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Mauro Botta

Publications and source records attributed to Mauro Botta.

At least 37 records · Page 2Linked to original sources
PubMed2004

Novel gadolinium(III) polyaminocarboxylate macrocyclic complexes as potential magnetic resonance imaging contrast agents.

Two novel Gd(III) complexes with functionalised polyaminocarboxylate macrocycles, 1,4,7-tris(carboxymethyl)-9,24-dioxo-14,19-dioxa-1,4,7,10,23- pentaazacyclododecane (L(1)) and 1,4,7-tris(carboxymethyl)-9,25-dioxo-14,17,20-trioxa-1,4,7,10,23- pentaazacyclotridecane (L(2)), were prepared in good yield. Their potential use as magnetic resonance imaging (MRI) contrast agents (CAs) was evaluated by investigating their relaxation behaviour as a function of pH, temperature and magnetic field strength. The 1/T(1) proton relaxivities at 20 MHz and 25 degrees C of GdL(1) (5.87 mM(-1) s(-1)) and GdL(2) (6.14 mM(-1) s(-1)) were found to be significantly higher than the clinically used Gd 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd(DOTA)(-)) and Gd diethylenetriaminepentaethanoic acid (Gd(DTPA)(2-)). The complexes possess one water molecule in the inner coordination sphere whose mean residence lifetime was estimated to be 1.1 and 1.5 micros at 25 degrees C by variable temperature (VT) (17)O NMR spectroscopy.

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PubMed2003

A highly stable gadolinium complex with a fast, associative mechanism of water exchange.

The stability and water exchange dynamics of gadolinium (GdIII) complexes are critical characteristics that determine their effectiveness as contrast agents for magnetic resonance imaging (MRI). A new heteropodal GdIII chelate, [Gd-TREN-bis(6-Me-HOPO)-(TAM-TRI)(H2O)2] (Gd-2), is presented which is based on a hydroxypyridinate (HOPO)-terephthalamide (TAM) ligand design. Thermodynamic equilibrium constants for the acid-base properties and the GdIII complexation strength of TREN-bis(6-Me-HOPO)-(TAM-TRI) (2) were measured by potentiometric and spectrophotometric titration techniques, respectively. The pGd of 2 is 20.6 (pH 7.4, 25 degrees C, I = 0.1 M), indicating that Gd-2 is of more than sufficient thermodynamic stability for in vivo MRI applications. The water exchange rate of Gd-2 (kex = 5.3(+/-0.6) x 107 s-1) was determined by variable temperature 17O NMR and is in the fast exchange regime - ideal for MRI. Variable pressure 17O NMR was used to determine the volume of activation (DeltaV) of Gd-2. DeltaV for Gd-2 is -5 cm3 mol-1, indicative of an interchange associative (Ia) water exchange mechanism. The results reported herein are important as they provide insight into the factors influencing high stability and fast water exchange in the HOPO series of complexes, potentially future clinical contrast agents.

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PubMed2003

Enantioselective recognition between chiral alpha-hydroxy-carboxylates and macrocyclic heptadentate lanthanide(III) chelates.

Three novel heptacoordinated Ln(III) complexes (Ln = Gd and Yb) have been synthesized and investigated by (1)H NMR spectroscopy. These complexes contain two stereogenic centers, one associated with a deltadeltadeltadelta or lambdalambdalambdalambda conformation of the ethylenediamine moieties in the tetraazamacrocycle and the latter arises from the orientation (Delta or Lambda) of the coordinating arms. Evidence has been gained for the occurrence of a fast exchange between all the possible conformers. Upon addition of several (S)-alpha-hydroxy-carboxylate substrates, the formation of stable ternary adducts has been obtained. Their (1)H NMR spectra are consistent with the presence of two diastereoisomers differing in the conformation adopted by the macrocyclic ligand wrapping the lanthanide(III) ion. The interaction leading to the formation of the ternary complexes is enantioselective depending on the hydrophilicity of the alpha-hydroxy-carboxylate.

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PubMed2003

Ternary complexes between cationic GdIII chelates and anionic metabolites in aqueous solution: an NMR relaxometric study.

