Abstract
The semistable chelate manganese (Mn) dipyridoxyl diphosphate (MnDPDP, mangafodipir), previously used as an intravenous (i.v.) contrast agent (Teslascan™, GE Healthcare) for Mn-ion-enhanced MRI (MEMRI), should be reappraised for clinical use but now as a diagnostic drug with cytoprotective properties. Approved for imaging of the liver and pancreas, MnDPDP enhances contrast also in other targets such as the heart, kidney, glandular tissue, and potentially retina and brain. Transmetallation releases paramagnetic Mn2+ for cellular uptake in competition with calcium (Ca2+), and intracellular (IC) macromolecular Mn2+ adducts lower myocardial T1 to midway between native values and values obtained with gadolinium (Gd3+). What is essential is that T1 mapping and, to a lesser degree, T1 weighted imaging enable quantification of viability at a cellular or even molecular level. IC Mn2+ retention for hours provides delayed imaging as another advantage. Examples in humans include quantitative imaging of cardiomyocyte remodeling and of Ca2+ channel activity, capabilities beyond the scope of Gd3+ based or native MRI. In addition, MnDPDP and the metabolite Mn dipyridoxyl diethyl-diamine (MnPLED) act as catalytic antioxidants enabling prevention and treatment of oxidative stress caused by tissue injury and inflammation. Tested applications in humans include protection of normal cells during chemotherapy of cancer and, potentially, of ischemic tissues during reperfusion. Theragnostic use combining therapy with delayed imaging remains to be explored. This review updates MnDPDP and its clinical potential with emphasis on the working mode of an exquisite chelate in the diagnosis of heart disease and in the treatment of oxidative stress.
Highlights
MRI is an imaging modality which in its native form produces important diagnostic information with purely instrument-based techniques [1]
Following a side track from contrast agent research into the field of “oxidative,” i.e., combined oxidative-nitrosative, stress and antioxidants [53,54,55], Asplund et al discovered that MnDPDP and Mn dipyridoxyl diethyl-diamine (MnPLED) dilated arteries [20] by mimicking MnSOD, with the proposed mechanism that suppression of superoxide preserved endothelial derived nitric oxide (NO) for activation of adenylate cyclase and cyclic GMP thereby relaxing vascular smooth muscle cells [43]. ereafter, electron paramagnetic resonance (EPR) spectroscopy with MnDPDP and MnPLED [21] added to an in vitro superoxide-generating reaction proved that they mimic MnSOD [34] with a half maximal response concentration (EC50) of 5–10 μM, a highly relevant plasma level in humans [29]
In AMI in pigs (Figure 6(a)), MnPLED, but not MnDPDP, ameliorated ROS-RNS inflicted reperfusion injury, thereby reducing infarct size by 55%, whereas both agents prevented arrhythmias [10]. ese findings imply that MnPLED accessed mitochondrial sites critical for cell survival [61] and that MnDPDP may have acted at the cell membrane level
Summary
MRI is an imaging modality which in its native form produces important diagnostic information with purely instrument-based techniques [1]. There is a demand for new contrast enhancing techniques with properties beyond the scope of both native and Gd based MRI. Improve upon the treatment of patients undergoing diagnostic imaging In retrospect, such an agent, manganese (Mn) dipyridoxyl diphosphate (MnDPDP), has already been available but vanished before its potential was recognized by the imaging community. 2. Basic Properties e behavior of MnDPDP as chelated prodrug in medical biology represents a blend of disciplines, ranging from physics and chemistry to pharmacokinetics and physiology in health and disease. Basic Properties e behavior of MnDPDP as chelated prodrug in medical biology represents a blend of disciplines, ranging from physics and chemistry to pharmacokinetics and physiology in health and disease From traversing these fields, come the basics of MRI and of antioxidant treatment. In spite of an inherent complexity, interactions between multiple factors seem mostly fortuitous
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