SPECIAL CONTRIBUTION A Brief History of Positron Emission Tomography Dayton A. Rich Yale University Medical School, New Haven and the VA Connecticut Healthcare System, Positon Emission Tomography Center, West Haven, Connecticut "The true delight is in the finding out, rather than in the knowing." -Issac Asimov ties that are useful for the study of physiologic processes. The Shortly before the time of this writing, Michael Ter-Pogos­ most widely used radionuclides in PET are cyclotron produced sian, PhD, passed away at the age of 71. He was considered such as 11;F, 11 C, 150 and 13N with half-lives of 109.8, 20.0, 2.0. by many to be the father of PET and is best known for and 10.0 min, respectively. These are isotopes of elements that experiments beginning in the 1950s, which led to the devel­ are abundantly present in nature and can be incorporated into opment of PET as a practical diagnostic tool (Fig. 1). In my the organic compounds without significantly altering their research of the literature for this article, Dr. Ter-Pogossian's 11 structural or biological properties. For example. C can be name appeared frequently on many of the landmark publi­ incorporated into acetate or palmitate and will be metabolized cations and I have drawn heavily from his work as a historian and scientist. His death is a great loss to the nuclear med­ by the myocardium in the same manner as the unlabeled natural 2 icine community. It is with his achievements in mind, as well substrate (1). Also, R Rb is widely used as a myocardial flow agent as the achievements of many other outstanding scientists, and is available through a generator infusion system. that I have written this article. I have tried to be as accurate as possible in my documentation of events as well as in my interpretation of their significance. I trust that the reader will HISTORY gain as much as I have from this endeavor. Key Words: PET; history; instrumentation The history of PET started shortly after the moment of creation, the Big Bang. Cosmologists hypothesize that all mat­ J Nucl Med Techno/1997; 25:4-11 ter in the universe was contracted into an infinitely small space called a singularity and then exploded producing an enormous fireball at a temperature of 100 billion K. During the very early PET is a nuclear medicine procedure which takes advantage of stages (t = 10-2 sec) of this cosmic fireball, the universe was the unique signal produced by the annihilation of a positron dominated by a great density of energy in the form of radia­ and an electron yielding two photons of 511 ke V traveling in tion. The density was so great that there was an energy equiv­ nearly opposite directions. If the two photons are detected in alent of an electron-positron pair in a volume of space corre­ coincidence, the origin of the event is known to lie within a well sponding to the size of electron-positron pair. Newly created define cylinder between the detectors. This electronic collimation beta particles would immediately annihilate creating gamma eliminates the necessity for absorbing type collimators present on radiation after the equivalence of energy and matter formula, single-photon imaging devices, resulting in some distinct advan­ 2 E = mc . The energy state was continually alternating from tages: (a) higher contrast and resolution, (b) detection sensitivity electromagnetic radiation to electrons, positrons and back independent of the depth of the activity in tissue, and (c) the again to radiation. Not until the universe had expanded, (t = 4 ability to correct for the attenuation of the radiation signal. Con­ min) and hence cooled was it possible for the heavier particles, temporary PET cameras consist of a series of detector rings which protons and neutron to exist (2). From this boiling sea of produce tomographic images by reconstructing the distribution of nuclear reactions emerged positrons, electrons and the anni­ radioactivity from measurements taken at different angles, similar hilation radiation signal used by today's PET systems. to that used in computerized axial tomographic (CT) imaging. The development of PET in more modern times took place In addition to the physical characteristic mentioned above, in phases as a result of advances in physics, mathematics, many positron emitting radionuclides exhibit chemical proper- chemistry, computer science and fundamental biology. Most of these advances were accomplished independently but drove For correspondence or reprints contact: Dayton A. Rich. CNMT. VA Connecticut Healthcare System, Positron Emission Tomography Center-liSA, the progress of the other. There were three significant phases 950 Campbell Ave., West Haven, CT 06516. in which important advances were made (J). 