The (1)H and (17)O NMR relaxometric properties of two cationic complexes formed by Gd(III) with a macrocyclic heptadentate triamide ligand, L(1), and its Nmethylated analogue, L(2), have been investigated in aqueous media as a function of pH, temperature and magnetic field strength. The complexes possess two water molecules in their inner coordination sphere for which the rate of exchange has been found to be sensibly faster for the Nmethylated derivative and explained in terms of electronic effects (decrease of the charge density at the metal center) and perturbation of the network of hydrogen-bonded water molecules in the outer hydration sphere. The proton relaxivity shows a marked dependence from pH and decreases of about six units in the pH range 6.5 to 9.0. This has been accounted for by the displacement of the two water molecules by dissolved carbonate which acts as a chelating anion. The formation of ternary complexes with lactate, malonate, citrate, acetate, fluoride and hydrogenphosphate has been monitored by (1)H NMR relaxometric titrations at 20 MHz and pH 6.3 and the value of the affinity constant, K, and of the relaxivity of the adducts could be obtained. Lactate, malonate and citrate interact strongly with the complexes (log K > or =3.7) and coordinate in a bidendate mode by displacing both water molecules. Larger affinity constants have been measured for GdL(2). Acetate, fluoride and hydrogenphosphate form monoaqua ternary complexes which were investigated in detail with regard to their relaxometric properties. The NMR dispersion (NMRD) profiles indicate a large contribution to the relaxivity of the adducts from water molecules belonging to the second hydration shell of the complexes and hydrogen-bonded to the anion. A VT (17)O NMR study has shown a marked increase of the rate of water exchange upon binding which is explained by coordination of the anion in an equatorial site, thus leaving the water molecule in an apical position, more accessible for interactions with the solvent molecules of the second hydration shell which facilitate the exchange process.

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PubMed2003

The effect of ligand scaffold size on the stability of tripodal hydroxypyridonate gadolinium complexes.

The variation of the size of the capping scaffold which connects the hydroxypyridonate (HOPO) binding units in a series of tripodal chelators for gadolinium (Gd) complexes has been investigated. A new analogue of TREN-1-Me-3,2-HOPO (1) (TREN = tri(ethylamine)amine) was synthesized: TREN-Gly-1-Me-3,2-HOPO (2) features a glycine spacer between the TREN cap and HOPO binding unit. TRPN-1-Me-3,2-HOPO (3) has a propylene-bridged cap, as compared to the ethylene bridges within the TREN cap of the parent complex. Thermodynamic equilibrium constants for the acid-base properties of 2 and the Gd(3+) complexation strength of 2 and 3 were measured and are compared with that of the parent ligand. The most basic ligand is 2 while 3 is the most acidic. Both 2 and 3 form Gd(3+) complexes of similar stability (pGd = 16.7 and 15.6, respectively) and are less stable than the parent complex Gd-1 (pGd = 19.2). Two of the three complexes are more stable than the bis(methylamide)diethylenetriamine pentaacetate complex Gd(DTPA-BMA) (pGd = 15.7) while the other is of comparable stability. Enlargement of the ligand scaffold decreases the stability of the Gd(3+) complexes and indicates that the TREN scaffold is superior to the TRPN and TREN-Gly scaffolds. The proton relaxivity of Gd-2 is 6.6 mM(-)(1) s(-)(1) (20 MHz, 25 degrees C, pH 7.3), somewhat lower than the parent Gd-1 but higher than that of the MRI contrast agents in clinical practice. The pH-independent relaxivity of Gd-2 is uncharacteristic of this family of complexes and is discussed.

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PubMed2002

Structural, luminescence, and NMR studies of the reversible binding of acetate, lactate, citrate, and selected amino acids to chiral diaqua ytterbium, gadolinium, and europium complexes.

