Position Emission Tomography at the Turn of the Century: A Perspective Henry N. Wagner, Jr Nuclear medicine translates advances in molecular biology into the care of patients. In the future, diseases will be characterized at the molecular rather than the cellular level, often before detectable structural changes have occurred. Position emission tomography (PET) will play a major role in the study of intercellular communication by making it possible to characterize the actions of "molecules w i t h messages.'" Diseases will be characterized by defects in intercellular communication. Treatment will be planned based on molecular abnormalities, and the response to treatment will be monitored with molecular probes. PET studies of the brain, heart, and cancer will be extended to all organs of the body. Pharmacology will be strongly influenced by PET because most drugs act by stimulating or blocking "recognition sites" on the surface of cells. In the next century, will single photon emission computed tomography (SPECT) makes PET unneces-

sary? The answer is no, because both PET and SPECT will have achieved a permanent role in medical practice; both make it possible to examine regional in vivo chemistry in human beings. Carbon-11 and fluorine- 18 will continue t o lead the way, but many drugs, and some body constituents such as proteins, can be radiolabeled with iodine-123 and technetium-99m. Today, PET is limited by the need to make one's own radiotracers. This is likely to change when regional radiopharmacies become widespread. Just as the field of nuclear medicine moved initially into an exponential phase of growth only after industry undertook the commercial distribution of gamma-emitting tracers, so also w i l l the involvement of industry be required if PET radiotracers are to be made available for the care of patients. Copyright 9 1992by W.B. Saunders Company

DECADES AGO, nuclear mediT HREE cine imaging involved only the thyroid,

The practice of modern medicine can be traced back to a concept described 150 years ago by the great physiologist, Claude Bernard, ie, the concept of the milieu interieur, or internal environment, which buffers the cells of the body from the changes that occur constantly in the external environment. Homeostasis is the basis for freedom of activities in a stressful world. Today, examination of the molecules and cells in blood and urine reflects Bernard's concepts. The great contribution of positron emission tomography (PET) is to extend molecular medicine from the study of body fluids to the study of the cells of the body in situ, including the important interface of cells with the extracellular fluid that surrounds them. PET makes it possible to examine regional blood flow, cellular bioenergetics, and intercellular communication in the living human body, including plasma membrane and intracellular chemoreceptors, enzymes, and substrate transport systems. The development of large numbers of positron emitting tracers has moved nuclear medicine from the study of elements such as iodine to the

liver, spleen, kidneys, and pericardial effusion. Its focus at that time was the visualization of the structure of organs that could not be seen by x-rays. No one at the time could foresee what lay ahead at the turn of the 20th century. Movement in the direction of physiological imaging was marked by the development of lung perfusion scanning in 1963 (1) to help select patients for pulmonary embolectomy and (2) to solve the problem of quantification of the size of perfusion defects treatment with the thrombolytic agent, urokinase. The need for quantification of lung perfusion studies stimulated the development of microcomputers in nuclear medicine. Shigekotu Kaihara, a Japanese fellow working at Hopkins, published the concept of a functional image and described it in a 1969 article as the "Construction of a functional image from spatially localized free constants obtained from serial camera or rectilinear scan data." The computer system developed for quantification of lung perfusion imaging was then used in the development of gated blood pool images, which together with first-transit studies became one of the foundations of nuclear cardiology. Today, nuclear medicine's concepts, discoveries, and applications have brought about major changes in biomedical sciences and medical practice. What lies ahead?

From Johns Hopkins Medical Institutions, Baltimore, MD. Address reprint requests to Henry N. Wagner, Jr, AID, Johns Hopkins Medical Institutions, 615 N Wolfe St, Room 2001, Baltimore, MD 21205-2179. Copyright 9 1992 by W.B. Saunders Company 0001-2998/92/2204-0007505.00/0

Seminarsin NuclearMedicine,Vol XXII, No 4 (October), 1992: pp 285-288

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study of molecules, but the tracer principle remains the core of the field. The era of "molecular nuclear medicine" began with PET. The principle of the dynamic state of body constituents remains and is reflected in the early studies of the thyroid. Whitehead wrote: It is a well-founded historical generalization that the last thing to be discovered in any science is what the science is really about. Men go on groping, guided merely by a dim instinct and a puzzled curiosity until at last some great truth is loosened.

