Positron emitting radionuclides have unique properties that make them nearly ideal as radioactive tracers for in vivo metabolic studies. Using positron emission tomographic (PET) scanning and positron-labeled radiopharmaceuticals, one can study local glucose metabolism in tissues, blood flow, oxygen utilization, protein synthesis, and many other functions noninvasively in normal subjects and patients who have various diseases. A review of some of these techniques and the relative advantages and problems associated with the PET approach is presented

Keyes, John W., Jr.

English

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Henry Ford Hospital Medical Journal Volume 33 Number 2 Medical Imaging 1985 Article 14 6-1985 Current Concepts of Metabolic Functional Imaging with Positron Emitters John W. Keyes Jr. Follow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournal  Part of the Life Sciences Commons, Medical Specialties Commons, and the Public Health Commons Recommended Citation Keyes, John W. Jr. (1985) "Current Concepts of Metabolic Functional Imaging with Positron Emitters," Henry Ford Hospital Medical Journal : Vol. 33 : No. 2 , 138-141. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol33/iss2/14 This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Henry Ford Hosp Med J Vol 33, Nos 2 and 3, 1985 Current Concepts of Metabolic Functional Imaging with Positron Emitters John W. Keyes, Jr, MD* Positron emitting radionucUdes have unique properties that make them nearly ideal as radioactive tracers for in vivo metabolic studies. Using positron emission tomographic (PET) scanning and positron-labeled radiopharmaceuticals, one can study local glucose metabolism in dssues, blood Developments in radiopharmaceutical science, nuclear medicine imaging technology, and computer modeling of biological processes have led to techniques that now per-mit the noninvasive measurement of basic physiologic pro-cesses within the human body. Determination of blood flow in tissues, local glucose metabolism in tissues, utilization of oxygen, efficiency of oxygen extraction from blood, and mea-surements of local receptor density and binding activity are all possible. The nuclear medicine techniques that make possible these determinations are designated the collective name of positron emission tomography (PET). Requirements for Functional Imaging To measure a physiologic process within the body (for ex-ample, local glucose metabolism in tissues), it is necessary to have a tag or tracer for glucose that can be accurately followed through the metabolic process. The ideal tracer must not disturb the measured physiologic process, must be safe, and should be measurable from outside the body for in vivo studies. Commonly used positron radionuclides include positron emitting isotopes of carbon, oxygen, and nitrogen, which are the basic building-block atoms of organic molecules, and fluorine-18, which can be substituted for hydrogen in many organic molecules without significantly changing their bio-physical behavior. These four radioisotopes provide positron emitting tags that can be synthesized into physiologically im-portant substrates without altering the chemical or biophysi-cal behavior of these substrates within the body. Thus, they meet the first criterion for an ideal tracer, not altering nor-mal body biochemistry. The positron mode of radioactive decay is unique among the radioactive tracers currently used for nuclear medicine imaging. The positron emitted during such decay represents an electron with a positive charge. Such a particle, unable to exist in normal matter, promptly undergoes what is called an annihilation reaction with a normal (negatively charged) electron. To satisfy the requirement for conservation of energy, two gamma rays are emitted as a result of this flow, oxygen udlizadon, protein synthesis, and many ot/,e functions noninvasively in normal subjects and patients who have various diseases. A review of some of these techniques and the relative advantages and problems associated with the PET approach is presented. annihilation reaction. These gamma photons, which carry the energy equivalent of the rest-mass of two electrons, are given off in exactly 180° opposite directions from one another, pro. viding an ideal format for external detection and localiza-tion. This pair of annihilation gamma rays are the means for easy, quantitative, noninvasive localization within the body, When considering the use of radioactive tracers, safety usual-, ly refers to limiting patient radiation from the tracer. Positron-1 labeled tracers are usually safe for two reasons. First, because' of the extremely short physical half-life of most positron emit-ters (Table) the radioactivity disappears from the body rapidly. Thus, total time of exposure is short, and the total integrated radiation dose is small. Second, because it is often possible to