Headline

THE DISCOVERY of technetium-99m and iodine-131.

Authors

Sergio Modoni (1)

Nicoletta Urban (2)

Luigi Mansi (3)

(1) , Oncological Referral Center of Basilicata, Rionero in Vulture (PZ)

(2) Division of Nuclear Medicine, European Institute of Oncology, Milan.

(3) Chair of Nuclear Medicine, Faculty of Medicine and Surgery, 2nd University of Naples.

For correspondence: Sergio Modoni Unit of Nuclear Medicine Oncological Referral Center of Basilicata Prov.le Road 8 85028 Rionero in Vulture (PZ) tel.: 0972 726340 Mobile. 333 2822062 e mail: [email protected]

Introduction Technetium-99m (99m Tc) and iodine-131 (131 I) are the everyday tools of Nuclear Physician. The discovery of these radioisotopes, as well as constitute a crucial step in the history of radiation in medicine, it also intersects with crucial events of the last century, with the most important discoveries in the field of physics of radiation, which is no stranger to the Italian genius, and events that have improved and sometimes shocked, but determined the history of humanity.

Some premises of physics In the light of the knowledge acquired, we now know that the nucleus of an atom there are Z protons and N neutrons and Z that identifies the atomic number and the mass number A is given by the sum of N + Z, ie the number of protons and neutrons present in the nucleus of that element. Therefore, a nuclide of an element is identified by the values of A and Z and its symbol is:

Nuclides with the same atomic number (Z) and different mass number (A) are called :

Until 1919, the only known nuclear phenomena were those related to natural radioactivity produced by the last 12 elements of the periodic system, with Z from 81 to 92. Today there are more than 1400 nuclides. Each radioactive is characterized by certain physical parameters which enable the identification: the physical half-life, ie, the time in which the original radioactivity is halved, the type of radioactive emission (alpha, beta, gamma) and the energy of the the emitted radiation. In the case of radioisotopes which we speak of these characteristics are shown in Table 1.

The Birth of Nuclear Medicine Although the use, for therapeutic purposes, of compounds containing radio goes back to the early 1900's, we can align the birth of nuclear medicine with the discoveries of Georg de Hevesy, Hungarian physicist, of noble family, who went to work with Rutherford at 'University of Manchester. At the time, Rutherford was studying the radioactive properties of what was then known as the Radium-D (today would be the Lead-210). To complicate his life and his studies, lead present in Radium-D interfered with his analysis. Not yet aware that the Radium-D was an isotope of lead, Rutherford thought he could isolate and chemically, therefore, entrusted this task to de Hevesy, saying: "My boy, if you are worth your salt, you try to separate radium -D from all that lead ". [1] Ironically, this was his inability to lead out the task entrusted to him, which allowed one of the greatest discoveries in the field of radioactive tracers, for which Georg de Hevesy today is considered the Father of Nuclear Medicine. In fact, he thought of using radioisotopes to study the biological behavior of their stable isotopes. Therefore performed studies on plants and animals and finally employed the water containing deuterium (an isotope of hydrogen) to study the turnover of the water in the human body. In 1935, together with O. Chieivitz administered phosphate labeled with -32 to rats and demonstrated the renewal of the mineral components of bone and in this way laid the groundwork for what would become the therapy of bone metastases, widely used today. With his studies, de Hevesy paved the way for the use of radioisotopes as "tracers" of metabolic pathways in the human body. For these studies, in 1943 he was awarded the Nobel Prize for chemistry.

