Use of 13C Isotopes in MR Research

Dr. Pratip Bhattacharya

California Institute of Technology and Huntington Medical Research Institutes

Stable isotopes have played a very useful role in MR research which involves both MRI and MRS. Of the various NMR active nuclei, 13C, 15N 31P, 23Na and 19F are the most biologically relevant. 13C MR research is the most comprehensive of all of them because of the versatile availability of organic molecules in the biological systems.

13C MRS : The power of 13C MRS lies in its unique chemical specificity, enabling detection and quantification of metabolic intermediates which would not be so readily monitored using conventional radiochemical techniques. Improvements in NMR technologies, now permits us to obtain in vivo localized 1 and non-localized 2 13C NMR spectra from rodent and human brain with similar quantity to those obtained earlier only under in vitro conditions, providing in this way a wealth of information on neurotransmitter recycling, cerebral bioenergetics in situ. In vivo and in vitro13C MRS was also accomplished in liver, skeletal muscle, heart, adipose tissue, kidney and pancreatic islets yielding a variety of invaluable information. Furthermore, 13C NMR has applied in clinical scene and has received FDA approval. Novel 13C neurochemical data has contributed to the understanding of Alzheimer’ Disease, Canavan’s Disease, mitochondrial and hepatic encephalopathy, epilepsy, childhood leuco dystrophy, schizophrenia normal brain development and lipid uptake. 3,4,5 Both in vivo ,in vitro and clinical 13C NMR methods employing labeled glucose and acetate, methionine, propionate, fatty acids have provided invaluable information on various aspects of modern biochemistry and neurochemistry, including the activity of the neuronal and glial TCA cycles and the operation of the intracellular glutamate-glutamine-GABA cycle in vivo 6, on carbohydrate metabolism and cerebral glycogen turnover 7, on cerebral metabolic pathways like pyruvate recycling system 8, on the exchange of metabolities between neuronal and glial cells 9, on the subcellular compartmentation of neurotransmitter amino acids 10, dynamic isotopomer analysis 11 etc. However 13C MRS is severely limited by its inherent low sensitivity and the clinical applications remain at low level because of the considerable cost of the 13C enriched isotopes.

Hyperpolarization: The sensitivity issue associated with the in vivo 13C NMR can be largely overcome by hyperpolarization techniques. Hyperpolarization involves several techniques like PHIP-PASADENA 12,13, DNP (14), Xe/He15 and are currently coming of age where 13C labeled molecules can be polarized exceeding the thermal equilibrium polarization by several orders of magnitude (SNR>10,000), which can then be employed to yield high resolution ultra fast MR images and spectra. Even though these techniques are under intense research, 13C isotopes will be used for various in vivo applications like high speed and high resolution angiography /morphology, quantitative and regional perfusion, metabolic mapping, molecular imaging, tissue pathology etc.

Pratip Bhattacharya, PhD is the James G. Boswell Fellow at California Institute of Technology and Huntington Medical Research Institute, Pasadena. His research includes 13C MRS, development of hyperpolarization techniques and its applications in chemistry, biology and in vivo systems.

References

1.
Blüml S, Hwang J, Moreno A, Ross BD. 2000. Novel Peak Assignments of in Vivo13C MRS in Human Brain at 1.5 T. Journal of Magnetic Resonance. 143(2):292-298. http://dx.doi.org/10.1006/jmre.1999.2001
2.
Gruetter R, Adriany G, Choi I, Henry P, Lei H, Öz G. 2003. Localizedin vivo13C NMR spectroscopy of the brain. NMR Biomed.. 16(67):313-338. http://dx.doi.org/10.1002/nbm.841
3.
Ross B, Lin A, Harris K, Bhattacharya P, Schweinsburg B. 2003. Clinical experience with13C MRSin vivo. NMR Biomed.. 16(67):358-369. http://dx.doi.org/10.1002/nbm.852
4.
Hwang J, Bluml S, Leaf A, Ross BD. 2003. In vivo characterization of fatty acids in human adipose tissue using natural abundance1H decoupled13C MRS at 1.5 T: clinical applications to dietary therapy. NMR Biomed.. 16(3):160-167. http://dx.doi.org/10.1002/nbm.824
5.
Harris K, Lin A, Bhattacharya P, Tran T, Wong W, Ross B. 2004. Proceedings of First International Symposium of N-Acetyl Aspartate NIH. Maryland: Bethesda.
6.
Rothman DL, Behar KL, Hyder F, Shulman RG. 2003. In vivo NMR Studies of the Glutamate Neurotransmitter Flux and Neuroenergetics: Implications for Brain Function. Annu. Rev. Physiol.. 65(1):401-427. http://dx.doi.org/10.1146/annurev.physiol.65.092101.142131
7.
Sonnewald U, Qu H, Aschner M. 2002. Pharmacology and Toxicology of Astrocyte-Neuron Glutamate Transport and Cycling. J Pharmacol Exp Ther. 301(1):1-6. http://dx.doi.org/10.1124/jpet.301.1.1
8.
Waagepetersen HS, Sonnewald U, Larsson OM, Schousboe A. 2001. Multiple compartments with different metabolic characteristics are involved in biosynthesis of intracellular and released glutamine and citrate in astrocytes. Glia. 35(3):246-252. http://dx.doi.org/10.1002/glia.1089
9.
Henry P, Öz G, Provencher S, Gruetter R. 2003. Toward dynamic isotopomer analysis in the rat brainin vivo: automatic quantitation of13C NMR spectra using LCModel. NMR Biomed.. 16(67):400-412. http://dx.doi.org/10.1002/nbm.840
10.
Ardenkjaer-Larsen JH, Fridlund B, Gram A, Hansson G, Hansson L, Lerche MH, Servin R, Thaning M, Golman K. 2003. Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR. Proceedings of the National Academy of Sciences. 100(18):10158-10163. http://dx.doi.org/10.1073/pnas.1733835100
11.
Bhattacharya P, Weitekamp D, Harris K, Lin A, Ross B. 2004. Abstract of the 21st ESMRMB Meeting. .
12.
Golman K, Ardenkjaer-Larsen JH, Petersson JS, Mansson S, Leunbach I. 2003. Molecular imaging with endogenous substances. Proceedings of the National Academy of Sciences. 100(18):10435-10439. http://dx.doi.org/10.1073/pnas.1733836100
13.
Cherubini A, Payne G, Leach M, Bifone A. 2003. Hyperpolarising 13C for NMR studies using laser-polarised 129Xe: SPINOE vs thermal mixing. Chemical Physics Letters. 371(5-6):640-644. http://dx.doi.org/10.1016/s0009-2614(03)00318-x

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