synthesize labeled compounds with high specific activi-ties, only small amounts of labeled material must be admin-istered to be detected. The 180° opposed pair of annihilation photons provides ideal geometry for external localization and quantification of radiotracers within the body. The key to accurate extemal tracer imaging has been the development of positron emis-sion tomographs, so-called PET scanners. The fact that a pair of gamma rays traveling in exactly opposite directions is emit' ted with each annihilation event is used to determine exact-ly the line along which the annihilation event occurred. Detectors placed on opposite sides ofthe body are directed toward each other and operated in what is known as the co-incidence mode, wherein a radioactive decay event is no*! counted unless both detectors simultaneously detect a gam-ma ray. A ring of such detectors surrounding the body si' multaneously measure the multiple lines of localization for many individual radioactive decay events. With this infor-mation and computer technology, a computed tomograp'' Submitted for publication: February 18, 1985 Accepted for publication: May 17, 1985 * Catherine McAuley Health Center, Department of Radiology, Ann Arbor, Ml ' • 8 ' ' * Formerly Department of Diagnostic Radiology, Division of Nut lear Medicine, H ^ " Ford Hospital Reprints not available of the dis matics ar< tomograp tion of rat ments ar( applied, 1 ly accura in a volu Modern I tiguous t( scanners tion of r. Thus, usi pharmac maps art the met£ Finally, t cesses re metabol the trace labeled ofthe tr; local rati of the al tual rate to one, metabol evaluate cess pel comput FDC de metabo Current local tis in spec tissues ( circulat ^ great local ti: gers (6, curate r fTieabih Eve to ryp inve 138 Metabolic Imaging Table Position Emitting Radionuclides in Current Use Radionuclide Oxygen-15 Carbon-11 Nitrogen-13 Fluorine-18 Gallium-68 Rubidium-81 Rubidium-82 Physical Half-Life (minutes) 2.1 20.4 10.0 110.0 68.5 274.8 1.3 ofthe distribution of radioactivity is calculated. The mathe-matics are exactly the same as those used in X-ray computed tomography, but the resulting tomogram shows the distribu-tion of radioactivity rather than X-ray density. Ifthe measure-ments are made properly and certain correction factors are applied, the resulting computed tomogram is a quantitative-ly accurate map of the distribution of radioactive tracer with-in a volume section of the body. Modern PET scanners simultaneously produce multiple, con-tiguous tomographic images. In effect, such multisection PET scanners provide a three-dimensional image ofthe distribu-tion of radioactive tracer within a given part of the body. Thus, using an appropriately selected positron-labeled radio-pharmaceutical and a modern, multisection PET scanner, maps are constructed of the distribution and time-course of the metabolism of physiologic substrates within the body. Finally, the use of positron technology to study in vivo pro-cesses requires a computerized mathematical model of the metabolism of a given physiologic substrate. For example, the tracer i'*F-fluoro-2-deoxy-D-glucose (FDC) is a positron-labeled analog of glucose. After intravenous administration ofthe tracer, its distribution within the body is related to the local rate of glucose metabolism by specific tissues. The ratio of the absolute tracer uptake of a specific tissue and the ac-tual rate of glucose metabolism within that tissue is not one to one, however. Detailed knowledge of how the tracer is metabolized and localized within the tissue is necessary to evaluate results of the study. Knowledge of the exact pro-cess permits construction of a mathematical model and a computer program that wil l convert the initial PET scan of FDC detected within the tissue into a map of local glucose metabolism. Currently, models are available for accurately measuring local tissue glucose metabolism rates (1,2), blood flow with-in specific tissues (3-5), oxygen utilization within specific tissues (4,5), and the extraction fraction of oxygen from blood circulation through a given organ or area of an organ (4). ^ great deal of work now underway is designed to measure 'ocal tissue receptors for a variety of biochemical messen-gers (6,7). Similarly, investigators are trying to develop ac-curate models for parameters such as blood-brain barrier per-'Tieability and local rates of protein synthesis (8). Applications of PET Scanning Every physiologic/metabolic process is potentially amenable "mvestigation using PET techniques, provided a suitable tracer can be synthesized in a short enough period of time. Methods for studying a large number of physiologic processes have already been developed and applied to many normal and pathologic conditions. A large percentage of PET re-search has focused on normal and abnormal central nervous system (CNS) function. A few selected examples serve to