The first "particle accelerators" In the 20s, the only method available for the study of the core was developed by Rutherford, who was to bombard the nuclei with alpha particles. But the repulsive forces between the nuclei and alpha particles, both positively charged, and the low energies of the latter, did not allow good results especially with elements of high atomic number. In 1929 Ernest Orlando Lawrence, UC Berkeley, he began to develop the idea of the cyclotron noting that potassium ions that passed through two metal tubes subjected to oscillating voltage were accelerated and emerged with an energy twice that of entry. Lawrence built two rooms in the form of D (from which the name of "dees"), and placed between the poles of a magnet. Inside the "dees" ions were accelerated on a spiral path and then extracted with a very high energy. Between 1931 and 1940 Lawrence cyclotrons built bigger and bigger. Suffice it to say that the first cyclotron 80,000 eV staying in the palm of a hand, while the last, from 100 million electron volts, could accommodate dozens of people inside the magnet. Lawrence took these cyclotrons to study nuclear processes and to produce a variety of new isotopes, some of which are very important for medicine, so much so that in 1935 he had this to say: "Shall we call it nuclear physics or shall we call it nuclear chemistry ? ". For this work, Lawrence received in 1939 the Nobel Prize for Physics.

The discovery of artificial radioactivity Another important finding, after the natural radioactivity, has marked the development of knowledge of modern physics. E 'on the afternoon of December 31, 1933. Irene Curie, daughter of Marie, who has followed in the footsteps of his mother, and her husband Frederick Joliot, are coming out of their lab to go home to celebrate the New Year, when a hastily called by their assistant who noted the presence of radioactivity of uncertain origin. Let's see how they themselves describe the discovery of artificial radioactivity: "... when an aluminum foil is irradiated by a preparation of polonium, the emission of positrons does not cease immediately with the removal of the active preparation. The foil remains radioactive and the emission decays exponentially ... We have proposed for the new radioactive elements ... the name radioazoto, radiosilicone, and radiophosphorus. These and other elements can be formed by bombarding with other particles: protons, deuterons, neutrons ... "[2]. And the neutrons are the basis of a Italian story, which became known to the world the value of our physics. And 'the story of and the Group of Panisperna that, under the enlightened guidance of Orso Mario Corbino, including Rasetti, Emilio Segre, Ettore Maiorana, Edoardo Amaldi, Bruno Pontecorvo and Gian Carlo Wick. It 's the story of the discovery, but intuitive reasoned, of slow neutrons, which led to a step from the discovery of nuclear fission then demonstrated by Lise Meitner, Otto Hahn and Fritz Strassmann. From this story comes the Appendix important for nuclear medicine, which can be placed as a source in 1925, and sees Emilio Segre, one of the main collaborators of Enrico Fermi at the center of these events.

