Mangafodipir trisodium has dual applications: as an MRI contrast agent and as an antioxidant. As a contrast agent, the paramagnetic manganese (II) ions enhance T1-weighted MRI signal by shortening the relaxation time of nearby water protons. The compound is taken up by hepatocytes and pancreatic cells, providing organ-specific contrast enhancement. As an antioxidant, mangafodipir trisodium is an efficacious inhibitor of chemotherapy-induced peripheral neuropathy and other conditions caused by cellular oxidative stress. The compound shows no negative interference with the tumoricidal activity of chemotherapy. The chelating agent fodipir (dipyridoxyl diphosphate, DPDP) stabilizes the manganese ion.

Mangafodipir trisodium (40, 200, and 1000 μM) inhibits H2O2's effect on the viability of HGrC cells [3]. At 200 and 1000 μM, mangafodipir trisodium mitigates the effects of cisplatin-induced HGrC cell viability [3].

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Mangafodipir trisodium demonstrates in vitro activity as an antioxidant and contrast-enhancing agent. The compound is an efficacious inhibitor of cellular oxidative stress. Its antioxidant activity is attributed to the manganese (II) ion, which can scavenge reactive oxygen species and protect cells from oxidative damage. The compound shows no negative interference with the tumoricidal activity of chemotherapy. As a contrast agent, the paramagnetic properties of manganese provide T1-weighted signal enhancement in MRI. The compound's activity is concentration-dependent, with effects observed at appropriate concentrations. Comprehensive in vitro activity data are available from research publications.

Mice treated with manfodipir trisodium (10 mg/kg; intraperitoneal injection, once) did not exhibit skin injury from paclitaxel or cisplatin [3].

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In vivo, Mangafodipir trisodium has been used as a hepatocellular-specific contrast agent for MRI. Following intravenous administration, manganese is distributed to the liver and pancreas and shortens the T1-weighted relaxation time, enhancing MRI contrast. The compound is also an efficacious inhibitor of chemotherapy-induced peripheral neuropathy and other conditions caused by cellular oxidative stress. Mangafodipir trisodium shows no negative interference with the tumoricidal activity of chemotherapy. The compound's dual functionality as a contrast agent and antioxidant makes it a valuable tool for diagnostic imaging and oxidative stress research.

In vitro assays for Mangafodipir trisodium are primarily analytical and antioxidant-related. The compound's structure and purity can be characterized using analytical methods. High-performance liquid chromatography (HPLC) and mass spectrometry are used to verify the molecular weight (757.32 g/mol) and chemical composition (C22H27MnN4Na3O14P2). Purity (≥97.0%) is confirmed by HPLC analysis. Antioxidant activity can be assessed by measuring the compound's ability to scavenge reactive oxygen species in cell-free systems using fluorescent probes such as DCFH-DA or by measuring the inhibition of oxidative stress markers. The compound's paramagnetic properties can be characterized by measuring T1 relaxation times in vitro using MRI or NMR relaxometry.

In vitro cellular assays for Mangafodipir trisodium are performed using neuronal cell lines or other cell types to assess its antioxidant and neuroprotective effects. Cells are treated with chemotherapeutic agents (e.g., paclitaxel, oxaliplatin) to induce oxidative stress and neuropathy, in the presence or absence of the compound. Cell viability is measured using MTT or CellTiter-Glo assays. Reactive oxygen species (ROS) production is measured using fluorescent probes such as DCFH-DA. Mitochondrial membrane potential is assessed using fluorescent dyes such as JC-1. Apoptosis is measured using annexin V/propidium iodide staining or caspase activity assays. Cytotoxicity is assessed in parallel to ensure that observed effects are not due to cell death. The compound shows no negative interference with the tumoricidal activity of chemotherapy.

Animal/Disease Models: Female CD-1 (ICR) mice cisplatin and paclitaxel-induced ovarian injury [3]
Doses: 10 mg/kg
Route of Administration: intraperitoneal (ip) injection; 10 mg/kg, once
Experimental Results: Reduce the loss of primordial follicles, Decrease in secondary follicles and increase in antral follicles. Prevent changes in primary follicles caused by cisplatin and paclitaxel. Reduces the increase in caspase-3 levels induced by cisplatin and paclitaxel.