Nuclear medicine has become molecular nuclear medicine. Its images are concerned with the temporal as well as spatial movement of molecules within the living body. More diseases will characterized at the molecular rather than the cellular level, often before detectable structural changes have occurred. PET makes it possible to extend to the care of sick people and the prevention of disease the enormous advances being made in molecular biology and genetics. Two principles of genetics are of special relevance to nuclear medicine: pleotropism and genetic heterogeneity. Pleotropism describes the fact that a single gene defect usually affects a polypeptide segment of DNA, producing many different manifestations of disease that can be characterized biochemically. Genetic heterogeneity is the principle that abnormalities in different genes can result in the same clinical syndrome so that characterizing chemically homogeneous groups of patients facilitates genetic analysis. The invention of the microscope focused attention on the cell as a fundamental unit of biology and medicine. The invention of radioactive tracers, beginning with carbon-14 (14C) and tritium and extending into the living human body via carbon-ll (llC), fluorine-18 (18F), oxygen-15, nitrogen-13, iodine-123 (1231), and technetium-99m (99mTc), moved medicine further along the pathway from anatomy to physiology to biochemistry. Among the most important areas in which PET is extending modern medicine is intercellular communication, ie, the characterization of "molecules with messages." Many of these molecules carry information from one cell to another via 1,000 to 10,000 synapses that connect the hundred of billions of neurons in the body; via the interfaces of neurons and hormones with

muscle cells and glands; and via circulating and fixed immunoglobulins. Information is carried via binding proteins in blood, circulating cell membrane receptors, plasma membrane receptors, and a whole string of second and subsequent chemical messengers, all of which can be examined by radioligands readily labeled with 11C or other radiotracers. The patterns and quantities of these "recognition sites," as well as the genome, integrate the cells of the body to make the person a unique individual. "Disintegration of communication" will become a new way to characterize disease. Treatment will be planned based on molecular abnormalities, and the response to treatment will be monitored with molecular probes. The supply of energy via carbohydrates, fats, and amino acids will also be used to characterize diseases, direct treatment, and monitor patient response. PET applications to the study of the brain, heart, and cancer will be extended to all organs of the body because chemistry is applicable to the study of all cells and organs. Molecules must repair themselves when injured and reproduce themselves when they wear out. Wrinkled skin, poor healing of wounds, poor memory, cancer, heart disease, and dementia are but few of the processes that will be characterized bioehemicaUy. Pharmacology will be strongly influenced by PET because most drugs act by stimulating or blocking recognition sites on the surface of cells. Will other technologies replace PET? Certain fundamental principles make it unlikely. One of the characteristics of chemical receptors, such as those on postsynaptic neurons, is their exceedingly low concentrations (in the range of picomoles per gram). The great sensitivity with which radioactivity can be measured is needed to measure receptor concentrations in different parts of the body such as the brain. Techniques such as fluorescence have adequate sensitivity, but the energy of the emitted photons is not sufficiently great to penetrate from the inside to the outside of the body where they can be detected. Only the higher energies of ionizing radiation have sufficient penetrating power. Administered drugs and naturally-occurring neurotransmitter molecules affect intercellular communication. These include amines such as norepinephrine, dopamine, and serotonin;

PERSPECTIVE ON PET

amino acids such as gamma-aminobutyric acid, glutamic acid, aspartic acid, and glycine; and peptides such as endogenous enkephalins. All of these can be examined by PET. In addition to involvement in neuron-toneuron information transfer, neurotransmitters, including enkephalins, act as modulators of regional neuronal activity. Some chemical "messengers" act within fractions of a second, and others have an effect over hours or even days. The availability of 20 different amino acids means that a vast number of different combinations are possible that and can encode a tremendous of information. How this is done will be a subject of research involving PET for centuries. Molecular blueprints are encoded at birth in the inherited DNA within each cell of the body, making up the genome or genotype, which determine cell structure and, eventually, function. The location of over 1,800 genes on specific chromosomal regions is known. As a result of the Human Genome Initiative, established in the United States in 1988, eventually all 50,000 or more genes will have been assigned locations on chromosomes. Approximately 4,000 human diseases are believed to be genetic in origin. The Human Genome Initiative is a joint effort sponsored by the National Institutes of Health (NIH) and the Department of Energy (DOE). The proposal for the project was made originally by the DOE to study the genetic effects of radiation on DNA. The NIH was included because of the potential impact on health care. The human genome will affect future clinical practice. Where does nuclear medicine fit into the picture? Genetic mutations result in biochemical abnormalities such as enzyme deficiencies. Molecular abnormalities have been identified in approximately 430 disorders out of the over 1 million classifiable human diseases. Radioactive tracers make it possible to detect and quantify the molecular abnormalities brought about by the genes. Geneticists search for genetic abnormalities in patients with specific syndromes. "Reverse genetics" is the search for manifestations of disease when abnormal genes are found. PET will play a major role in this process because abnormal proteins may not be found in lymphocytes or blood, but they may require detection