The nature of the ternary complexes formed in aqueous media at ambient pH on reversible binding of acetate, lactate, citrate, and selected amino acids and peptides to chiral diaqua europium, gadolinium, or ytterbium cationic complexes has been examined. Crystal structures of the chelated ytterbium acetate and lactate complexes have been defined in which the carboxylate oxygen occupies an "equatorial" site in the nine-coordinate adduct. The zwitterionic adduct of the citrate anion with [EuL1] was similar to the chelated lactate structure, with a 5-ring chelate involving the apical 3-hydroxy group and the alpha-carboxylate. Analysis of Eu and Yb emission CD spectra and lifetimes (H2O and D2O) for each ternary complex, in conjunction with 1H NMR analyses of Eu/Yb systems and 17O NMR and relaxometric studies of the Gd analogues, suggests that carbonate, oxalate, and malonate each form a chelated (q = 0) square-antiprismatic complex in which the dipolar NMR paramagnetic shift (Yb, Eu) and the emission circular polarization (gem for Eu) are primarily determined by the polarizability of the axial ligand. The ternary complexes with hydrogen phosphate, with fluoride, and with Phe, His, and Ser at pH 6 are suggested to be monoaqua systems with Eu/Gd with an apical bound water molecule. However, for the ternary complexes of simple amino acids with [YbL1]3+, the enhanced charge demand favors a chelate structure with the amine N in an apical position. Crystal structures of the Gly and Ser adducts confirm this. In peptides and proteins (e.g. albumin) containing Glu or Asp residues, the more basic side chain carboxylate may chelate to the Ln ion, displacing both waters.

Acetates↗
PubMed2002

Highly luminescent Eu(3+) and Tb(3+) macrocyclic complexes bearing an appended phenanthroline chromophore.

A two-component ligand system (1) containing 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) as the hosting unit for the lanthanide cations and an appended asymmetrically functionalized 1,10-phenanthroline (phen) as the chromophore was synthesized. The 1:1 complexes with Eu(3+), Gd(3+), Tb(3+), and Yb(3+) have been prepared and studied in aqueous solution. For Gd.1, a relaxivity value of 2.4 mM(-1) s(-1) has been measured at 20 MHz and 25 degrees C, which indicates that there are no water molecules in the first coordination sphere of the metal ion. The analysis of high resolution (1)H NMR spectra of Yb.1 supports this view and suggests the direct involvement of the phen moiety in the coordination of the metal ion. For Eu.1 and Tb.1, the absorption and luminescence spectra, the overall luminescence efficiencies, and the metal-centered (MC) lifetimes were obtained; coordination features were also determined by comparing luminescence properties in water and deuterated water. For Eu.1 and Tb.1, the overall emission sensitization (se) process in air-equilibrated water was found to be notably effective with phi(se) = 0.21 and 0.11, respectively. A detailed study of the steps originating from light absorption at the phen unit and leading to MC sensitized emission was performed.

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PubMed2002

Molecular dynamics simulation of [Gd(egta)(H(2)O)](-) in aqueous solution: internal motions of the poly(amino carboxylate) and water ligands, and rotational correlation times.

Molecular dynamics simulations of [Gd(egta)(H(2)O)](-) (egta(4-)=3,12-bis(carboxymethyl)-6,9-dioxa-3,12-diazatetradecanedioate(4-)) have been performed without any artificial constraint on the first coordination sphere, such as covalent bonds between the Gd(3+) and the coordination sites. Two new crystallographic structures were determined for this gadolinium chelate and used to start two molecular dynamics simulations. [Gd(egta)(H(2)O)](-) and [Gd(egta)](-) were both observed during the simulations, with a mean volume for the reaction of dissociation [Gd(egta)(H(2)O)](-)-->[Gd(egta)](-)+H(2)O of +7.2 cm(3)mol(-1), which corroborates the previously published experimental value of +10.5 cm(3)mol(-1). Changes in the conformation of the complex with the inversion of several dihedral angles are observed in the simulations independently from the water dissociation. Very fast changes of the third-order rotation axis direction of the Gd(3+) coordination polyhedron (of symmetry D(3h)) are observed during the simulations and are related to the mechanism of electronic relaxation of the complex. Different rotational correlation times (tau(R)) were calculated from the simulations on various observables of the complex. Protons of the inner sphere have different tau(R). The mean tau(R) of the two Gd-HW(HW=hydrogen of water molecule) vectors is 72% lower than tau(R) of the complex, and 75% lower than tau(R) of the vector Gd-OW (OW=oxygen of water molecule). This discrimination of the tumbling rates should be taken into account in future global (17)O NMR, EPR and NMRD (nuclear magnetic relaxation dispersion) data analysis.

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PubMed2002

Separation of intra- and extracellular lactate NMR signals using a lanthanide shift reagent.

