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An unexpectedly slow exchange rate has been observed for the coordinated water molecule of [Yb(AAZTA)(H 2 O)] - using 1 H-NMR and CEST-MRI studies. This made it possible for the first time to exploit the bound water molecule of a Ln III complex with carboxylic donor groups for CEST imaging. This result envisages the development of a new family of thermodynamically stable ParaCEST probes based on anionic chelates.

We report two novel macrocyclic ligands based on the 1,4-DO2AM platform (1,4-DO2AM = 2,2'-(1,4,7,10-tetraazacyclododecane-1,4-diyl)diacetamide) and containing two benzyl groups attached either to the nitrogen atoms of the macrocyclic unit (1,4-BzDO2AM) or to the amide pendant arms (1,4-DO2AMBz). The protonation constants of the ligands and the stability constants of their Mn 2+ complexes were determined using pH potentiometry. The introduction of benzyl groups results in a slight decrease of the stability constants of the Mn 2+ complexes and a slight increase of their acid-catalysed dissociation reactions. A detailed relaxometric characterisation of the complexes using nuclear magnetic dispersion relaxation (NMRD) and 17 O NMR studies indicated that the increase in molecular weight associated with the presence of benzyl groups results in a remarkable increase of proton relaxivities r 1p , which take values of 3.8, 3.5 and 2.5 mM -1 s -1 for [Mn(1,4-BzDO2AM)] 2+ , [Mn(1,4-DO2AMBz)] 2+ and [Mn(1,4-DO2AM)] 2+ (at 25 °C and 20 MHz). The [Mn(1,4-BzDO2AM)] 2+ and [Mn(1,4-DO2AMBz)] 2+ complexes form relatively strong adducts with Human Serum Albumin (HSA) with association constants of (3.9 ± 0.6) × 10 3 and (2.0 ± 0.3) × 10 3 M -1 , respectively. The interaction with the protein slows down the rotational tumbling of the complex in solution, which results in adducts endowed with remarkably high proton relaxivities (r 1p b = 18.5 ± 0.7 and 27.4 ± 1.4 mM -1 s -1 for [Mn(1,4-BzDO2AM)] 2+ and [Mn(1,4-DO2AMBz)] 2+ , respectively).

Indocyanine green was encapsulated inside the pores of pegylated amino-functionalized MCM-41 Mesoporous Silica Nanoparticles (ICG-MSNs). In addition to a greater stability and a decrease of toxicity, the photoacoustic effect of ICG-MSNs increases by nearly 400% compared to free ICG due to fluorescence quenching and high photothermal conversion of the encapsulated dyes. Upon i.v. administration in tumor-bearing mice, an overall photoacoustic enhancement of ca. 25% was measured in the tumor region.

Two amphiphilic mono- and dimeric GdAAZTA-like chelates composed of stable bis-aquo Gd(III) complexes (q=2) linked to one (for the monomer) or two dodecyl aliphatic chains (for the dimer) were synthesized. Both chelates showed high relaxivity when incorporated into the lipid bilayer of liposomes or after interaction with human serum albumin (HSA). The ditopic complex shows a significantly decreased internal motion relative to the monomeric complex, associated with an enhanced relaxivity (r1 ≈60 mm(-1)  s(-1) , at 30 MHz and 310 K). The presence of two metal-bound water molecules in fast exchange and the restricted rotational freedom make the relaxivity of this system the highest measured for paramagnetic liposomes., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Water exchange kinetics on [Ln(AAZTAPh-NO2)(H2O)q](-) (Ln = Gd(3+), Dy(3+), or Tm(3+)) were determined by (1)H nuclear magnetic resonance (NMR) measurements. The number of inner-sphere water molecules was found to change from two to one when going from Dy(3+) to Tm(3+). The calculated water exchange rate constants obtained by variable-temperature proton transverse relaxation rates are 3.9 × 10(6), 0.46 × 10(6), and 0.014 × 10(6) s(-1) at 298 K for Gd(3+), Dy(3+), and Tm(3+), respectively. Variable-pressure measurements were used to assess the water exchange mechanism. The results indicate an associative and dissociative interchange mechanism for Gd(3+) and Dy(3+) complexes with ΔV(⧧) values of -1.4 and 1.9 cm(3) mol(-1), respectively. An associative activation mode (Ia or A mechanism) was obtained for the Tm(3+) complex (ΔV(⧧) = -5.6 cm(3) mol(-1)). Moreover, [Dy(AAZTAPh-NO2)(H2O)2](-) with a very high transverse relaxivity value was found as a potential candidate for negative contrast agents for high-field imaging applications.

