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Biomedical subjects

Enzo Terreno

Publications and source records attributed to Enzo Terreno.

At least 19 recordsLinked to original sources
PubMed2006

A R2/R1 ratiometric procedure for a concentration-independent, pH-responsive, Gd(III)-based MRI agent.

A novel procedure for making the pH responsiveness of a Gd-based probe independent of its concentration has been developed. The method is based on a ratiometric approach and requires the measurement, at magnetic fields higher than 1 T, of the paramagnetic contribution to the longitudinal and the transverse NMR relaxation rates of water protons in the presence of a Gd-based probe with a rotational mobility in the nanosecond time scale. The method has been tested and validated in vitro by using a macromolecular adduct based on the polyornithine backbone, whose rotational mobility is pH dependent. The results reported in this communication improve substantially the diagnostic potential of MRI responsive agents.

Journal Article↗
PubMed2006

Effect of the intracellular localization of a Gd-based imaging probe on the relaxation enhancement of water protons.

Gd-HPDO3A has been internalized into rat hepatocarcinoma cells in the cytoplasm (by electroporation) or in intracellular vesicles (by pinocytosis), respectively. In the former case, the observed relaxation rates are likely dependent upon the amount of internalized paramagnetic complex, whereas in the latter case the relaxation enhancement is "quenched" to a plateau value (about 3 s(-1)) when the entrapped amount of Gd-chelate is higher than 1 x 10(10) Gd/cell. The observed behavior has been accounted in terms of a theoretical treatment based on equations formally derived by Labadie et al. (J Magn Reson B 1994;105:99-102). On this basis, entrapment into intracellular vesicles has been treated as a three-site water exchange (extracellular/cytoplasm/vesicle compartments), whereas the cell pellets containing the paramagnetic agent spread out in the cytoplasm can be analyzed by a two-site exchange system.

Animals↗
PubMed2005

A multinuclear NMR relaxometry study of ternary adducts formed between heptadentate Gd(III) chelates and L-lactate.

Dramatic relaxation enhancements of L-lactate resonances have been observed upon formation of ternary adducts with Gd(III) complexes of heptadentate DO3A and DO3A-like ligands (DO3A = 1,4,7,10-tetraazaciclododecane-1,4,7-triacetic acid). Detailed 1H and 17O NMR relaxometry investigations allow us to obtain structural, dynamic and thermodynamic information on the ternary complexes in which L-lactate acts as a bidentate ligand replacing two water molecules in the inner coordination sphere of the Gd(III) ion. It has been found that the exchange rate of the coordinated L-lactate is modulated by the structural and electronic properties of the parent Gd-heptacoordinated macrocyclic chelate. In addition to the characterisation of the relaxation behaviour of the 1H methyl resonance of L-lactate, this study has been extended to its 13C isomer (fully enriched at the three positions) and to the trifluoro-L-lactate. The obtained results may be relevant to the development of relaxation agents able to promote the relaxation enhancement of specific substrates detectable by in vivo magnetic resonance spectroscopy.

Chelating Agents↗
PubMed2005

Iopamidol: Exploring the potential use of a well-established x-ray contrast agent for MRI.

Iopamidol is one of the most common contrast media used for diagnostic CT-based clinical protocols. Chemically, this molecule contains two pools of mobile protons (amide and alcoholic) that are in exchange with water. At 7.05 T, pH 7.4, and 312 K, the exchange rate of the alcoholic protons is too fast to affect the NMR properties of water protons, whereas the slowly exchanging amide protons induce a T(2)-shortening effect on the "bulk" water signal that is detectable when the concentration is about 12 mM. Moreover, a more pronounced contrast is observed when the amide resonances are saturated by the application of an appropriate RF irradiation field, making iopamidol a potential chemical exchange saturation transfer (CEST) agent whose effect can be detected at a concentration as low as 7 mM (at 7.05 T). The exploitation of the MRI properties of iopamidol could facilitate novel and interesting diagnostic applications for combined MRI and CT studies.

Contrast Media↗
PubMed2005

The extraordinary ligand binding properties of human serum albumin.

Human serum albumin (HSA), the most prominent protein in plasma, binds different classes of ligands at multiple sites. HSA provides a depot for many compounds, affects pharmacokinetics of many drugs, holds some ligands in a strained orientation providing their metabolic modification, renders potential toxins harmless transporting them to disposal sites, accounts for most of the antioxidant capacity of human serum, and acts as a NO-carrier. The globular domain structural organization of monomeric HSA is at the root of its allosteric properties which are reminiscent of those of multimeric proteins. Here, structural, functional, biotechnological, and biomedical aspects of ligand binding to HSA are summarized.