The discovery of technetium Before 1925, all stable elements found in nature had been discovered. The elements with atomic numbers 43, 61, 85 and 87 were "missing" because they were only radioactive. In that year, two German chemists, Ida Tacke and Walter Noddack, reported the discovery in some minerals, element 43, which they called masurium and, two years later, the element 75, which they called Rhenium, in honor of the eastern borders (the Masuri lakes) and western (the Rhine) in Germany. These names were not without a certain nationalistic spirit since in these regions the German troops during the First World War, had achieved important victories. The two discoverers, however, they made no mention that the element 43 was radioactive. While the discovery of rhenium was confirmed and were prepared significant amounts, the masurium was ignored for several years and the spouses themselves Noddack-Tacke, especially because they were not able to document their discovery, they were ignored by the mainstream physics even when they provided, probably for the first, the correct scientific explanation of nuclear fission in 1938. So when, in 1936, Emilio Segre in Rome was working on the element 43, as he himself points out, he found the masurium: "I often had the task of procuring the necessary things to work. Luckily there was no bureaucracy. For chemicals ... I turned to Mr. Troccoli, an old shopkeeper highly competent in this field, he was proud to have a rich collection of rare substances also. He had studied at the seminary and liked to speak Latin, offering every so often, gratis et amore gods, some product that he had kept on his shelves for years without smerciarlo. The good man helped me in every possible way, especially after he had explained what we were doing. Only when in my ignorance I asked a sample of masurium, told me that he had never seen that element, "numquam I saw." A few years later I had to know what was right: masurium does not exist. "[3]. Although skeptical of this discovery, however Segre wanted to avoid a confrontation, partly because of the political situation in Europe. He tells the story in his autobiography so American, "was in 1938. There were two German chemists who claimed their 'discovery'. Who was I, an Italian physicist in Sicily [in the period 1936-38 Segre directed the Institute of Physics in Palermo, ed] to contradict them? I would be a fool to do it! I did not want to enter into the dispute related to this discovery, that time would prove to be erroneous. " During one of his frequent trips to Berkeley [we are in 1936], where he worked Ernest Lawrence, met with the cyclotron deflector 27 ", made of molybdenum, which had been removed to be replaced. Dennis Patton, historian of the Society of Nuclear Medicine, tells this story well: "They [the flap] were intensely radioactive. Segre wondered if irradiation with positive particles of molybdenum, element 42, had produced a bit 'of the element 43. Churches in Lawrence therefore be able to have these pieces of molybdenum and these, too glad to get rid of these radioactive waste in such a simple way, gave them to her, and took them to Palermo Segre in his suitcase "(!). [4]. Back in Palermo, Segre gets to work together with Carlo Perrier, Professor of Mineralogy, "... it was a nice person, a true gentleman Piedmont, devoted to Giolitti and anti-fascist. He was twenty years older than me, was a bachelor, and knew the classical mineralogy and analytical chemistry. "[3] Together, chemically separated from the element 43 molybdenum determined its physical and chemical properties and I published the results in 1937. "With this work we discovered the first element created by man. Perrier by then and I decided not to give him any names. They were not missed suggestions that name celebrassero fascism or Sicily, as Trinacrio, all things we do not garbavano. ... After the war, when nuclear reactors they provided macroscopic quantities of 43, I had the satisfaction to see that we had not made mistakes and that we had indeed found the most important things Only then gave the name of technetium, derived from the greek τ ε χ ν η τ ο σ, which means artificial, the new element, to commemorate the fact that it was the first artificial element. ". Meanwhile, we are in the first half of 1938, and anti-Semitism is rampant in Italy. Segre, who is of Jewish origin, he continues his travels to Berkeley, and during one of these ... but let's hear it in his own words: "I landed in New York July 13, 1938 with the intention of returning to Italy in the fall for the new year school. But when I returned to Italy for the first