The 1 H and 17 O relaxometric behaviour in aqueous solution of GdF 3 nanoparticles (<5 nm) coated with citrate molecules (Gd-NPs) was investigated as a function of magnetic field strength and temperature in order to unravel the mechanisms underlying their magnetic interaction with water molecules.

The adsorption isotherms of methane in four micro- and mesoporous materials, based on the diamond structure with (poly)phenyl chains inserted in all the C-C bonds, have been simulated with Grand Canonical Monte Carlo technique. The pressure range was extended above 250 bar and the isotherms were computed at 298, 313, and 353 K, to explore the potentiality of these materials for automotive applications, increasing the capacity of high-pressure tanks or storing a comparable amount of gas at much lower pressure. The force field employed in the simulations was optimized to fit the correct behavior of the free gas in all the pressure range and to reproduce the methane-phenyl interactions computed at high quantum mechanical level (post Hartree-Fock). All the examined materials showed a high affinity for methane, ensuring a larger storage of gas than simple compression in all the conditions: two samples exceeded the target proposed by U.S. Department of Energy for methane storage in low-pressure fuel tanks (180 cm(3) (STP)/cm(3) at 35 bar and room temperature).

The investigation of new Mn(II)-based MRI/Molecular Imaging probes responsive to the enzyme tyrosinase for potential diagnostic applications is herein described. The expression of the enzyme tyrosinase, an oxidoreductase, is up-regulated in melanoma cancer cells. Three novel ligands (L(1), L(2) and L(3)) were designed as modified acyclic polyaminocarboxylate chelates by introducing an l-tyrosine residue in place of an aminoacetate unit. The corresponding Mn(II) complexes were fully characterised by (1)H NMR relaxometric techniques in aqueous media. The responsive activity towards the expression of tyrosinase was then assessed by monitoring the (1)H 1/T(1) relaxivity changes during incubation experiments in buffered solutions containing tyrosinase at different concentrations and in B16F10 melanoma cell homogenate. New insight on the mechanism of action of these systems was gained by measuring the magnetic field dependence of the relaxivity and ESR spectra of the incubated solutions. The systems developed showed responsive activity to tyrosinase with a relaxation enhancement spanning from 50% (MnL(1)) to 350% (MnL(3)) which augurs well for the development of diagnostic probes to detect melanoma cancer., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Functionalised MCM-41 mesoporous silica nanoparticles were used as carriers of Gd(III) complexes for the development of nanosized magnetic resonance imaging contrast agents. Three Gd(III) complexes based on the 1,4,7,10-tetraazacyclododecane scaffold (DOTA; monoamide-, DOTA- and DO3A-like complexes) with distinct structural and magnetic properties were anchored on the silica nanoparticles functionalised with NH(2) groups. The interaction between Gd(III) chelates and surface functional groups markedly influenced the relaxometric properties of the hybrid materials, and were deeply modified passing from ionic -NH(3)(+) to neutral amides. A complete study of the structural, textural and surface properties together with a full (1)H relaxometric characterisation of these hybrid materials before and after surface modification was carried out. Particularly for the anionic complex 2 attached to MCM-41, an impressive increase in relaxivity (r(1p)) was observed (from 20.3 to 37.8 mM(-1) s(-1), 86.2% enhancement at 20 MHz and 310 K), mainly due to a threefold faster water exchange rate after acetylation of the surface -NH(3)(+) ions. This high r(1p) value, coupled with the large molar amount of grafted 2 onto the silica nanoparticles gives rise to a value of relaxivity per particle of 29,500 mM(-1) s(-1), which possibly allows it to be used in molecular imaging procedures. Smaller changes were observed for the hybrid materials based on neutral 1 and 3 complexes. In fact, whereas 1 shows a weak interaction with the surface and acetylation induced only some decrease of the local rotation, complex 3 appears to be involved in a strong interaction with surface silanols. This results in the displacement of a coordinated water molecule and in a decrease of the accessibility of the solvent to the metal centre, which is unaffected by the modification of ammonium ions to neutral amides.

