Anatomy, Functionality, and Neuronal Connectivity with Manganese Radiotracers for Positron Emission Tomography
- 290 Downloads
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 wordsManganese 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.
- 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. https://doi.org/10.1152/ajpendo.90336.2008 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1002/1522-2586(200007)12:1<186::AID-JMRI21>3.0.CO;2-2 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.2337/db16-1285 CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Martin RF, Bowden DM (2000) Primate brain maps: structure of the macaque brain. Elsevier © 2000 University of WashingtonGoogle Scholar