![]() ![]() Zhu, Jiang Gale, Eric M Atanasova, Iliyana et al. (2015) A Manganese Alternative to Gadolinium for MRI Contrast. Gale, Eric M Atanasova, Iliyana P Blasi, Francesco et al. Neuropharmacology 108:462-73īoros, Eszter Gale, Eric M Caravan, Peter (2015) MR imaging probes: design and applications. (2016) Functional modulation of G-protein coupled receptors during Parkinson disease-like neurodegeneration. Jenkins, Bruce G Zhu, Aijun Poutiainen, Pekka et al. Gale, Eric M Caravan, Peter (2018) Gadolinium-Free Contrast Agents for Magnetic Resonance Imaging of the Central Nervous System. We will validate this hypoxia probe in mouse and rabbit tumor models by comparing to direct pO2 electrode measurements, a positron emission tomography hypoxia probe, and blood oxygen level dependent MR. In this application we will focus on developing an MR oxygen sensor for hypoxia imaging, where MR signal is only generated in hypoxic regions. With development of a tunable redox core, it is possible to design probes sensitive to pH, enzymatic activity, ion flux, or specific haptens. We will prepare stable manganese complexes that can reversibly convert from a truly MR-off state (Mn3+) to a MR-on state (Mn2+) in the presence of an environmental stimulus. Divalent manganese (Mn2+) is a potent MR relaxation agent but Mn3+ is generally a poor relaxor. We propose a new paradigm for activatable MR probes based on the reduction-oxidation (redox) chemistry of manganese. In this way, any change in MR signal after probe injection must be due to activation of the probe. We propose activatable probes that are completely MR silent in the """"""""off"""""""" state. Currently there is no practical way to distinguish active from inactive probe. Signal change could be a result of distribution of inactive probe or could be due to probe activation. Relative to normal tissue, concentrations may be higher in diseased tissue due to increased endothelial permeability, or lower because of poor perfusion. However in vivo, the probe concentration is unknown and changes with time. In vitro, where concentration does not change, these probes act as elegant sensors. Although relaxivity can be exquisitely sensitive to a stimulus, the MR signal change depends on both relaxivity and probe concentration: two unknowns. the probe is transformed via enzymatic reaction from a low relaxivity state to a high relaxivity state, or the probe's relaxivity changes upon binding an analyte, e.g. It is possible to design activatable or """"""""smart"""""""" probes where the relaxivity changes in response to an environmental stimulus, e.g. Relaxivity is dependent on a number of molecular factors including the hydration state of the probe and its rotational diffusion rate. This effect depends on probe concentration and the probe's relaxivity. ![]() In MRI primarily water is imaged and the probe is detected indirectly by its effect on the water signal. The fundamental limitation of activatable MR probes that stifles their translation is the difficulty in distinguishing """"""""active"""""""" from """"""""inactive"""""""" probe. The deep tissue penetration and high resolution make MR make it possible to directly translate findings from cells to mice to humans. MR allows the interrogation of intact, opaque organisms in three dimensions at cellular resolution (~10 5m) on high field systems and sub millimeter resolution on clinical scanners. Potential applications of such probes include direct imaging of neuronal currents, pancreatic islet viability, gene activation, and key elements of the heterogeneous tumor microenvironment. MR probes responsive to Ca2+ flux, Zn2+ flux, reporter genes, enzymatic activity, pO2, and pH have been reported. Activatable MR Imaging Probes Activatable magnetic resonance (MR) imaging probes offer the potential to provide unprecedented biological insights.
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