in-troduce the beauty and depth of these techniques. Cerebral glucose metabolism rate When administered intravenously, the tracer FDC enters the metabolized pool of glucose and is taken up by cells that are actively metabolizing glucose. Once within the cell, FDC is phosphorylated but cannot progress further in the meta-bolic pathway for glucose. In essence, the labeled compound becomes trapped in the cell. By obtaining a PET scan after the administration of FDC, the local rate of glucose metab-olism can be calculated using an appropriate computer model, and the result can be presented as a functional im-age, a quantitative map of the rate of glucose metabolism in the tissue (1). Figure 1 is an example of such a functional image of glu-cose metabolism in the normal human brain. Images are shown at four levels. The darker the area, the greater the local 0% B SLICE • 'sm nst n uKt Fig 1 Computer processed functional images depicting glucose metabolic rate in healthy 26-year-old male volunteer. Scale is in mg of glucose metabolized per minute per 100 g of tissue. Sections are contiguous; A = lowest, D = highest. (Courtesy of University of Michigan.) 139 Keyes B Fig 2 Images of glucose metabolism rate in four patients with left middle cerebral artery infarct (A), Huntington's chorea (B), left temporoparietal glioma (O, and left temporal lobe epilepsy (D). (Courtesy of University of Michigan.) metabolic rate. Note the clear localization of glucose metab-olism in the cerebral gray matter, the basal ganglia, and the thalamus; much lower rates of glucose utilization are seen within white matter. Figure 2 shows representative sections of four patients who have, respectively, a left hemispheric stroke, Huntington's chorea, a large glioma, and left temporal lobe epilepsy. Note the decreased glucose utilization within the area of infarct, disclosing the tissue injury and loss of function within this area. In the patient who has Huntington's chorea, the study demonstrated a striking loss of glucose in the area of the cau-date nuclei (compare with Fig 1), concordant with the ana-tomic abnormality found in such patients. In addition to many studies of various CNS diseases (2-4, 9-14), PET scanning has been used extensively to study nor-mal CNS function (2,5,15). Striking alterations in regional glucose utilization in the brain occur with various normal physiologic functions such as listening, memorizing, and see-ing (15,16). For example, Mazziotta and coworkers (15) demonstrated changes in lateralization of function related to hearing that depended on whether the individual was lis-tening to music or speech. Cerebral blood flow A number of methods have been developed to measure cere, bral blood flow using PET methods (3-5). Figure 3 is a repre. sentative example of a functional map of cerebral blood flow in a normal individual. The tracer was oxygen-15 labeled water. As expected in this normal subject, the local cerebral blood flow rather closely paralleled the local cerebral meta-bolic rate for glucose (Fig 1). This parallelism does not exist in many disease states; physiologic/metabolic imbalances have been documented in such states as acute stroke, luxury-perfusion syndrome, misery-perfusion syndrome, and neoplasm (3,4). Other applications Much excellent work relating PET methods to heart and myo-cardial metabolism has been accomplished. Because the heart normally uses free fatty acids as a primary substrate for energy metabolism, carbon-11 labeled palmitic acid is an excellent tracer for determination of myocardial metabo-lism. Schon et al produced functional images of local myo-cardial fatty acid metabolic rate and have studied a wide variety of cardiac conditions with this technique (17). Problems and Predictions The ability to make such elegant measurements of various Fig 3 Functional image of cerebral blood flow in normal subject. Calculated "O-HjO method. (Courtesy of University of Michigan.) 140 Metabolic Imaging hysiologic processes within the body is bought at a price, however. The physical half-life ofthe various positron emit-jipg radioisotopes is quite short (Table). Fluorine-18, for ex-ampIS' has a physical half-life of less than two hours, and oxygen-'iS, a half-life of only two minutes. Elaborate and fechnologically complex solutions are required in order to jse tracers that have such an evanescent existence. Typical-ly a fully equipped radiosynthetic chemistry laboratory is needed immediately adjacent to the scanning site. Most posi-tron emitting radionuclides are produced using cyclotrons thatare small enough to be installed and operated physically close to a medical research facility. A large number of posi-tron research sites developed around the world in recent years have on-site cyclotrons for the local, immediate pro-duction ofthe tracer radioisotopes that they use. However, in their present state of development, these machines are