Molecular Imaging and Biology

, Volume 20, Issue 4, pp 562–574 | Cite as

Anatomy, Functionality, and Neuronal Connectivity with Manganese Radiotracers for Positron Emission Tomography

  • Galit Saar
  • Corina M. Millo
  • Lawrence P. Szajek
  • Jeff Bacon
  • Peter Herscovitch
  • Alan P. KoretskyEmail author
Research Article



Manganese ion has been extensively used as a magnetic resonance imaging (MRI) contrast agent in preclinical studies to assess tissue anatomy, function, and neuronal connectivity. Unfortunately, its use in human studies has been limited by cellular toxicity and the need to use a very low dose. The much higher sensitivity of positron emission tomography (PET) over MRI enables the use of lower concentrations of manganese, potentially expanding the methodology to humans.


PET tracers manganese-51 (Mn-51, t1/2 = 46 min) and manganese-52 (Mn-52, t1/2 = 5.6 days) were used in this study. The biodistribution of manganese in animals in the brain and other tissues was studied as well as the uptake in the pancreas after glucose stimulation as a functional assay. Finally, neuronal connectivity in the olfactory pathway following nasal administration of the divalent radioactive Mn-52 ([52Mn]Mn2+) was imaged.


PET imaging with the divalent radioactive Mn-51 ([51Mn]Mn2+) and [52Mn]Mn2+ in both rodents and monkeys demonstrates that the accumulation of activity in different organs is similar to that observed in rodent MRI studies following systemic administration. Furthermore, we demonstrated the ability of manganese to enter excitable cells. We followed activity-induced [51Mn]Mn2+ accumulation in the pancreas after glucose stimulation and showed that [52Mn]Mn2+ can be used to trace neuronal connections analogous to manganese-enhanced MRI neuronal tracing studies.


The results were consistent with manganese-enhanced MRI studies, despite the much lower manganese concentration used for PET (100 mM Mn2+ for MRI compared to ~ 0.05 mM for PET). This indicates that uptake and transport mechanisms are comparable even at low PET doses. This helps establish the use of manganese-based radiotracers in both preclinical and clinical studies to assess anatomy, function, and connectivity.

Key words

Manganese PET MEMRI Mn-51 Mn-52 Neuronal connectivity Pancreas 



This research was supported (in part) by the Intramural Research Program of the NIH, NINDS. We thank Nadia Bouraoud and Kathy Sharer for assistance with animal procedures and animal handling. We thank the NIH PET Department for providing excellent technical support and for production of the PET radiotracers. We thank Dr. Baris Turkbey and Dr. Dima Hammoud for their help with CT registration.

Compliance with Ethical Standards

All animal studies were approved by the Animal Care and Use Committees of the National Institute of Neurological Disorders and Stroke (rats), and the NIH Clinical Center (monkeys) and were performed in accordance with the regulations of the Division of Radiation Safety, at the National Institutes of Health (Bethesda, MD, USA).

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

11307_2018_1162_MOESM1_ESM.pdf (206 kb)
ESM 1 (PDF 205 kb)


