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Even though alterations in the microenvironmental properties of tissues underlie the development of the most prevalent and morbid pathologies, they are not directly observable in vivo by Magnetic Resonance Imaging (MRI) or Spectroscopy (MRS) methods. This circumstance has lead to the development of a wide variety of exogenous paramagnetic and diamagnetic MRI and MRS probes able to inform non invasively on microenvironmental variables such as pH, pO(2), ion concentration o even temperature. This review covers the fundamentals of environmental contrast and the current arsenal of endogenous and exogenous MRI and MRS contrast enhancing agents available to visualize it. We begin describing the physicochemical background necessary to understand paramagnetic and diamagnetic contrast enhancement with a special reference to novel magnetization transfer and C-13 hiperpolarization strategies. We describe then the main macrocyclic structures used to support the environmentally sensitive paramagnetic sensors, including CEST and PARACEST pH sensitive probes, temperature probes and enzyme activity or gene expression activatable probes. Finally we address the most commonly used diamagnetic contrast agents including imidazolic derivatives to reveal extracellular pH and tissue pO(2) values by MRS. The potential applications of these agents in mutimodal and molecular imaging approaches are discussed.

The binding site and backbone dynamics of a bioactive complex formed by the acidic fibroblast growth factor (FGF-1) and a specifically designed heparin hexasaccharide has been investigated by HSQC and relaxation NMR methods. The comparison of the relaxation data for the free and bound states has allowed showing that the complex is monomeric, and still induces mutagenesis, and that the protein backbone presents reduced motion in different timescale in its bound state, except in certain points that are involved in the interaction with the fibroblast growth factor receptor (FGFR).

The first direct NMR determination of the conformation of a conformationally flexible heparin-like hexasaccharide bound to a key receptor, FGF-1, is described. The determination has been based on the use of a 13C-labeled protein and a regular 12C sugar. FGF-1 recognizes several conformations of the iduronic moieties of the hexasaccharide. Therefore, this case is different than that described for the controversial recognition of heparin-like saccharides by AT-III, which seems to recognize just one conformation of the iduronic acid residues.

The temperature dependence of the spectral distributions of the glass, crystalline, and supercooled-liquid phases of glycerol is investigated by means of neutron inelastic scattering. The importance of anharmonic effects is quantified by the temperature dependence of reduced spectral frequency moments. The onset of relaxational (i.e., stochastic, zero-frequency) motions in the supercooled liquid state is monitored by neutron quasielastic scattering. A substantial deviation of the observed linewidths from the hydrodynaimc prescription is observed and is interpreted at a microscopic level, by comparison with the crystalline phase. ©1998 American Physical Society

The structures of the liquid, glass (i.e., amorphous), rotator-phase (RP) crystal, orientational glass (OG), and the stable (monoclinic) crystal phases of ethanol are investigated by means of neutron and x-ray diffraction. The RP crystal and OG phases show an intermediate kind of disorder between that of the fully disordered glass and liquid phases and that of the stable crystal. The Bragg pattern of the RP and OG crystals provides information about the time-averaged distribution of single-molecule orientations, and a contribution comprising intermodular correlations is isolated from the diffuse intensity. Finally, the RP→OG rotational freezing transition is analyzed in detail and shown to constitute a physical realization of the glass transition found in hard-needle models. ©1997 American Physical Society