4 JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY FIGURE 1. Michel M. Ter-Pogossian in the late 1960s. Dr. Ter-Pogossian was a member of the Institute of Medicine of the National Acad­ emy of Sciences. During his career he was a recipient of both the SNM Paul C. Aebersold Award for outstanding achievement in basic science in nuclear medicine and the Hevesy Nuclear Medicine Pioneer Award. (Photograph courtesy of the Mallinckrodt Institute of Radiol­ ogy, Washington University Medical School, St. Louis, MO). Phase one, late 1920s to the late 1940s: The discovery of the solutions to the equation he was working with that described positron and artificial radiation, invention of the cyclotron, the behavior of the electron ( 4). One solution corresponded to recognition that the radionuclides 1 1C, uN, 1"0 as well as 1HF the electron, which carried a negative charge and one to a then were important for the tracing of important biochemical path­ unknown particle carrying a positive charge. Dirac thought that ways and lastly, invention of the scintillation detector. this positive charge might represent the proton. However, he Phase two, mid-1950s to the early 1970s: The first installa­ argued against ignoring the unwanted solution to the equation tion of a cyclotron in a medical center, use of J.'O in biomedical and stated, " Further, in the accurate quantum theory in which studies, development of single-photon tomography, develop­ the electromagnetic field also is subjected to quantum laws, ment of different types of positron scanning devices and de­ transitions can take place in which the energy of the electron velopment of CT using x-rays. changes from a positive to a negative value even in the absence 2 Phase three, mid 1970s to the present: The development of of any external field, the surplus energy, at least 2 mc ••.• " a positron detection tomograph that incorporated the funda­ He also noted that the laws of conservation of energy and mental features of modern day PET systems, the synthesis of momentum would require at least two light-quanta to be si­ 1 the numerous PET compounds including, 2-[ ~'F]fluoro-2-de­ multaneously formed (4). oxy-D-glucose and the evolution of the self shielded negative­ Other physicists doubted Dirac's calculations were telling ion cyclotron for medical uses. them anything significant about nature and thus ignored the unwanted solution (2). This may be explained, in simplicity, by PHASE ONE the example of a quadratic equation which ends up with the In 1929, the physicist Paul Dirac published a paper titled, "A square root of a number, one being positive and one negative. Theory of Electrons and Protons," in which he found two For example the square root of 9 is both + 3 and -3 as each VOLUME 25, NUMBER 1, MARCH 1997 5 multiplied times itself equals 9. It was not until 1932 that the The group allowed the plants to grow in an atmosphere of [ 11 C] C0 in the presence and absence of light. They were able concept of the positron was postulated by Carl Anderson while 2 studying cosmic ray interactions with a cloud chamber (5). to demonstrate that a reversible carboxylation reaction was the 13 While investigating the influence of a magnetic field on the initial step of photosynthesis. Ruben's group also used N to trails left by cosmic rays, Anderson found some trails were bent study nitrogen fixation by nonlegumenous plants. Cramer and 11 by exactly the same amount but in the opposite path of the Kristiakowsky labeled C to lactic acid to study the synthesis electron. This was of great significance to him, as only a of liver glycogen (7). Fluorine-18 was used to study the absorp­ particle with the identical mass but opposite charge of an tion of fluorides in dentine enamel and bone by Volker eta!. electron could act in such a way. Anderson called these parti­ (8) and the secretion of intravenously injected fluorine in the cles antielectrons or positrons which was then confirmed to be saliva of cats by Willis (9). the same particles predicted by Dirac's equation. This novel Possibly the first use of positron-emitting radionuclides in piece of work earned Anderson his Nobel Prize and in 1933 humans was by Tobias, Lawrence, Roughton, Root and Gre­ Dirac and Erwin Schrodinger received the prize for the pre­ gersen in 1945 (10). This group used "C labeled to carbon diction of this new particle. monoxide to study its fate in man. Several subjects inhaled 11 In 1934, Irene Curie and Frederick Joliot were credited with [ C] CO followed by the inhalation of 100% oxygen. The the discovery that three elements, aluminum, boron and mag­ exhaled ["C] C02 was collected in soda lime while at the same nesium, when bombarded by alpha particles emitted by polo­ time measurements over the thigh, chest, spleen and liver were nium, continued to be sources of penetrating radiation even performed using a Geiger-Muller counter.