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of abnormalities in specific sites within the body. Abnormal proteins include enzymes, receptors, and structural proteins. In the next century, radioactive tracers will play a major role in connecting the genome to human disease. Nuclear medicine can be defined as "in vivo molecular medicine." Molecular nuclear medicine will make it possible not only to classify disease biochemically, but also to provide a new approach to the design and development of drugs. One can determine the relationship between a specific molecular configuration and the in vivo biochemical effects of a drug. The effects of drugs on energy metabolism, synthetic processes, communication, and regulatory mechanisms can be expressed in molecular terms. In the past, pharmacological research consisted of an alliance between organic chemists to make new compounds and pharmacologists to screen them for possible effectiveness in animals. Molecular nuclear medicine is now involved in drug design, development, evaluation, and monitoring in humans as well as animals. Nuclear medicine techniques will be used more often to assess the effectiveness of surgery or radiation therapy and to document the extent of tumors and the progression or regression in response to different forms of treatment. Such data permit modifications of the treatment plan sooner than can be determined by the clinical response of the patients or changes in the size of the lesions. Thus, treatment need no longer be based solely on clinical response, gross morphology of the lesions, and histopathological examination of biopsies. An important characteristic of neoplastic tissue is its increased rate of cell division. In general, accumulation of thymidine into neoplasms is increased in the presence of increased DNA synthesis. Amino acid transport across tumor cell membranes has also been found to differentiate many malignant from nonmalignant tumors. Membrane transport and protein synthesis can be examined if suitable mathematical modeling is used in data analysis. The accumulation of fluorodeoxyglucose will become a widespread method for characterizing benign and malignant lesions. Most malignant tumors have accelerated glycolysis compared with that of surrounding tissue.

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In addition to measuring blood flow to tumors, blood volume, substrate incorporation, or DNA synthesis, PET and single photon emission computed tomography (SPECT) will be widely used to measure the number and affinity of hormone receptors that characterize certain tumors. Estrogen receptors are increased in many breast tumors in both primary and metastatic sites. Dopamine receptors are often increased in pituitary adenomas. Fluorine-18 estradiol accumulation as determined by PET makes it possible to tailor the treatment of a specific patient on the basis of the number of estrogen receptors. A tumor that contains estrogen receptors is more likely to be treated successfully with estrogen-receptor blocking drugs such as tamoxifen than is a tumor that does not contain estrogen receptors. The presence of progesterone receptors as well as estrogen receptors is the best prognostic sign. Radioactive tracers that bind to estrogen receptors make it possible to assess the status of the primary breast cancer and regional metastatic deposits. Histopathology alone need no longer be the only criterion for diagnosis, prognosis, and therapy. Receptors are also found on pituitary tumors. Using the dopamine receptor binding agent [11C]N-methylspiperone, it has been possible to classify pituitary adenomas according to whether or not they possess dopamine receptors. If the tumors contain such receptors, they can be treated chemically rather than surgically, that is, by administering the dopamine receptor agonist, bromocryptine. After treatment, measurement of the metabolic activity of the tumor makes it possible to

HENRY N. WAGNER, JR

detect persistence or recurrence of the tumor and damage to normal brain tissue, such as that resulting from radiation. For example, [11C]methionine is useful for delineating the boundaries of brain tumors, providing information of value in planning and performing brain surgery by permitting differentiation of the metabolizing brain tumor from simple disruption of the blood-brain barrier. In the next century, will SPECT makes PET unnecessary? The answer is no, because both PET and SPECT will have achieved a permanent role in medical practice. Both techniques can examine regional in vivo chemistry in human beings. Carbon-ll and 18F lead the way, but many drugs and some body constituents, such as proteins, can be radiolabeled with 123I and 99~Tc, which can be shipped over long distances, thereby facilitating their use. Today, PET is limited by the need to make one's own radiopharmaceuticals. This is likely to change when regional radiopharmacies are further developed. Just as the field of nuclear medicine moved initially into an exponential phase of growth only after industry undertook the commercial distribution of gamma emitting tracers to extend the use of 14C- and tritiumlabeled tracers to the study of living persons, so also is PET likely to expand when industry produces ~1C and XaF tracers. PET will always have the advantage of being able to be used to study carbon chemistry. Although the application of PET faces greater technical complexity related chiefly to the short-half life of 11C and ~8F, it is predictable that PET will eventually achieve a permanent, widespread role in medical practice.

Position emission tomography at the turn of the century: a perspective.

Nuclear medicine translates advances in molecular biology into the care of patients. In the future, diseases will be characterized at the molecular ra...
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