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

<div><p>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 <i>manganism</i>. 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 (<i>t</i>_<i>1/2</i> = 5.6 d) by proton bombardment (<i>E</i>_<i>p</i><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. <i>Ex vivo</i> 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 <i>in vivo</i> imaging by positron emission tomography (PET) and <i>ex vivo</i> 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.</p></div

Plot showing results from <i>ex vivo</i> biodistribution of saline solutions containing ⁵²Mn administered via intravenous injection or inhalation.

<p>The timepoints shown represent the time after administration of the dose. Results for the <i>p</i>-values from Student’s <i>t</i>-test with Welch’s correction at 1 d p.i. only: *: <i>p</i><5%; **: <i>p</i><0.1%; ***: <i>p</i><0.01%; -: <i>p</i>≥5%. Sample sizes for each timepoint were n = 4 mice for injection and n = 3 for inhalation. Uncertainties: one absolute standard deviation in units of %ID/g. Error bars were only drawn in the positive direction for visual clarity. The plotted data is presented in numerical form in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0174351#pone.0174351.t001" target="_blank">Table 1</a>.</p

Radiosynthesis and Biological Distribution of ¹⁸F‑Labeled Perfluorinated Alkyl Substances

A novel method for radiolabeling perfluorinated alkyl substances (PFAS) with fluorine 18 has been developed, and after purification, the stability and biological distribution in healthy mice were evaluated. Three PFAS, [¹⁸F]­PFOA (C8), [¹⁸F]­PFHxA (C6), and [¹⁸F]­PFBA (C4), were readily labeled and isolated in average yields between 12 and 31%. The stability of each compound was monitored in 0.1% ammonium hydroxide (NH₄OH) in methanol, in saline, and in human, mouse, and rat sera. The amount of intact, radiolabeled PFAS was determined by radiometric instant thin layer chromatography and was calculated by the amount of free fluorine 18 observed over time. All compounds were highly stable in 0.1% NH₄OH in methanol and saline, with <10% defluorination observed after 4 h. Interestingly, each compound had differing affinities for the serum proteins. <i>In vivo</i> biodistribution studies in mice showed uptake in all organs examined, with the highest uptake being exhibited in the liver for both [¹⁸F]­PFOA and [¹⁸F]­PFHxA and the stomach for [¹⁸F]­PFBA. The results of this initial study suggest that this method could be valuable in helping to determine the biological uptake of any PFAS in mammals