To design efficient targeting strategies in magnetic resonance (MR) molecular imaging applications, the formation of supramolecular adducts between (strept)avidin ((S)Av) and tribiotinylated Gd-DOTA-monoamide complexes (DOTA=1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) was explored. Two compounds based on the trivalent core of tris(2-aminoethyl)amine each containing three biotin molecules and one (L1) or three (L2) DOTA-monoamide (DOTAMA) ligands were synthesized. In these tribiotinylated derivatives the biotins are spaced far enough apart to allow the formation of the supramolecular adduct with the protein and to host the chelating units in between the (S)Av layers. Size exclusion HPLC analyses indicated complete formation of very high molecular weight polymers (>2 MDa) with (S)Av in solution. A (1)H NMR spectroscopy relaxometric study on the obtained polymeric adducts showed a marked increase of the relaxivity at 35-40 MHz as a consequence of the lengthening of the tumbling time due to the formation of Gd-chelates/(S)Av polymers. The most efficient Gd(3)L2/(S)Av polymeric system was used for a test in cell cultures. The target is represented by a neural cell adhesion molecule (NCAM), which is overexpressed in Kaposi's sarcoma cells and tumor endothelial cells (TEC) and that is efficiently recognized by a biotinylated tetrameric peptide (C3d-Bio). In vitro experiments showed that only cells incubated with both C3d-Bio and Gd(3)L2/SAv polymer were hyperintense with respect to the control. Relaxation rates of cell pellets incubated with Gd(3)L2/SAv alone were not significantly different from the untreated cells demonstrating the absence of a specific binding.

Two novel octadentate ligands have been synthesized by attaching two terminal iminodiacetic groups to either 1,4-diazepane (BCAED) or piperazine (BCAEP) as central scaffold. The introduction of the seven- or six-membered ring into the ligand backbone is expected to modify their overall flexibility and then to affect the stability of the corresponding lanthanide(III) complexes. In this work, thermodynamic stability data are determined for the formation of the complexes of BCAED and BCAEP with La(3+), Nd(3+), Eu(3+), Gd(3+), Ho(3+), and Lu(3+). The ligand BCAED shows a strong binding affinity for Lu(3+) (logK = 20.99), moderate for Gd(3+) (logK = 17.15) and rather weak for La(3+) (logK = 12.77). Thus, the variation of logK across the Ln series assumes the remarkable value of 8.22, the largest so far reported. This points to a predominant role of a suitable size match between the metal ion and the ligand cavity, determined by its structure and flexibility. The ligand BCAEP forms less stable complexes with lanthanide(III) cations although it retains a good selectivity (DeltalogK(La-Lu) = 5.66). The Gd(III) complexes have been investigated in aqueous solution by measuring their relaxivity as a function of pH, at 20 MHz and 25 degrees C. The results can be interpreted very well in terms of the species distribution curves calculated from the thermodynamic data and indicate that in these complexes Gd(3+) is octacoordinated, without any bound water molecule. This coordination geometry is maintained in the solid state as shown by the X-ray crystal structure of [Na(H(2)O)(2)][Gd(BCAED)] where the metal ion is at the center of a bicapped-trigonal prism. Finally, the (13)C NMR spectra (9.4 T, 25 degrees C) of the diamagnetic La(3+), Y(3+), and Lu(3+) complexes show that a pronounced stereochemical rigidity is associated with the thermodynamically more stable complexes.

Three new magnetic resonance imaging probes that target glutamine transporters have been synthesized. They consist of a Gd-DOTA-monoamide moiety (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) linked through a six carbon atom chain to a vector represented by a glutamine residue bound through alpha-carboxylic, gamma-carboxamidic, or alpha-amino functionalities. Their uptake by HTC (rat hepatocarcinoma) and healthy rat hepatocytes has shown that the system containing the glutamine vector bound through the alpha-carboxylic group displays a markedly higher affinity for tumor cells. The observed behavior is rationalized in terms of the exploitation of an additional glutamine transporter active in hepatic tumor cells.