This work describes the use of [Pr-DO3A] as a shift reagent for differentiating intra- and extracellular L-lactate resonance in (1)H- and (13)C-NMR spectra. DO3A acts as heptadentate ligand towards lanthanide(III) ions, leaving two coordination vacancies for the coordination of the L-lactate ion. The exchange between free and [Pr-DO3A]-bound L-lactate is fast on the NMR timescale, thus yielding a paramagnetically shifted L-lactate signal for the substrate in the compartment containing the paramagnetic chelate. The evaluation of the method was carried out on a model system based on sealed ghosts from human red blood cells.

Acetates↗
PubMed2001

Relaxometric evaluation of novel manganese(II) complexes for application as contrast agents in magnetic resonance imaging.

Three novel Mn(II) complexes bearing benzyloxymethyl functionalities are reported and their ability to enhance water (1H and 17O) relaxation times is investigated in detail. Two of them contain one coordinated water molecule and display relaxivity values only slightly smaller than those shown by the most clinically used contrast agents (e.g. [Gd(DTPA)(H2O)]2-). Moreover, in these Mn(II) chelates the exchange rate of the coordinated water is ca. one order of magnitude higher if compared to the exchange rates previously reported for Gd(III) complexes with octadentate ligands. The occurrence of such fast exchange rates of the coordinated water is exploited in the formation of macromolecular adducts with human serum albumin to attain systems displaying relaxivity values in the upper range of those so far reported for analogous Gd(III) systems. These results strongly support the view that Mn(II) complexes, in spite of the lower effective magnetic moment, can be considered as viable alternatives to the currently used Gd(III) complexes as contrast agents for MRI applications.

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PubMed1999

Synthesis, X-ray Structure, and Solution NMR Studies of Ln(III) Complexes with a Macrocyclic Asymmetric Compartmental Schiff Base. Preference of the Ln(III) Ions for a Crown-Like Coordination Site.

The compartmental ligand H(2)L(A), containing an N(3)O(2) Schiff base and an O(2)O(3) crown like coordination site, has been prepared by reaction of 3,3'-(3-oxapentane-1,5-diyldioxy)bis(2-hydroxybenzaldehyde) with 1,5-diamino-3-azamethylpentane. The formation of a [1+1] macrocycle was inferred by IR, NMR, and mass spectrometry. When reacted with the rare-earth hydrate chlorides, LnCl(3).nH(2)O (Ln = La, Ce, Pr, Nd, Eu, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y), H(2)L(A) or its precursors (template reaction) form the mononuclear complexes [Ln(H(2)L(A))(H(2)O)(4)]Cl(3).nH(2)O where the lanthanide ion coordinates the O(2)O(3) crown like site. The solid-state X-ray structures of [Ln(H(2)L(A))(H(2)O)(4)]Cl(3).nH(2)O (Ln = Ce, Dy, Lu) have been determined. [Lu(H(2)L(A))(H(2)O)(4)]Cl(3).3H(2)O is monoclinic space group P2(1)/n (Z = 4) with a = 15.269(5) Å, b = 11.484(5) Å, c = 19.389(6) Å, beta = 102.85(5) degrees; [Ce(H(2)L(A))(H(2)O)(4)]Cl(3).H(2)O and [Dy(H(2)L(A))(H(2)O)(4)]Cl(3).H(2)O are isomorphous, space group P2(1) (Z = 2), with a = 10.959(5) Å, b = 16.978(5) Å, c = 9.017(4) Å, beta = 97.73(5) degrees, and a = 10.874(5) Å, b = 16.797(5) Å, c = 9.046(4) Å, beta = 97.86(5) degrees for the cerium and dysprosium complexes, respectively. In the three compounds the metal ion is coordinated in a similar manner by the five oxygens (two phenolic and three etheric) of the cyclic ligand and the nine coordination around the central atom is reached by the oxygen atoms of four coordinated water molecules. Three chlorine ions are present in the asymmetric unit. A detailed (1)H NMR study was carried out in CD(3)OD for both the diamagnetic and paramagnetic [Ln(H(2)L(A))(H(2)O)(4)]Cl(3) complexes in order to compare their structure in solution with that found in the solid state. The quantitative analysis of the paramagnetic proton shifts indicates that the complexes from La to Tm are isostructural, maintain in solution the same type of coordination polyhedron found at the solid state, with the metal ion invariably coordinated in the O(2)O(3) compartment, and present a high degree of stereochemical nonrigidity. In the case of the Lu complex, the decreased fluxionality due to the reduced ionic radius allows the observation of two isomeric species in the (1)H NMR spectrum at low temperature.

