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, pO2, 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 13C 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 pO2 values by MRS. The potential applications of these agents in mutimodal and molecular imaging approaches are discussed.
Keywords: Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Tissue Microenvironment, Contrast Mechanisms, Paramagnetic Contrast Agents, Diamagnetic Contrast Agents, 13C Hyperpolarized molecules, Molecular Imaging, Possitron Emission Tomography, PET, Amide Proton Transfer (APT), paramagnetic chelates, PARACEST, Nitroimidazoles, Optical Pumping method, Parahydrogen method, Dynamic Nuclear Polarization, magnetization transfer, single-molecule CEST agents, ADC, Apparent Diffusion Coefiicient, MRSI, Magnetic Resonance Spectroscopic Imaging, DIACEST, Diamagnetically Induced Chemical Exchange Saturation Transfer, DTPA, Diethylen diamino pentaacetic acid, DNP