Allosteric Regulation↗
PubMed2004

Ln(III)-DOTAMGly complexes: a versatile series to assess the determinants of the efficacy of paramagnetic chemical exchange saturation transfer agents for magnetic resonance imaging applications.

RATIONALE AND OBJECTIVES: Paramagnetic Ln-DOTAMGly complexes (Ln not equal La, Lu, and Gd) are the prototypes of a novel class of contrast agents for magnetic resonance imaging based on chemical exchange saturation transfer (CEST). Their ability to reduce the water signal intensity depends on the interplay of several physico-chemical properties of the agent and instrumental parameters. This study aims to identify possible routes for their optimization METHODS: Saturation transfer (ST) has been measured in vitro at 7.05 T as a function of pH, temperature, and concentration of the agent. RESULTS: Large saturation transfer effects have been observed upon irradiating the coordinated water protons (for Ln = Pr, Nd, Eu, and Tb). The comparison of the results obtained by irradiating water versus amide protons allows the set-up of ratiometric methods through which the ST response can be made independent on the concentration of the agent. CONCLUSIONS: The modulation of the magnetic properties along the lanthanide series allows an in-depth understanding of the determinants of ST effect and provides useful insights for the design of more efficient agents.

Chemical Phenomena↗
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.

Journal Article↗
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.

Chelating Agents↗
PubMed2002

A paramagnetic MRI-CEST agent responsive to lactate concentration.

A paramagnetic Yb(III) complex bearing six exchangeable amide protons, [Yb(MBDO3AM)](3+), has been investigated with the aim of developing a MRI-CEST (chemical exchange saturation transfer) contrast agent responsive to the concentration of L-lactate. The complex binds the substrate quantitatively to yield [Yb(MBDO3AM)L-lactate](2+). The exchange between the free and the L-lactate-bound complex is slow on the NMR time scale, and the resonances of their corresponding amide protons are sufficiently separated (more than 10 ppm) to allow their selective irradiation. Therefore, the CEST properties of the two forms can be independently assessed. In turn, the resulting saturation transfer to the bulk water signal is dependent on the L-lactate concentration.

Contrast Media↗
PubMed2002

A paramagnetic probe to localize residues next to carboxylates on protein surfaces.

It is shown that the paramagnetic properties of lanthanides can be exploited to obtain information on specific parts of a protein surface. Owing to the high affinity of coordinatively unsaturated lanthanide complexes for oxygen donors, carboxylate groups can be used as preferential targets for the interaction. The DO3A ligand is particularly useful in these studies, as it coordinates lanthanides in a heptadentate fashion, leaving two sites available for exogenous donors. A solution of a (15)N-labeled sample protein, calbindin D(9k) (75 residues), was titrated with up to 200% of Gd(III)-DO3A complex, and an inversion recovery (15)N-(1)H HSQC experiment was used to measure the paramagnetic contributions to the longitudinal relaxation rates of the amide protons. Relaxation data were used as distance constraints to estimate the number of interacting complexes and the occupancies of their binding sites. Four preferential interaction sites on the protein surface are found. Inspection of the various carboxylate side chains on the surface of the protein indicates that Gd(III)-DO3A interacts preferentially with carboxylate-rich regions, rather than with isolated carboxylates, suggesting the possibility of chelation of one Gd(III)-DO3A molecule by two carboxylate groups. Gd(III)-DO3A is thus a valuable semi-selective probe for clusters of negative charges on the protein surface.

Algorithms↗
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↗
PubMed2002

Paramagnetic lanthanide(III) complexes as pH-sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications.

The recently introduced new class of contrast agents (CAs) based on chemical exchange saturation transfer (CEST) may have a huge potential for the development of novel applications in the field of MRI. In this work we explored the CEST properties of a series of Lanthanide(III) complexes (Ln = Eu, Dy, Ho, Er, Tm, Yb) with the macrocyclic DOTAM-Gly ligand, which is the tetraglycineamide derivative of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). These complexes possess two pools of exchangeable protons represented by the coordinated water and the amide protons. Yb-DOTAM-Gly displays the most interesting CEST properties when its amide N-H resonance (16 ppm upfield H2O signal) is irradiated. Up to 70% suppression of the water signal is obtained at pH 8. As the exchange rate of amide protons is base-catalyzed, Yb-DOTAM-Gly results to be an efficient pH-responsive probe in the 5.5-8.1 pH range. Moreover, a ratiometric method has been set up in order to remove the dependence of the observed pH responsiveness from the absolute concentration of the paramagnetic agent. In fact, the use of a mixture of Eu-DOTAM-Gly and Yb-DOTAM-Gly, whose exchangeable proton pools are represented by the coordinated water (ca. 40 ppm downfield H2O signal at 312K) and amide protons, respectively, produces a pH-dependent CEST effect which is the function of the concentration ratio of the two complexes.

Chelating Agents↗