Optimized procedures for manganese-52: Production, separation and radiolabeling

Fonslet, Jesper; Tietze, Sabrina; Jensen, Andreas Tue Ingemann; Graves, Stephen A.; Severin, Gregory

doi:10.1016/j.apradiso.2016.11.021

Cited by 42 publications

(45 citation statements)

References 17 publications

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“…Several separation procedures have been published for 52 Mn from a chromium metal target [39, 43, 46–52]. Following a method published by Buchholz, et al in 2013 [50], cation-exchange chromatography was used to separate 52 Mn from the chromium metal target after proton bombardment.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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“…The isotope production and separation methods have been elaborated (Lahiri et al, 2006, Buchholz et al, 2013, Buchholz et al, 2015, Fonslet et al, 2017 and the first preclinical application study has been performed (Lewis et al, 2015). In that work, 52 Mn was proposed as a dual-modality (PET-MRI) tool for long-term tracking of human stem cells transplanted into a rat brain.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, 52 Mn production and separation methods have been recently developed and optimized (Lahiri et al, 2006, Buchholz et al, 2013, Buchholz et al, 2015, Fonslet et al, 2017 and the tracer has been just introduced into the field of preclinical imaging (Topping et al, 2013, Lewis et al, 2015. The biggest advantage of using 52 Mn for tracing neuronal pathways would lie in the possibility to reduce the manganese dose to the pico-molar range which should eliminate the toxic effects and allow multiple administrations.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats

et al. 2017

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Manganese in its divalent state (Mn 2+ ) has features that make it a unique tool for tracing neuronal pathways. It is taken up and transported by neurons in an activity dependent manner and it can cross synapses. It also acts as a contrast agent for magnetic resonance imaging (MRI) enabling visualization of neuronal tracts. However, due to the limited sensitivity of MRI systems relatively high Mn 2+ doses are required. This is undesirable, especially in long-term studies, because of the known toxicity of the metal.In order to overcome this limitation, we propose 52 Mn as a positron emission tomography (PET) neuronal tract tracer. We used 52 Mn for imaging dopaminergic pathways after a unilateral injection into the ventral tegmental area (VTA), as well as the striatonigral pathway after an injection into the dorsal striatum (STR) in rats. Furthermore, we tested potentially noxious effects of the radioactivity dose with a behavioral test and histological staining. 24 h after 52 Mn administration, the neuronal tracts were clearly visible in PET images and statistical analysis confirmed the observed distribution of the tracer. We noticed a behavioral impairment in some animals treated with 170 kBq of 52 Mn, most likely caused by dysfunction of dopaminergic cells. Moreover, there was a substantial DNA damage in the brain tissue after applying 150 kBq of the tracer. However, all those effects were completely eliminated by reducing the 52 Mn dose to 20-30 kBq. Crucially, the reduced dose was still sufficient for PET imaging.

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“…52 Mn can be produced in small biomedical cyclotrons at low proton energies using pressed natural chromium targets. 56 For incident proton energies of 16 MeV and "thick" targets, average production yields of 6.2 MBq/ μAh are typical. Importantly, due to the high natural abundance of 52 Cr (83.8%) and low coproduction yields of Mn radioisotopic impurities, nat Cr targets are a viable, inexpensive alternative to the enriched target material for preclinical studies.…”

Section: Y-86mentioning

confidence: 99%

“…The most recently reported separations of 52 Mn from the target material use solid-phase anion exchange in ethanolic HCl and recover >90% of the 52 Mn with 10 5-6 decontamination factors from chromium, copper, iron, cobalt, and zinc. 56 Similar to other hard transition metals, Mn 2+ forms highly stable complexes with polyaminocarboxylic acid chelators. From those, DOTA has been the most common choice of chelator for the manganese chelation.…”

Section: Y-86mentioning

confidence: 99%

PET radiometals for antibody labeling

Aluicio‐Sarduy

Ellison

Barnhart

et al. 2018

Labelled Comp Radiopharmac

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Recent advances in molecular characterization of tumors have made possible the emergence of new types of cancer therapies where traditional cytotoxic drugs and nonspecific chemotherapy can be complemented with targeted molecular therapies. One of the main revolutionary treatments is the use of monoclonal antibodies (mAbs) that selectively target the disseminated tumor cells while sparing normal tissues. mAbs and related therapeutics can be efficiently radiolabeled with a wide range of radionuclides to facilitate preclinical and clinical studies. Non-invasive molecular imaging techniques, such as Positron Emission Tomography (PET), using radiolabeled mAbs provide useful information on the whole-body distribution of the biomolecules, which may enable patient stratification, diagnosis, selection of targeted therapies, evaluation of treatment response, and prediction of dose limiting tissue and adverse effects. In addition, when mAbs are labeled with therapeutic radionuclides, the combination of immunological and radiobiological cytotoxicity may result in enhanced treatment efficacy. The pharmacokinetic profile of antibodies demands the use of long half-life isotopes for longitudinal scrutiny of mAb biodistribution and precludes the use of well-stablished short half-life isotopes. Herein, we review the most promising PET radiometals with chemical and physical characteristics that make the appealing for mAb labeling, highlighting those with theranostic radioisotopes.

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Optimized procedures for manganese-52: Production, separation and radiolabeling

Cited by 42 publications

References 17 publications

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

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

Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats

PET radiometals for antibody labeling

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