Search

DPA-713 is the lead compound of a recently reported pyrazolo[1,5-a]pyrimidineacetamide series, targeting the translocator protein (TSPO 18 kDa), and as such, this structure, as well as closely related derivatives, have been already successfully used as positron emission tomography radioligands. On the basis of the pharmacological core of this ligands series, a new magnetic resonance imaging probe, coded DPA-C6-(Gd)DOTAMA was designed and successfully synthesized in six steps and 13% overall yield from DPA-713. The Gd-DOTA monoamide cage (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) represents the magnetic resonance imaging reporter, which is spaced from the phenylpyrazolo[1,5-a]pyrimidineacetamide moiety (DPA-713 motif) by a six carbon-atom chain. DPA-C6-(Gd)DOTAMA relaxometric characterization showed the typical behavior of a small-sized molecule (relaxivity value: 6.02 mM−1 s−1 at 20 MHz). The good hydrophilicity of the metal chelate makes DPA-C6-(Gd)DOTAMA soluble in water, affecting thus its biodistribution with respect to the parent lipophilic DPA-713 molecule. For this reason, it was deemed of interest to load the probe to a large carrier in order to increase its residence lifetime in blood. Whereas DPA-C6-(Gd)DOTAMA binds to serum albumin with a low affinity constant, it can be entrapped into liposomes (both in the membrane and in the inner aqueous cavity). The stability of the supramolecular adduct formed by the Gd-complex and liposomes was assessed by a competition test with albumin. Copyright © 2013 John Wiley & Sons, Ltd.

Para-hydrogen–induced polarization effects have been observed in the 29Si NMR spectra of trimethylsilyl para-hydrogenated molecules. The high signal enhancements and the long T1 values observed for the 29Si hyperpolarized resonances point toward the possibility of using 29Si for hyperpolarization applications. A method for the discrimination of multiple compounds and/or complex mixtures of hydroxylic compounds (such as steroids), consisting of the silylization of alcoholic functionalities with an unsaturated silylalkyl moiety and subsequent reaction with para-H2, is proposed. Copyright © 2012 John Wiley & Sons, Ltd.

DPA-713 is the lead compound of a recently developed 2-phenylpyrazolo[1,5-a]pyrimidineacetamide series that has been shown to display a good targeting capability toward peripheral benzodiazepine receptors, recently renamed translocator protein (18 kDa) or in short TSPO. On the basis of this structure, a novel derivative bearing a [13C]butynoate moiety has been designed and synthesized (three steps—42% overall yield) providing, upon rapid and quantitative para-hydrogenation, the corresponding hyperpolarized [13C]alkene. Para-hydrogen-induced polarization effects have been detected in both 1H and 13C-NMR spectra. Upon applying a field cycling procedure, the spin order of para-H2 added hydrogens is transferred on the 13 C carboxylate moiety yielding a signal enhancement of approximately 4500 times. T1 of the carboxylate carbon atom is approximately 21.9 s (at 9.37 T). A 13 C-MR image has been acquired by using the 13 C RARE (Rapid Acquisition by Relaxation Enhancement) acquisition protocol on a 10-mM solution. The main limitation to the in vivo use of this novel para-hydrogenated [13 C]derivative is its relatively low solubility in aqueous systems. Copyright © 2011 John Wiley & Sons, Ltd.

The Gd(III) complexes of three new octadentate chelators, prepared by substitution of four, two, and one carboxylate groups of EGTA with phosphonate groups, have been investigated by 1H and 17O NMR relaxometric techniques in aqueous solutions. The analysis of the solvent proton relaxivity data as a function of pH, temperature, and magnetic field strength (nuclear magnetic relaxation dispersion (NMRD) profiles) in combination with the 17O transverse relaxation rate data at variable temperature allowed assessing the hydration state of the complexes, the occurrence of pH-dependent oligomerization processes for the tetraphosphonate derivative, the presence of a well-defined second sphere of hydration that markedly contributes to the relaxivity, and the values of the structural and dynamic relaxation parameters. In addition, in the case of the monophosphonate derivative the presence of a coordinated water molecule has allowed evaluation of the kinetic parameters of the exchange process, highly relevant for the possible use of this Gd(III) complex as an MRI probe. The rate of exchange of the water molecule, (298)k(ex) = 4.2 x 10(8)s(-1), is one of the highest measured so far for a nonacoordinate Gd(III) chelate and optimal for developing contrast-enhancing probes of high efficacy at high magnetic fields.

A novel, radical responsive MRI contrast agent based on a gadolinium chelate conjugated to a liposome through a disulfide linker was synthesized, with the aim of pursuing the in vivo mapping of radicals. The liposome was prepared by incorporating a thiol-activated phospholipid, which was subsequently reacted with a gadolinium chelate containing a free thiol group. The long reorientational motion of the supramolecular adduct endows the paramagnetic agent with a relaxivity significantly higher than that of the free complex. The disulfide bond represents a radical-sensitive moiety and a large decrease in contrast efficacy (T1 relaxivity) is shown upon its cleavage. A preliminary assessment of the system was made by means of in vitro gamma-irradiation and thiol–disulfide bond exchange with dithiothreitol. Both methods showed a clear dose-dependent decrease in T1-relaxivity. Copyright © 2003 John Wiley & Sons, Ltd.