time it had been nine years since I was kicked ... "[3]. At the station in Chicago ... [to go from New York to Berkeley needed to change not only train station but also in Chicago, ed] bought the newspaper where I read a brief but chilling news on the Manifesto of the race ... "[3]. At that point Segre decides to stay in the and among the suggestions that come from Columbus University in New York and the University of California at Berkeley, choose the latter. "Very soon after arriving in Berkeley met at the University Faculty Club, where usually had breakfast, Glenn T. Seaborg ... He had just graduated. ... Was interested in everything that was going on around him and knew how to keep your ears and eyes open. The first research undertaken within a few days of arrival, and together with Seaborg, it was time to find short-life isotopes of technetium. It was the natural continuation of the work of Palermo, the reason why I came to Berkeley, and a problem for which I was fully prepared. The new radioactivity, obtained from the bombardment of molybdenum with deuterons, immediately presented an interesting and unexpected phenomenon, it was in fact a case of nuclear isomerism, ie a nucleus that had excited states of long life. We could not dream about that quell'isomero would later become a diagnostic tool of primary importance for medicine. In fact, for a variety of fortunate circumstances the substance is perfectly suited to many clinical and today its applications undertake hundreds of doctors and industry many millions of dollars. Seaborg and then ... I wrote a letter to the 'Physical Review' about it, but a few days later we found out that Lawrence, without saying anything, had stopped her with a telegram to the director of the magazine, and this by the advice of Oppenheimer who had told him - who knows why - that the work was wrong. I resented the extent permitted by my position and the letter, with a delay, was published. "[3]. The medical use of Technetium Segre again brought to the fore, especially in the Congress of Nuclear Medicine. Remains in the memory of all of us his inaugural lecture of the Italian Association of Nuclear Medicine Congress 1987, held not by chance in Palermo, the city of discovery. He himself cites one of these occasions in his autobiography: "The discovery of Tc99 brought me a certain notoriety among nuclear medicine physicians, and rightly so, since quell'isotopo feeds them. Therefore I have been invited several times to speak at meetings of nuclear physicians and are an honorary member of a couple of their professional associations: the Society of Nuclear Medicine and the American College of Nuclear Physicians. The latter had, at the end of January 1982, a meeting in Tucson, Arizona, and invited me to make us a speech. Willingly accepted and we went with Rosa. We had fun and we were able to compare, without envy, the luxurious way of life of doctors, compared to ours. "[3]. Many years passed before the technetium in fact it was used in the activities of Nuclear Medicine. The first obstacle to overcome was his short physical half-life, so it was needed product with the user. In the first study, in 1952, Maurice Goldhaber determined the pattern of decay of molybdenum-99 and later, in 1956, Walter Tucker and Margaret Greene developed the technetium generator. The principle of operation of the generator was the following: the radionuclide "parent", the molybdenum-99, was fixed on a chromatographic column. It, to decay, generated the radionuclide "son", the technetium-99m, which was eluted by passing saline through the column. This system had fairly small size and therefore could be shipped easily. Once designed the generator had to spend another year before the 99m Tc was used for medical purposes and this happened in 1964, when Paul Harper at the University of Chicago carried out the first studies on the and presented at the Meeting of Badgastein the first clinical results with 99m Tc. Alexander Gottschalk says so what happened when the first examination was performed with 99m Tc with the gamma camera, which in those years was built by Hal Anger: "We could not believe what happened When We administered the first dose of pertechnetate to a patient to perform a brain scan. The overabundance of counts Compared with our positron brain images was staggering and the lights glow on the old-fashioned counter on the gamera flashed like an aurora borealis. "[5]. In 1965, the first commercial generator was sold by the Nuclear Consultant Co. (Mallinckrodt) and since then thousands of technetium generators are used daily by all departments of Nuclear Medicine.

