Research Article: Biodistribution and PET Imaging of pharmacokinetics of manganese in mice using Manganese-52

Date Published: March 17, 2017

Publisher: Public Library of Science

Author(s): A. Lake Wooten, Tolulope A. Aweda, Benjamin C. Lewis, Rebecca B. Gross, Suzanne E. Lapi, Ludwig Dubois.

http://doi.org/10.1371/journal.pone.0174351

Abstract

Manganese is essential to life, and humans typically absorb sufficient quantities of this element from a normal healthy diet; however, chronic, elevated ingestion or inhalation of manganese can be neurotoxic, potentially leading to manganism. Although imaging of large amounts of accumulated Mn(II) is possible by MRI, quantitative measurement of the biodistribution of manganese, particularly at the trace level, can be challenging. In this study, we produced the positron-emitting radionuclide 52Mn (t1/2 = 5.6 d) by proton bombardment (Ep<15 MeV) of chromium metal, followed by solid-phase isolation by cation-exchange chromatography. An aqueous solution of [52Mn]MnCl2 was nebulized into a closed chamber with openings through which mice inhaled the aerosol, and a separate cohort of mice received intravenous (IV) injections of [52Mn]MnCl2. Ex vivo biodistribution was performed at 1 h and 1 d post-injection/inhalation (p.i.). In both trials, we observed uptake in lungs and thyroid at 1 d p.i. Manganese is known to cross the blood-brain barrier, as confirmed in our studies following IV injection (0.86%ID/g, 1 d p.i.) and following inhalation of aerosol, (0.31%ID/g, 1 d p.i.). Uptake in salivary gland and pancreas were observed at 1 d p.i. (0.5 and 0.8%ID/g), but to a much greater degree from IV injection (6.8 and 10%ID/g). In a separate study, mice received IV injection of an imaging dose of [52Mn]MnCl2, followed by in vivo imaging by positron emission tomography (PET) and ex vivo biodistribution. The results from this study supported many of the results from the biodistribution-only studies. In this work, we have confirmed results in the literature and contributed new results for the biodistribution of inhaled radiomanganese for several organs. Our results could serve as supporting information for environmental and occupational regulations, for designing PET studies utilizing 52Mn, and/or for predicting the biodistribution of manganese-based MR contrast agents.

Partial Text

Manganese is a micronutrient that is essential for human life in only trace amounts [1, 2], but deficiency is rare [3]. Existing primarily in the Mn(IV) oxidation state in the earth’s crust [4], manganese is the third most abundant transition metal in the crust [4] and is taken up by plants, where it is utilized in green leaves as an oxidizer in photosynthesis [4]. Manganese(II) is by far the most electrochemically stable oxidation state for manganese [4] and the state that is predominantly used as an enzymatic cofactor. Manganese in the blood is found as Mn(III) bound to binding sites for Fe(III) on transferrin [5, 6] or as Mn(II) bound to other serum proteins [7], but the vast majority of manganese leaves the blood quickly and is accumulated in various organs or excreted [8]. The necessity of manganese as a nutrient is sometimes overshadowed by its neurotoxic effects that can result in manganism [2], a condition that was first described in 1837 [9]. In mangansim, early-stage patients often present with psychiatric symptoms [10, 11] that are sometimes referred to as “manganese madness” [12]. Later-stage patients develop symptoms of parkinsonism, including intellectual impairment, tremors, and rigidity similar to idiopathic Parkinson’s disease [9, 12–14], with a few key differences [12].

For the biodistribution-only study, bombardment of natCr metal foils with ~13.4 MeV protons for a total of 27 μA·h (12 μA), which produced 41 MBq (1.1 mCi) (decay-corrected to end-of-bombardment), which was 69.6% of theoretical yield based on our published cross-section results [41]. Fig 1 and Table 1 show the results from ex vivo biodistribution of 52Mn in saline administered via intravenous injection or by inhalation. Manganese-52 was cleared rapidly from the blood, as demonstrated by its rapid decrease from 1 h to 1 d p.i., and the activity in the gastrointestinal tract—stomach and intestines—also decreased rapidly between these timepoints. At 1 h p.i., the highest activity was found, in decreasing order, in the liver, kidney, lung, heart, pancreas, spleen, and salivary glands (Table 1); however, by 1 d p.i., the concentration of 52Mn in all of these organs of high initial uptake had decreased substantially, except for the salivary glands, pancreas, and kidney, as shown in Fig 1. Among the other tissues, which had lower uptake at 1 h p.i., 52Mn was retained to various degrees in the brain, bone, and thyroid.

For the comparison of IV injection to inhalation of 52Mn in mice, the concentration of 52Mn in most tissues at both 1 h and 1 d timepoints is higher than in the inhalation results. The activity in the gastrointestinal tract was much greater in the inhalation results, suggesting that some of the dose may have been swallowed directly from the aerosol or inhaled, cleared by mucociliary clearance, and then swallowed. Also in our studies, we observed uptake in the pancreas and brain, while 52Mn that entered the stomach or intestines did not appear to be retained, although the one hour amounts were much higher in the inhalation groups likely due to putative swallowing of some of the dose. Retention of 52Mn in the brain, thyroid, and thymus was observed in results from both injection and inhalation. We also found significant uptake of 52Mn at 1 d in the bone (2.6%ID/g) resulting from injection, but not from inhalation.

In this work, we have produced 52Mn via the natCr(p,x) reaction, chemically isolated this radioisotope of manganese from the chromium metal target material, and reported new data for the biodistribution of manganese in mice following administration by IV injection or inhalation. Manganese-52 was produced by cyclotron bombardment with low-energy protons on chromium metal, and subsequent chemical separation of 52Mn(II) was performed by cation-exchange chromatography and re-dissolved in saline solution for ex vivo biodistribution studies in mice. The doses were administered by IV injection or inhalation, always resulting in uptake of 52Mn in the brain, thyroid, and pancreas. Interestingly, uptake from IV administration was higher in brain and pancreas, but lower in thyroid, compared to inhalation results. While 52Mn might find use as a PET agent in preclinical studies, our biodistribution results in mice may be used to inform regulations for safe levels of environmental and occupational exposure to Mn(II) and the predicted biodistribution of Mn(II) following exposure by IV injection or inhalation.

“This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or limited, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States Government or any agency thereof. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof.”

 

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http://doi.org/10.1371/journal.pone.0174351

 

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