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In vivo animal studies for Mangafodipir trisodium are conducted using rodent models of chemotherapy-induced peripheral neuropathy (CIPN). Animals are treated with chemotherapeutic agents (e.g., paclitaxel, oxaliplatin) to induce neuropathy, in the presence or absence of the compound. Neuropathy is assessed by measuring mechanical allodynia using von Frey filaments and thermal hyperalgesia using the Hargreaves apparatus. Motor function is assessed using the rotarod test. Oxidative stress markers are measured in nerve tissues. For MRI studies, the compound is administered intravenously, and T1-weighted imaging is performed to assess liver and pancreas contrast enhancement. Pharmacokinetic studies assess drug concentrations in plasma and tissues. Efficacy is expressed as improvement in neuropathic parameters compared to vehicle-treated controls.

Metabolism / Metabolites
Organophosphate metabolism primarily occurs through oxidation, esterase hydrolysis, and reactions with glutathione. Demethylation and glucuronidation may also occur. Oxidation of organophosphate pesticides can produce moderately toxic products. Generally, thiophosphates themselves are not directly toxic and require oxidative metabolism to be converted into proximal toxins. Products produced by glutathione transferase reactions are generally less toxic. Paraoxygenase (PON1) is a key enzyme in organophosphate metabolism. PON1 can inactivate certain organophosphates through hydrolysis. PON1 hydrolyzes active metabolites in various organophosphate pesticides and nerve agents such as soman, sarin, and VX. The existence of PON1 polymorphism leads to differences in the enzyme level and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effects of organophosphate exposure.

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Pharmacokinetic properties of Mangafodipir trisodium have been characterized in preclinical and clinical studies. The compound has a molecular formula of C22H27MnN4Na3O14P2 and a molecular weight of 757.32 g/mol. Following intravenous administration, the compound is distributed to the liver and pancreas. Mangafodipir trisodium is a hepatocellular-specific contrast agent. The manganese ion is released from the chelate over time and is eliminated primarily through biliary excretion. The compound's pharmacokinetic profile supports its use as an MRI contrast agent. Comprehensive pharmacokinetic parameters including half-life, volume of distribution, clearance, and bioavailability have been characterized in clinical studies.

Toxicity Summary
Manganese is a cytotoxic agent that impairs transport systems, enzyme activity, and receptor function. It primarily targets the central nervous system, particularly the globus pallidus of the basal ganglia. Manganese ions (Mn(II)) are thought to enhance the auto-oxidation or turnover of various intracellular catecholamines, leading to increased production of free radicals, reactive oxygen species, and other cytotoxic metabolites, while simultaneously depleting cellular antioxidant defense mechanisms, ultimately resulting in oxidative damage and selective destruction of dopaminergic neurons. In addition to dopamine, manganese is also thought to disrupt other neurotransmitters, such as gamma-aminobutyric acid (GABA) and glutamate. For oxidative damage to occur, manganese must first inhibit the activity of the antioxidant enzyme manganese superoxide dismutase. The neurotoxicity of Mn(II) is also related to its ability to substitute for Ca(II) under physiological conditions. It can enter mitochondria via calcium uniporters, inhibiting mitochondrial oxidative phosphorylation. It may also inhibit Ca(II) efflux, leading to impaired mitochondrial membrane integrity. Mn(II) has been shown to significantly inhibit the activity of mitochondrial aconitase, thereby altering amino acid metabolism and cellular iron homeostasis. (L228)

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Mangafodipir trisodium has been evaluated for safety in clinical studies as an MRI contrast agent. The compound is generally well-tolerated, with adverse effects including mild to moderate reactions such as nausea, headache, and injection site reactions. As a manganese-based compound, there is a potential for manganese accumulation with repeated dosing. Standard toxicology studies in rodents and non-rodent species have evaluated the compound's safety profile. Parameters assessed include clinical observations, body weight, hematology, clinical chemistry, organ weights, and histopathology. The compound is also an efficacious inhibitor of CIPN and other conditions caused by cellular oxidative stress. Mangafodipir trisodium has been approved for use as an MRI contrast agent in some regions.

[1]. Karlsson JOG, et al. Mangafodipir a Selective Cytoprotectant - with Special Reference to Oxaliplatin and Its Association to Chemotherapy-Induced Peripheral Neuropathy (CIPN). Transl Oncol. 2017 Aug;10(4):641-649.
[2]. Wang C. Mangafodipir trisodium (MnDPDP)-enhanced magnetic resonance imaging of the liver and pancreas. Acta Radiol Suppl. 1998;415:1-31.
[3]. Qin Y, et al. Protective effects of mangafodipir against chemotherapy-induced ovarian damage in mice. Reprod Biol Endocrinol. 2018 Oct 27;16(1):106.

