Industry Experts

The Essential Role of Enriched Stable Nuclides in Positron Emission Tomography (PET)

Professor Michael J. Welch
Division of Radiological Sciences
Washington University School of Medicine

Positron Emission Tomography (PET) is one of the most rapidly expanding areas of medical diagnosis. PET is routinely used in determining the extent of tumor metastases, utilizing an analog of glucose in which the hydroxy group at the two position is replaced by a radioactive fluorine atom. This compound, 2-fluoro-2-deoxy-Dglucose (FDG), is taken up in tissues in an amount very similar to glucose, but is retained in the tissue unlike normal glucose, which is rapidly metabolized largely to water and carbon dioxide. This retention of the radioactivity allows the visualization of tumors, which metabolize glucose to a greater extent than normal tissue. In research studies, the glucose utilization of the tumors can be quantified. Due to the two-hour half-life of fluorine-18, this compound must be distributed from regional centers. All of these centers utilize enriched oxygen-18 to produce the fluoride used to make FDG. Fluorine-18 is reacted with agents also supplied by Sigma-Aldrich to produce the radioactive drug used in the medical diagnostic studies.

Other enriched compounds include enriched molecular oxygen and nitrogen enriched in nitogen-13 and are also used as target materials to produce PET radiopharmaceuticals. Oxygen gas is used in several centers to produce another radioactive drug, fluorine-18-labeled dopamine, used to study brain function, particularly in patients with schizophrenia and other psychiatric diseases. In the most common cyclotron used to produce PET radiopharmaceuticals, the enriched nitrogen is used to produce a series of very simple compounds containing radioactive oxygen-15. Oxygen-15, which has a two-minute half-life, can be used to study brain blood flow and brain oxygen metabolism. In a multicenter study funded by the National Institutes of Neurological Diseases and Stroke, labeled oxygen is being used to predict which patients will benefit from a brain surgery intracranial/extracranial bypass surgery, which restores blood flow to areas of the brain where delivery of oxygen is significantly reduced. Imaging relies upon the supply of enriched stable isotopes. In the future, it is anticipated that a whole battery of new compounds will be used to study many other parameters in tumors, brain and heart diseases, and they will rely upon the continued supply of stable isotopes.

Literature of Interest

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2. Welch, M. J.; Lifton, J. F.; Seck, J. A. Tracer Studies with Radioactive Oxygen-15. Exchange Between Carbon Dioxide and Water. J. Phys. Chem. 1969, 73, 3351.


3. Rodriguez, M.; Rehn, S.; Ahlstrom, H.; Sundstrom, C.;Glimelius, B. Predicting malignancy grade with PET in non-Hodgkin’s lymphoma. J. Nucl. Med. 1995, 36, 1790.


4. Yoshioka, T.; Takahashi, H.; Oikawa, H.; Maeda, S.; Wakui, A.; Watanabe, T.; Tezuka, F.; Takahashi, T.; Ido, T.; Kanamaru, R. Accumulation of 2-deoxy-2[sup>18F]fluoro-d-glucose in human cancers heterotransplanted in nude mice: comparison between histology and glycolytic status. J. Nucl. Med. 1994, 35, 97.


5. Gallagher, B. M.; Ansari, A.; Atkins, H.; Casella, V.; Christman, D. R.; Fowler, J. S.; Ido, T.; MacGregor, R. R.; Som, P.; Wan, C. N.; Wolf, A. P.; Kuhl, D. E.; Reivich, M. Radiopharmaceuticals XXVII. ¹⁸F-labeled 2-deoxy-2-fluorod-glucose as a radiopharmaceutical for measuring regional myocardial glucose metabolism in vivo: tissue distribution and imaging studies in animals. J. Nucl. Med. 1977, 18, 990.


6. Berry, J. J.; Baker, J. A.; Pieper, K. S.; Hanson, M. W.; Hoffman, J. M.; Coleman, R. E. The effect of metabolic milieu on cardiac PET imaging using fluorine-18-deoxyglucose and nitrogen-13-ammonia in normal volunteers. J. Nucl. Med. 1991, 32, 1518.

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Use of 13C Isotopes in MR Research




Dr. Pratip Bhattacharya
California Institute of Technology and Huntington Medical Research Institutes, Pasadena, California

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) 13}C 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/He(15) 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.

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