  1. 1.
    Antkowiak PF, Tersey SA, Carter JD, Vandsburger MH, Nadler JL, Epstein FH, Mirmira RG (2009) Noninvasive assessment of pancreatic beta-cell function in vivo with manganese-enhanced magnetic resonance imaging. Am J Physiol Endocrinol Metab 296(3):E573–E578. CrossRefPubMedGoogle Scholar
  2. 2.
    Hu TC, Christian TF, Aletras AH et al (2005) Manganese enhanced magnetic resonance imaging of normal and ischemic canine heart. Magn Reson Med 54(1):196–200. CrossRefPubMedGoogle Scholar
  3. 3.
    Kang YS, Gore JC (1984) Studies of tissue NMR relaxation enhancement by manganese. Dose Time Depend Invest Radiol 19(5):399–407. CrossRefGoogle Scholar
  4. 4.
    Ni Y, Petre C, Bosmans H et al (1997) Comparison of manganese biodistribution and MR contrast enhancement in rats after intravenous injection of MnDPDP and MnCl2. Acta Radiol 38:700–707CrossRefPubMedGoogle Scholar
  5. 5.
    Aoki I, Wu YJ, Silva AC et al (2004) In vivo detection of neuroarchitecture in the rodent brain using manganese-enhanced MRI. NeuroImage 22(3):1046–1059. CrossRefPubMedGoogle Scholar
  6. 6.
    Watanabe T, Natt O, Boretius S, Frahm J, Michaelis T (2002) In vivo 3D MRI staining of mouse brain after subcutaneous application of MnCl2. Magn Reson Med 48(5):852–859. CrossRefPubMedGoogle Scholar
  7. 7.
    Aoki I, Tanaka C, Takegami T et al (2002) Dynamic activity-induced manganese-dependent contrast magnetic resonance imaging (DAIM MRI). Magn Reson Med 48:927–933CrossRefPubMedGoogle Scholar
  8. 8.
    Hu TC, Pautler RG, MacGowan GA, Koretsky AP (2001) Manganese-enhanced MRI of mouse heart during changes in inotropy. Magn Reson Med 46(5):884–890. CrossRefPubMedGoogle Scholar
  9. 9.
    Lin YJ, Koretsky AP (1997) Manganese ion enhances T1-weighted MRI during brain activation: an approach to direct imaging of brain function. Magn Reson Med 38(3):378–388. CrossRefPubMedGoogle Scholar
  10. 10.
    Pautler RG, Silva AC, Koretsky AP (1998) In vivo neuronal tract tracing using manganese-enhanced magnetic resonance imaging. Magn Reson Med 40(5):740–748. CrossRefPubMedGoogle Scholar
  11. 11.
    Watanabe T, Michaelis T, Frahm J (2001) Mapping of retinal projections in the living rat using high-resolution 3D gradient-echo MRI with Mn2+-induced contrast. Magn Reson Med 46:424–429CrossRefPubMedGoogle Scholar
  12. 12.
    Chuang KH, Koretsky AP (2009) Accounting for nonspecific enhancement in neuronal tract tracing using manganese enhanced magnetic resonance imaging. Magn Reson Imaging 27(5):594–600. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Cross DJ, Minoshima S, Anzai Y et al (2004) Statistical mapping of functional olfactory connections of the rat brain in vivo. NeuroImage 23:1326–1335CrossRefPubMedGoogle Scholar
  14. 14.
    Murayama Y, Weber B, Saleem KS et al (2006) Tracing neural circuits in vivo with Mn-enhanced MRI. Magn Reson Imaging 24:349–358CrossRefPubMedGoogle Scholar
  15. 15.
    Van der Linden A, Verhoye M, Van Meir V et al (2002) In vivo manganese-enhanced magnetic resonance imaging reveals connections and functional properties of the songbird vocal control system. Neuroscience 112:467–474CrossRefPubMedGoogle Scholar
  16. 16.
    Allegrini PR, Wiessner C (2003) Three-dimensional MRI of cerebral projections in rat brain in vivo after intracortical injection of MnCl2. NMR Biomed 16(5):252–256. CrossRefPubMedGoogle Scholar
  17. 17.
    Tucciarone J, Chuang KH, Dodd SJ, Silva A, Pelled G, Koretsky AP (2009) Layer specific tracing of corticocortical and thalamocortical connectivity in the rodent using manganese enhanced MRI. NeuroImage 44(3):923–931. CrossRefPubMedGoogle Scholar
  18. 18.
    Saleem KS, Pauls JM, Augath M, Trinath T, Prause BA, Hashikawa T, Logothetis NK (2002) Magnetic resonance imaging of neuronal connections in the macaque monkey. Neuron 34(5):685–700. CrossRefPubMedGoogle Scholar