Gadolinium-chelates bearing hydrophobic substituents on their surfaces form inclusion complexes with β-cyclodextrin. When the chelate contains more than one substituent, the observed relaxation enhancement has to be analysed on the basis of the contributions arising from the actual speciation of the resulting inclusion complexes. This analysis allows the assessment of the binding constants for the individual inclusion complexes, as well as their specific relaxation enhancements. The relaxivities obtained of the supramolecular adducts display a good linearity with their molecular weights to outline that, in these systems, the main determinant of the relaxation enhancement is represented by the overall molecular reorientational time. Copyright © 2003 John Wiley & Sons, Ltd.

A survey of the use of Os-187 satellite subspectra in H-1 and P-31{H-1} spectra of triosmium carbonyl clusters is reported. By varying evolution delays in HMQC spectra of [Os-3(mu-H)(2)(CO)(10)] we have selectively extracted the values for (1)J(Os,H) and (2)J(Os,H), respectively. An analysis of the principal modes of phosphine coordination in triosmium clusters demonstrates that P-31{H-1} Os-187 satellite subspectra are diagnostic for equatorial coordination [(1)J(Os, P) = 211-223 Hz] or for axial coordination (perpendicular to the plane of the cluster) [(1)J(Os, P) approximate to 147 Hz]. Chelating and bridging diphosphines yield Os-187 satellite subspectra which are the sum of A(2)X and AA'X spin systems. If significant P-P coupling is present, the AA'X component requires simulation. All observed (2)J(Os,P) trans-equatorial couplings fall in the range 38-65 Hz. Copyright (C) 2001 John Wiley Sons, Ltd. (Less)

Reference LCIB-ARTICLE-2002-004doi:10.1002/mrc.968View record in Web of Science Record created on 2006-02-15, modified on 2017-05-12

The measurement of longitudinal relaxation rates of water protons in solutions containing horse heart and sperm whale metmyoglobins at various pH values and temperatures shows that the two species differ essentially in the exchange lifetime, τM, of the water molecule in the haem cavity. The 1/T1 nuclear magnetic relaxation dispersion dispersion profiles support this view whereas 17O NMR spectroscopy shows that the exchange mechanism involves the whole water molecule. The lack of any 1H/2H isotope effect on the exchange rate suggests that the displacement of the coordinated water molecule from Fe(III) is not the rate-determining step in the overall exchange process. In contrast to the parent species, no difference is detectable from the relaxometric investigations on the corresponding fluorometmyoglobin derivatives.

A novel method for water signal suppression in 1 H NMR spectra is proposed for biological system. It is based on the acquisition of a spin-echo spectrum in the presence of Dy(III) complexes, which cause a marked decrease of the water proton T 2 through the modulation of Δω M (chemical shift difference between the bulk and coordinated water resonance) by τ M (time associated with the exchange between the two sites)

The addition of β-cyclodextrin to a solution containing β-benzyloxy-α-propionic-substituted DOTA- and DTPA-Gd(III) complexes leads to the formation of inclusion compounds whose equilibrium constants have been determined by NMR titrations. The main effect associated with the formation of this «host-guest» interaction n a marked elongation of the molecular reorientational time, τ r , which in turn results in increased solvent proton relaxation rates

Chemical shift anisotropies and spin-lattice relaxation times, T1, were determined for bridging and terminal carbonyls in c's and trans isomers of [(η5-C5H5)2Fe2(CO) 2(μ2-CO)2]. The relaxation path of the 13CO resonances occurs through the dipolar interaction with the cyclopentadienyl protons modulated by the reorientational motion of the C5H5 (Cp) rings around their five-fold axes. Wide-line proton spin-lattice relaxation times, T1, at variable temperature allow the evaluation of the activation energies associated with the internal rotation of the cyclopentadienyl rings. In the cis isomer, the two crystallographically non-equivalent Cp ligands rotate at different rates (Ea = 7.2 and 15.8 kJ mol−1, respectively). Carbon-13 spin-lattice relaxation times in the rotating frame of the cyclopentadienyl carbons of the cis isomer support this view. Finally, good agreement is found between our work, the results obtained from crystallographic data and theoretical calculations on the energy barriers for the rotation of the Cp rings.

1 H Fast Field Cycling NMR (FFC-NMR) relaxometry is proposed as a powerful method to investigate tumour stroma in vivo upon the administration of a Gd-based contrast agent. To perform this study, an FFC-NMR equipment endowed with a wide bore magnet was used for the acquisition of Nuclear Magnetic Resonance Dispersion profiles on healthy muscle and tumour tissue in living mice. At magnetic field strengths < of ca. 1 MHz, the differences in the relaxation rates of the intra and extracellular compartment become of the same order of magnitude of the exchange rate across the cellular membranes. Under this condition, the water exchange rate between the two compartments yields to a biexponential magnetization recovery that can be analysed by fitting the experimental data with the two-Site eXchange (2SX) model. Using this model, it was possible to obtain, for the two compartments, both relaxation properties and water kinetic constants for water exchange across cell membranes. The method allowed us to determine the effect of the "matrix" on the water proton relaxation times and, in turn, to get some insights of the composition of this compartment, till now, largely unknown.

Large deuterium isotope effects on 17O resonances were observed for six common NMR solvents. Only in the case of acetone did the substitution of deuterium for hydrogen result in a downfield shift. The H/D isotope effect was also detected in a study of the reversible hydration of CH3CHO.