to the ideal value for an octahedral coordination (60°), such as that in [Mn(NOTPrA)]-, leads to a small ZFS energy, whereas this value increases as the coordination polyhedron approaches to a trigonal prism.

Mn(II)-Conjugated silica nanoparticles as potential MRI probes.

Novel Mn(II)-based nanoprobes were rationally designed as high contrast enhancing agents for magnetic resonance imaging (MRI) and obtained by anchoring a Mn(II)-CDTA derivative to the surface of organo-modified silica nanoparticles (SiNPs). Large payloads of paramagnetic metal-chelates have been immobilized on biocompatible SiNPs with spherical shape and narrow size distribution of 80-90 nm, resulting in a relaxivity gain of 250% at clinical fields (0.5 T) as compared to the free chelate. Such substantial efficacy enhancement of the nanoprobes is mainly attributed to the restriction of the rotational dynamics of the conjugated complex, as revealed by comprehensive 1H-NMR relaxometric investigations. The paramagnetic nanospheres exhibit good colloidal stability over time in biological matrices, allowing for MRI applications. High image contrast was found in T1w-MRI images collected at 1 T on phantoms containing relatively small amounts of contrast agent (CA), for which low cellular toxicity was observed on three different cell lines. Preliminary in vivo studies on healthy mice demonstrated the efficiency of the novel Mn-based silica nanoparticle as T1w-MRI probes, resulting in significant contrast enhancement in the liver. These findings demonstrate that these novel Mn-SiNPs are high efficacy CAs suitable for preclinical MRI applications.

Defining the conditions for the development of the emerging class of FeIII-based MRI contrast agents.

Fe(iii) complexes are attracting growing interest in chemists developing diagnostic probes for Magnetic Resonance Imaging because they leverage on an endogenous metal and show superior stability. However, in this case a detailed understanding of the relationship between the chemical structure of the complexes, their magnetic, thermodynamic, kinetic and redox properties and the molecular parameters governing the efficacy (relaxivity) is still far from being available. We have carried out an integrated 1H and 17O NMR relaxometric study as a function of temperature and magnetic field, on the aqua ion and three complexes chosen as reference models, together with theoretical calculations, to obtain accurate values of the parameters that control their relaxivity. Moreover, thermodynamic stability and dissociation kinetics of the Fe(iii) chelates, measured in association with the ascorbate reduction behaviour, highlight their role and mutual influence in achieving the stability required for use in vivo.

Rigid and Compact Binuclear Bis-hydrated Gd-complexes as High Relaxivity MRI Agents.

The first binuclear Gd-complex of the 12-membered pyridine-based polyaminocarboxylate macrocyclic ligand PCTA was synthesized by C-C connection of the pyridine units through two different synthetic procedures. A dimeric AAZTA-ligand was also synthesized with the aim to compare the relaxometric results or the two ditopic Gd-complexes. Thus, the 1 H relaxometric study on [Gd2 PCTA2 (H2 O)4 ] and on [Gd2 AAZTA2 (H2 O)4 ]2- highlighted the remarkable rigidity and compactness of the two binuclear complexes, which results in molar relaxivities (per Gd), at 1.5 T and 298 K of ca. 12-12.6 mM-1 s-1 with an increase of ca. 80 % at 1.5 T and 298 K (+70 % at 310 K) with respect to the corresponding mononuclear complexes.

A Single-Pot Template Reaction Towards a Manganese-Based T1 Contrast Agent.

Manganese-based contrast agents (MnCAs) have emerged as suitable alternatives to gadolinium-based contrast agents (GdCAs). However, due to their kinetic lability and laborious synthetic procedures, only a few MnCAs have found clinical MRI application. In this work, we have employed a highly innovative single-pot template synthetic strategy to develop a MnCA, MnLMe , and studied the most important physicochemical properties in vitro. MnLMe displays optimized r1 relaxivities at both medium (20 and 64 MHz) and high magnetic fields (300 and 400 MHz) and an enhanced r1b =21.1 mM-1 s-1 (20 MHz, 298 K, pH 7.4) upon binding to BSA (Ka =4.2×103  M-1 ). In vivo studies show that MnLMe is cleared intact into the bladder through renal excretion and has a prolonged blood half-life compared to the commercial GdCA Magnevist. MnLMe shows great promise as a novel MRI contrast agent.