Mangafodipir Trisodium is the trisodium salt of manganese fordespyr and possesses potential antioxidant and chemoprotective activity. It consists of manganese(II) ions chelated on fordespyr (dipyridine diphosphate, or DPDP), enabling it to scavenge oxygen free radicals such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, potentially preventing damage to macromolecules like DNA from oxygen free radicals and minimizing the damage to normal tissues caused by oxygen free radical-related chemotherapy toxicity. However, this drug may enhance the generation of oxygen free radicals in chemotherapy-induced tumor cells, thereby enhancing chemotherapy-induced cytotoxicity; tumor cells have higher levels of reactive oxygen species than normal cells, thus having a lower threshold for oxygen free radical-mediated cytotoxicity. Manganese fordespyr has traditionally been used as an imaging agent in magnetic resonance imaging (MRI). Manganese fordespyr is an intravenously injected contrast agent used to enhance the contrast of liver MRI. It consists of two parts: paramagnetic manganese(II) ions and the chelating agent fordespyr (dipyridine diphosphate, DPDP). Normal liver tissue absorbs more manganese than abnormal or cancerous tissue. Manganese shortens the longitudinal relaxation time (T1), making normal tissue appear brighter in magnetic resonance imaging (MRI) images. This enhanced contrast makes lesions easier to identify. Acute intravenous toxicity studies in mice, rats, and dogs showed that manganese floccopil has low to moderate toxicity. Repeat-dose toxicity studies have been conducted in rats, cynomolgus monkeys, and dogs. The liver, and to a lesser extent the kidneys, are the target organs for toxicity.

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Drug Indications
This drug is for diagnostic use only. As a contrast agent for diagnostic magnetic resonance imaging (MRI) to detect liver lesions suspected of being caused by metastatic disease or hepatocellular carcinoma. As an adjunct to MRI, to help examine focal pancreatic lesions.

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Mangafodipir trisodium (MnDPDP) is a hepatocellular-specific contrast agent for MRI. It is a chelate of paramagnetic manganese for intravenous administration. The compound has a molecular formula of C22H27MnN4Na3O14P2 and a molecular weight of 757.32 g/mol. Mangafodipir trisodium is also an efficacious inhibitor of CIPN and other conditions caused by cellular oxidative stress. The compound shows no negative interference with the tumoricidal activity of chemotherapy. Mangafodipir trisodium has been approved for use as an MRI contrast agent in some regions. It is available from research chemical suppliers for non-clinical research purposes.

C22H24N4O14P2-8.MN+2.3[NA+]

754.299360000001

757.007

140678-14-4

Mangafodipir;155319-91-8

160036

Brown to reddish brown solid powder

1049.1ºC at 760 mmHg

588.3ºC

0mmHg at 25°C

3

18

13

46

873

0

O=C1[O-][Mn+2]([N]2(C3)CC4=C5COP(O)(O)=O)([O-]C6=C(N=C7)C)([O-]C4=C(N=C5)C)([O-]C3=O)[N](CC6=C7COP([O-])(O)=O)(CC2)C1.[Na+].[Na+].[Na+]

BENFPBJLMUIGGD-UHFFFAOYSA-I

InChI=1S/C22H32N4O14P2.Mn.3Na/c1-13-21(31)17(15(5-23-13)11-39-41(33,34)35)7-25(9-19(27)28)3-4-26(10-20(29)30)8-18-16(12-40-42(36,37)38)6-24-14(2)22(18)32;;;;/h5-6,31-32H,3-4,7-12H2,1-2H3,(H,27,28)(H,29,30)(H2,33,34,35)(H2,36,37,38);;;;/q;+2;3*+1/p-5

trisodium;2-[2-[carboxylatomethyl-[[2-methyl-3-oxido-5-(phosphonatooxymethyl)pyridin-4-yl]methyl]amino]ethyl-[[2-methyl-3-oxido-5-(phosphonatooxymethyl)pyridin-4-yl]methyl]amino]acetate;hydron;manganese(2+)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~33.33 mg/mL (~44.01 mM)

Solubility in Formulation 1: 100 mg/mL (132.04 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)