  19. 19.
    Pautler RG, Mongeau R, Jacobs RE (2003) In vivo trans-synaptic tract tracing from the murine striatum and amygdala utilizing manganese enhanced MRI (MEMRI). Magn Reson Med 50:33–39CrossRefPubMedGoogle Scholar
  20. 20.
    Federle MP, Chezmar JL, Rubin DL, Weinreb JC, Freeny PC, Semelka RC, Brown JJ, Borrello JA, Lee JKT, Mattrey R, Dachman AH, Saini S, Harmon B, Fenstermacher M, Pelsang RE, Harms SE, Mitchell DG, Halford III HH, Anderson MW, Johnson CD, Francis IR, Bova JG, Kenney PJ, Klippenstein DL, Foster GS, Turner DA, Stillman AE, Nelson RC, Young SW, Patt RH, Rifkin M, Seltzer SE, Gay SB, Robison RO, Sherwin PF, Ballerini R (2000) Safety and efficacy of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the U.S. multicenter phase III clinical trials (safety). J Magn Reson Imaging 12(1):186–197.<186::AID-JMRI21>3.0.CO;2-2 CrossRefPubMedGoogle Scholar
  21. 21.
    Skjold A, Amundsen BH, Wiseth R, Støylen A, Haraldseth O, Larsson HBW, Jynge P (2007) Manganese dipyridoxyl-diphosphate (MnDPDP) as a viability marker in patients with myocardial infarction. J Magn Reson Imaging 26(3):720–727. CrossRefPubMedGoogle Scholar
  22. 22.
    Schima W, Fugger R, Schober E et al (2002) Diagnosis and staging of pancreatic cancer: comparison of mangafodipir trisodium-enhanced MR imaging and contrast-enhanced helical hydro-CT. AJR Am J Roentgenol 179:717–724CrossRefPubMedGoogle Scholar
  23. 23.
    Dastur DK, Manghani DK, Raghavendran KV (1971) Distribution and fate of 54Mn in the monkey: studies of differnnt parts of the central nervous system and other organs. J Clin Invest 50(1):9–20. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lyden A, Larsson BS, Lindquist NG (1983) Autoradiography of manganese: accumulation and retention in the pancreas. Acta Pharmacol Toxicol (Copenh) 52(3):205–210CrossRefGoogle Scholar
  25. 25.
    Sloot WN, Gramsbergen JB (1994) Axonal transport of manganese and its relevance to selective neurotoxicity in the rat basal ganglia. Brain Res 657(1-2):124–132. CrossRefPubMedGoogle Scholar
  26. 26.
    Tjalve H, Henriksson J, Tallkvist J et al (1996) Uptake of manganese and cadmium from the nasal mucosa into the central nervous system via olfactory pathways in rats. Pharmacol Toxicol 79:347–356CrossRefPubMedGoogle Scholar
  27. 27.
    Takeda A, Kodama Y, Ishiwatari S, Okada S (1998) Manganese transport in the neural circuit of rat CNS. Brain Res Bull 45(2):149–152. CrossRefPubMedGoogle Scholar
  28. 28.
    Mena I, Marin O, Fuenzalida S, Cotzias GC (1967) Chronic manganese poisoning. Clinical picture and manganese turnover. Neurology 17(2):128–136. CrossRefPubMedGoogle Scholar
  29. 29.
    Mahoney JP, Small WJ (1968) Studies on manganese. 3. The biological half-life of radiomanganese in man and factors which affect this half-life. J Clin Invest 47(3):643–653. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Atkins HL, Som P, Fairchild RG et al (1979) Myocardial positron tomography with manganese-52m. Radiology 133:769–774CrossRefPubMedGoogle Scholar
  31. 31.
    Chauncey DM Jr, Schelbert HR, Halpern SE et al (1977) Tissue distribution studies with radioactive manganese: a potential agent for myocardial imaging. J Nucl Med 18(9):933–936PubMedGoogle Scholar
  32. 32.
    Topping GJ, Schaffer P, Hoehr C, Ruth TJ, Sossi V (2013) Manganese-52 positron emission tomography tracer characterization and initial results in phantoms and in vivo. Med Phys 40(4):042502. CrossRefPubMedGoogle Scholar
  33. 33.