The discovery of Iodine-131 In the story of the discovery of technetium, Segre introduced us to the knowledge of Glenn Theodore Seaborg. Glenn Seaborg at Berkeley worked with Ernest Lawrence, and through the use of the cyclotron, summed up many radioactive isotopes, many of which are used today for medical purposes. One of these discoveries was an important contribution to the remarkable expansion of the fate of the nuclear medicine giving it a role that after more than sixty years remains central in the treatment of thyroid diseases: the Iodine 131. But to talk of Iodine necessarily have to take a step back and return to Italy. In May 1934 Enrico Fermi, University of Rome, radiating elements with slow neutrons, reported 14 new radioactive elements. The 11th isotope of this list had "iodine-intense effect, period about 30 minutes.". [6] It was the 128 I, which actually had a half-life of 25 minutes. We move now back in the United States, . It 'November 12, 1936 and Karl Compton, President of MIT [Massachusetts Institute of Technology] and brother of Arthur Holly Compton, another prominent figure of physics [his is the description of the Compton], is holding a conference entitled: "What Physics Can Do for Biology and Medicine." In the audience are James Howard Means, endocrinologist important time and Robley Evans, a physicist at MIT, famous for having studied the effects of radium on the human body, and having established the toxic dose . At the end of the conference, Means says, "There is a radioactive isotope of iodine?". Evans remembers, in a sort of flashback memory, those seven words of Fermi and so, in the days after, he began working with the 128 I, along with Saul Hertz and Arthur Roberts. They this isotope administered to rabbits and saw that they were located early in the thyroid gland in amounts 80 times greater than that which could be expected by simple diffusion. In rabbits rendered hyperthyroid with TSH, the uptake was significantly higher, while those treated with diet with cabbage, which contain substances gozzigene was reduced. These were the early studies on the thyroid's ability to capture inorganic anions such as iodine and further confirmation of the importance of the discovery of de Hevesy. In the following years [1938-40], was built at MIT's first cyclotron for medical and biological purposes. It was used to produce 130 I, who had a half-life of 12.5 hours, and that it contained 10% of 131 I as a contaminant. With the 130i, Hertz and Roberts, in March 1941, used it for the first time radioactive iodine for therapeutic purposes [7]. The 128 I was also used to Berkeley by Joseph G. Hamilton, one of the early pioneers of nuclear medicine. The short half-life of the isotope, however, did not provide a thorough study of the metabolism of the thyroid, which is longer physical half-life of 128 I (25 minutes), and this was an important limitation. These operating limitations led in some way to search for some other isotope of iodine with longer half-life physics. One day, on a landing of LeConte Hall [the Faculty of Physics at Berkeley] cross Hamilton and Seaborg. The meeting by telling him to do the latter. "The discovery of iodine-131 has given me a special satisfaction. In 1938, Dr. Joseph Hamilton spoke to me of the limitations in his studies on thyroid metabolism imposed by the short half-life of radioactive iodine tracer that was available. He worked with the 128 I, which has a half-life of only 25 minutes. When he inquired about the possibility of discovering another isotope of iodine with a half-life longer, I asked him who value [half-life] would be optimal for his work. And he said, 'Oh, about a week'. Immediately after this meeting, Jack Livingood and I sintetizzammo and we identified the 131 Iodine, with a half-life long fortunately, eight days. "[8]. Seaborg personally experienced the effectiveness of 131 I, as he himself says, "Iodine- 131 saved the life of my mother. She had a marked hyperthyroid condition that was diagnosed and treated with iodine 131, as well as George Bush and Barbara Bush, as you know, suffering from Graves' disease. "[9]. It was at a time when, with cyclotrons, is pelted everything to produce new radioisotopes. Seaborg describes it thus: "We have created isotopes that did not exist the day before, the use of which has yet to be discovered." The discovery of the 131 I therefore deserves greater consideration because this radioisotope was produced after a specific request and was promptly used in medical practice. This certainly was not a result of luck but of a study and preparation of the experiment very accurate. And that there was not much time to devote to the words he confirms the same Seaborg: "... in the discovery of iodine, was the letter to the editor of 217 words [10] and the discovery of technetium 99m was of 237 words [11 ]. We could not waste words in those days. "(Fig.1). Thus, in 1939, Hamilton and Mayo Soley they were able to publish the first scientific work on the use of diagnostic 131 I [12]. On October 12, 1941, Hamilton and John Lawrence used the radioiodine, the most prevalent form of 131 I in the treatment of . In the first three hyperthyroid patients treated was observed a significant reduction in basal metabolic rate, which was the only way to study thyroid function at the time, does not yet exist the hormonal assays [13]. The 130i, however, was still used for the treatment of thyroid tumors. In 1941 at Columbia University in New York, Albert Keston [among other things, inventor of the strips for rapid determination of blood glucose and discoverer, with Allen Reid in 1946, the 125 I] and Virginia Kneeland Frantz [first woman to chair the American Thyroid Society] used the 130 I in thyroid tumors . They observed a 6% uptake in the thyroid and even 30% in a femoral metastases [14]. On December 7, 1946 Samuel M. Seidlin, Leo D. Marinelli and Eleanor Oshry documenting the complete disappearance of metastases in a patient with thyroid tumor, treated with 130 I after . [15]. Among other things, Seidlin was among the first to realize that, for effective treatment with radioiodine, it was necessary to advance a total thyroidectomy. Indeed, due to the manner of its production and its usefulness when the 131 I was more available, it also helped to open for civilian knowledge that the had made for purely military purposes. Thus, n el June 1946 President Truman, as part of the Atomic Energy Act, ordered that the reactor would produce 131 The Oak Ridge also for medical purposes, out of the Manhattan Project. The 131 The pure product was two years later, as a byproduct of the fission process. The Atomic Energy Act was promulgated August 1, 1946. It transformed the Manhattan Project [whose official name was actually Manhattan Engineering District, ed] nell'Atomic Energy Commission, AEC. The next day was made the first shipment of radioactive material for medical purposes: it was carbon-14. [16]