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PubMed1997

Synthesis and NMR Studies of Three Pyridine-Containing Triaza Macrocyclic Triacetate Ligands and Their Complexes with Lanthanide Ions.

The synthesis of three triazamacrocycles containing the pyridine moiety and three acetate pendant arms (PCTA) is reported. The three systems differ due to the number of carbon atoms in the macrocyclic ring forming ligands PCTA-[12], -[13], and -[14], endowed with different coordination capabilities toward lanthanide(III) ions. Microscopic protonation sequences for the three ligands have been investigated by (1)H NMR spectroscopy. Complexes of PCTA-[12], -[13], and -[14] with La(III), Gd(III), and Lu(III) have been prepared. Relaxometric measurements on the aqueous solutions of the paramagnetic Gd(III) complexes in the presence of competitive ligands gave the following stability constants: log K(f) = 20.8 for Gd-PCTA-[12], log K(f) = 19.3 for GdPCTA-[13], and log K(f) = 12.5 for GdPCTA-[14]. The measurement of water relaxation rates indicated a tendency to decrease the degree of hydration upon increasing the ring size. The VT (1)H and (13)C-NMR spectra of the diamagnetic La(III) and Lu(III) complexes exhibit a large variability of the solution structures dictated by the matching of the size of the lanthanide ion and the macrocyclic cavity. This results in noticeable differences in their stereochemical nonrigidity, hydration state, and thermodynamic stability. To some extent the changes observed in continuing from the 12-14-membered ring macrocyclic complexes parallels the behaviors shown by the octacoordinated lanthanide(III) complexes with DOTA and TETA. GdPCTA-[12] and -[13] feature promising properties in view of their possible use as contrast agents for magnetic resonance imaging.

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PubMed1997

Conformational and Coordination Equilibria on DOTA Complexes of Lanthanide Metal Ions in Aqueous Solution Studied by (1)H-NMR Spectroscopy.

A variable-temperature, -pressure, and -ionic strength (1)H NMR study of the DOTA complexes of different trivalent cations (Sc, Y, La, Ce --> Lu) (DOTA = 1,4,7,10-tetraaza-1,4,7,10-tetrakis(carboxymethyl)cyclododecane) yielded data that are in contradiction with the hitherto used model of only two enantiomeric pairs of diastereoisomers that differ in the ligand conformations. A two-isomer equilibrium cannot explain the newly observed apparent reversal of the isomer ratio at the end of the series. As both conformers may lose their inner sphere water molecule, a coordination equilibrium may be superimposed on this conformational equilibrium, as shown by large positive reaction volumes for the isomerization of [Ln(DOTA)(H(2)O)(x)()](-) (Ln = Yb, Lu; x = 1, 0). The isomerization of [Nd(DOTA)(H(2)O)](-) and [Eu(DOTA)(H(2)O)](-) is purely conformational, as shown by near-zero reaction volumes. The measured isomerization enthalpies and entropies agree with this model. The shift of the isomerization equilibria by a variety of non-coordinative salts depends on the ligand conformation rather than the presence or absence of the inner sphere water molecule. This results from weak ion binding and water solvent stabilization of one ligand conformation, rather than the decrease of the activity of the bulk water in the solution, as shown by UV-vis measurements of the coordination number sensitive transition (5)F(0) --> (7)D(0) of Eu(III) as a function of ionic strength. Fluoride ions replace a water molecule in the inner coordination sphere, preferentially for one of the conformational isomers, as proven by (19)F-NMR shifts and the appearance of a third set of resonances corresponding to [Eu(DOTA)F](2)(-) in the (1)H-NMR spectrum of [Eu(DOTA)(H(2)O)](-).

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PubMedDate not supplied

Gd-enhanced MR images of substrates other than water.

This communication reports the dramatic relaxation enhancements that can be obtained upon the interaction of substrates like lactate, trifluorolactate and inorganic phosphate with the paramagnetic GdDO3A agent. This occurs thanks to the formation of kinetically labile ternary complexes in which the substrate nuclei are in close proximity to the paramagnetic center. It is demonstrated that heteronuclear (13)C, (19)F and (31)P-MR images can be obtained from phantoms containing the substrate in the millimolar concentration range.

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