not suitable for routine clinical production of radionuclides. Metabolic research using positron-labeled radiotracers requires a relatively elaborate and technically complex underpinning. An on-site cyclotron, a specially tailored radio-chemistry and radiopharmaceutical synthetic facility, a PET scanner, and relatively sophisticated computing and image processing facilities are all necessary to conduct such re-search successfully. Work is currently underway in many centers to simplify, miniaturize, and automate many ofthese procedures; it may be possible in the future to incorporate positron technology into general patient care, at least at large tertiary care centers. For the present, this approach to medical imaging and physiologic research remains a highly special-ized, albeit extremely elegant and productive, means of examining the human body. Acknowledgment The author thanks Mrs Andrea Harper for her editorial assis-tance. References 1. Phelps ME, Huang SC, Hoffman TJ, et al. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18) 2-fluoro-2-deoxy-D-glucose: Validation of method. Ann Neurol 1979; 6:371-88. 2. DiChiro G, Oldfield E, Bairamen D, etal. Metabolic imaging of the brain stem and spinal cord: Studies with positron emission tomography us-ing "F-2-dexoyglucose in normal and pathological cases. J Comput Assist Tomogr 1983;7:937-45. 3. Ackerman RH, Subramanyam R, Correla JA, et al. Positron imaging of cerebral blood flow during continuous inhalation o iC' ' '02. Stroke 1980; 11:45-9. 4. Baron JC, Bousser MC, Comar D, et al. Noninvasive tomographic study of cerebral blood flow and oxygen metabolism in vivo. Eur Neurol 1981; 20:273-84. 5. Frackowiak RSJ, Lenzi GL, Jones T, et al. Quantitative measurements of regional cerebral blood f low and oxygen metabolism in man using and positron emission tomography: Theory, procedures, and nor-mal values. J Comput Assist Tomogr 1980;4:727-36. 6. Friedman AM, Huang C, Kulmala, HA, et al. The use of radiobrominated p-bromospiroperidal for x-ray imaging of dopamine receptors. Med Biol Eng Comput 1982;9;57-61. 7. McElvany KD, Katzenellenbogan JA, Shafer KE, et al. 16 ("Br) bro-moestradiol: Dosimetry and preliminary clinical studies. J NucI Med 1982;23:425-30. 8. Bustany P, Sargent T, Saudubray JM, et al. Regional human brain up-take and protein incorporation of "C-L-methionine studied in vivo with PET. J Cereb Blood Flow Metab (SuppI) 1981;1:517-8. 9. Benson DF, Kuhl DE, Hawkins RA, et al. The fluorodeoxyglucose '»F scan in Alzheimer's disease and multi-infarct dementia. Arch Neurol 1983;40;711-4. to. deLeon MJ, George AE, Ferris SH, et al. Positron emission tomography and computed tomography assessments of the aging human brain. J Com-Put Assist Tomogr 1984;8:88-91. 11. Frackowiak RSJ, Pozzilll C, Legg NJ, et al. Regional cerebral oxygen supply and utilization in dementia. A clinical and physiological study with oxygen-15 and positron tomography. Brain 1981;104:753-78. 12. Friedland RP, BudingerTF, Ganz E, e ta l . Regional cerebral metabolic alterations in dementia of the Alzheimer type: Positron emission tomog-raphy with ("F) fluorodeoxyglucose. J Comput Assist Tomogr 1983; 7:590-8. 13. Kuhl DE, Phelps ME, Kowell AP, et al. Effects of human aging on pat-tems of local cerebral glucose utilization determined by V f ) fluorodeoxy-glucose method. J Cereb Blood Flow Metab 1982;2:163-71. 14. Kuhl DE, Phelps ME, Kowell AP, et al. Effects of stroke on local cere-bral metabolism and perfusion: Mapping by emission computed tomog-raphy of '»FDG and ' ^NHj . Ann Neurol 1980;8:47-60. 15. Mazziotta JC, Phelps ME, Miller J, et al. Tomographic mapping of human cerebral metabolism: Normal unstimulated state. Neurol 1981;31:503-16. 16. Phelps ME, Kuhl DE, Mazziotta JC. Metabolic mapping of the brain's response to visual stimulation: Studies in humans. Science 1981;211: 445-8. 1 7. Schon HR, Schelbert HR, Najafi A, et al. C-l 1 labeled palmitic acid for the noninvasive evaluation of regional myocardial fatty acid metabolism with positron computed tomography: I. Kinetics of C-l 1 palmitic acid in normal myocardium. Am Heart J 1982;103:532-47. The following reviews are excellent sources for further information and in-clude in-depth review of the current literature: Beaney RP. Positron emission tomography in the study of human tumors. Semin NucI Med 1984;14:324-41. Phelps ME, Mazziotta JC, Huang SC. Study of cerebral function with posi-tron computed tomography. J Cereb Blood Flow Metab 1982;2:113-62. Phelps ME, Schelbert HR, Mazziotta JC. Positron computed tomography for studies of myocardial and cerebral function. 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Current Concepts of Metabolic Functional Imaging with Positron Emitters

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Current Concepts of Metabolic Functional Imaging with Positron Emitters

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