    Brunnquell CL, Hernandez R, Graves SA et al (2016) Uptake and retention of manganese contrast agents for PET and MRI in the rodent brain. Contrast Media Mol Imaging 11:371–380CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Graves SA, Hernandez R, Fonslet J et al (2015) Novel preparation methods of (52)Mn for ImmunoPET imaging. Bioconjug Chem 26:2118–2124CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hernandez R, Graves SA, Gregg T, VanDeusen HR, Fenske RJ, Wienkes HN, England CG, Valdovinos HF, Jeffery JJ, Barnhart TE, Severin GW, Nickles RJ, Kimple ME, Merrins MJ, Cai W (2017) Radiomanganese PET detects changes in functional beta-cell mass in mouse models of diabetes. Diabetes 66(8):2163–2174. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Topping GJ, Yung A, Schaffer P, Hoehr C, Kornelsen R, Kozlowski P, Sossi V (2017) Manganese concentration mapping in the rat brain with MRI, PET, and autoradiography. Med Phys 44(8):4056–4067. CrossRefPubMedGoogle Scholar
  37. 37.
    Napieczynska H, Severin GW, Fonslet J, Wiehr S, Menegakis A, Pichler BJ, Calaminus C (2017) Imaging neuronal pathways with 52Mn PET: toxicity evaluation in rats. NeuroImage 158:112–125. CrossRefPubMedGoogle Scholar
  38. 38.
    Klein ATJ, Rosch F, Coenen HH, Qaim SM (2002) Production of the positron emitter Mn-51 via the Cr-50(d, n) reaction: targetry and separation of no-carrier-added radiomanganese. Radiochim Acta 90:167–177CrossRefGoogle Scholar
  39. 39.
    Sastri CS, Petri H, Kueppers G, Erdtmann G (1981) Production of Mn-52 of high isotopic purity by He-3-activation of vanadium. Int J Appl Radiat Isot 32(4):246–247. CrossRefGoogle Scholar
  40. 40.
    Gimi B, Leoni L, Oberholzer J et al (2006) Functional MR microimaging of pancreatic beta-cell activation. Cell Transplant 15:195–203CrossRefPubMedGoogle Scholar
  41. 41.
    Leoni L, Serai SD, Haque ME, Magin RL, Roman BB (2010) Functional MRI characterization of isolated human islet activation. NMR Biomed 23(10):1158–1165. CrossRefPubMedGoogle Scholar
  42. 42.
    Martin RF, Bowden DM (2000) Primate brain maps: structure of the macaque brain. Elsevier © 2000 University of WashingtonGoogle Scholar
  43. 43.
    Takagi SF (1986) Studies on the olfactory nervous system of the Old World monkey. Prog Neurobiol 27(3):195–250. CrossRefPubMedGoogle Scholar
  44. 44.
    Graves SA, Hernandez R, Valdovinos HF et al (2017) Preparation and in vivo characterization of 51MnCl2 as PET tracer of Ca2+ channel-mediated transport. Sci Rep 7:3033CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Aschner M, Erikson KM, Dorman DC (2005) Manganese dosimetry: species differences and implications for neurotoxicity. Crit Rev Toxicol 35(1):1–32. CrossRefPubMedGoogle Scholar
  46. 46.
    Nagata M, Kagawa T, Koutou D et al (2011) Measurement of manganese content in various organs in rats with or without glucose stimulation. Radiol Phys Technol 4:7–12CrossRefPubMedGoogle Scholar
  47. 47.
    Lee JH, Silva AC, Merkle H, Koretsky AP (2005) Manganese-enhanced magnetic resonance imaging of mouse brain after systemic administration of MnCl2: dose-dependent and temporal evolution of T1 contrast. Magn Reson Med 53(3):640–648. CrossRefPubMedGoogle Scholar
  48. 48.
    Yu X, Zou J, Babb JS, Johnson G, Sanes DH, Turnbull DH (2008) Statistical mapping of sound-evoked activity in the mouse auditory midbrain using Mn-enhanced MRI. NeuroImage 39(1):223–230. CrossRefPubMedGoogle Scholar
  49. 49.
    Eschenko O, Canals S, Simanova I et al (2010) Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: implication for longitudinal studies. NeuroImage 49:2544–2555CrossRefPubMedGoogle Scholar

Copyright information

© World Molecular Imaging Society 2018

Authors and Affiliations

  • Galit Saar
    • 1
  • Corina M. Millo
    • 2
  • Lawrence P. Szajek
    • 2
  • Jeff Bacon
    • 2
  • Peter Herscovitch
    • 2
  • Alan P. Koretsky
    • 1
    Email author
  1. 1.Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of HealthBethesdaUSA
  2. 2.PET Department, Clinical CenterNational Institutes of HealthBethesdaUSA

Personalised recommendations