These successes did say to the commissioners of the AEC that the discoveries of physics would be used "to build bombs in the strictest confidence, but to provide radioisotopes to treat cancer with the greatest possible publicity." To optimize the use of the radioisotope, which was still very expensive, Emil Baumann, chemical at Montefiore Hospital, radioiodine recovered from the urine of patients for reuse. How to tell David Becker and Clark Sawin [17] "... a young volunteer was given the task of purifying the urine. His name was Rosalyn Sussman, who then married Aaron Yalow, a physicist. When he received the Nobel Prize in 1977 for his work on the Yalow radioimmunoassay remembered that this was his first experience with radioiodine. ". These successes in cancer therapy were amplified by the press, who wrote: "the treatment of cancer found in the fiery canyon of death in Oak Ridge" [18]. Obviously impression on public opinion and the opinion movement that was to create increased pressure on the AEC for further liberalization in the distribution of radioisotopes for medical use. The official consecration of 131 Iodine occurs in 1951: The FDA approves the I-131 sodium iodide for use in thyroid disease. It 's the first radiopharmaceutical approved for clinical use by the FDA in the United States.

Close Technetium-99m and iodine-131 are two emblematic radioisotopes for nuclear medicine. The first was discovered in reality without knowing for what should be used only after many years. The second was almost created especially for use from the start that it was done. Even today, both are the cornerstones of the branch respectively diagnostic and the therapeutic Nuclear Medicine. Both are used as such in the diagnosis and treatment of diseases of the thyroid or other diseases, or used to mark other molecules, allowing for a much wider scope of diagnostic and therapeutic applications. Their use have forged much of the knowledge of radiation protection we have today and that allow operators to work more safely.

For all these reasons, this work is also intended as a modest tribute to all those who, like Marie Curie, Joseph Hamilton and many others, have sacrificed their lives for the improvement of knowledge in the field of radiation applied to Medicine, causing even Today Nuclear Medicine helps to save or improve the lives of many patients who are turning to it with confidence.

Bibliography 1. Figures in Radiation History. Georg de Hevesy. http://www.orcbs.msu.edu/radiation/radhistory/georgedehevesy.html 2. The Curie, Joliot F, Artificial production of a new kind of radioelement. Nature 133: 201, 1934. 3. Emilio Segre. Autobiography of a physicist. Ed Il Mulino, 1995. 4. Patton DD. How technetium was Discovered in a pile of junk. J.Nucl.Med. 39: 26N, 1998. 5. A. Gottschalk The early years with Hal Anger. Sem.Nucl.Med. 26: 171-9, 1996. 6. E. Fermi Radioactivity induced by neutron bombardment. Nature 133: 757, 1934. 7. Hertz S, Roberts A. Radioactive iodine in the study of thyroid physiology. VII. The use of radioactive iodine therapy in hyperthyroidism. JAMA 131: 81-6, 1946. 8. The Life of Glenn T. Seaborg in 1982 Autobiography: http://seaborg.nmu.edu/gts/auto.html 9. Glenn Seaborg, An early history of LBNL: www- itg.lbl.gov/Seaborg.talks/65th-anniv/start.html

10. JJ Livingood, Seaborg GT. Radioactive iodine isotopes. Phys. 53: 1015, 1938 (article available at: http://prola.aps.org/abstract/PR/v53/i12/p1015_2). 11. E. Segre, GT Seaborg. Nuclear Isomerism in Element 43. Phys. Rev. 54: 772, 1938 (article available at: http://prola.aps.org/abstract/PR/v54/i9/p772_2). 12. Hamilton JG, Soley MH. Studies in iodine metabolism by the use of a new radioactive isotope of iodine. Am.J.Physiol. 127: 557-72, 1939. 13. Hamilton JG, JH Lawrence. Recent clinical developments in the therapeutic application of radio-phosphorus and radio-iodine. J.Clin.Invest. 21: 624, 1942. 14. Keston AS, RP Ball, Frantz VK. Storage of radioactive iodine in a metastasis from thyroid carcinoma. Science 95: 362-2, 1942. 15. Seidlin S. Radioactive iodine therapy. Effect on functioning metastases of adenocarcinoma of the thyroid. JAMA. 132:838-47, 1946. 16. Patton DD. Radioisotope The First Commercial Shipment. J.Nucl.Med. 43: 30N, 2002. 17. Becker DV, Sawin CT, Radioiodine and Thyroid disease: The Beginning. Sem.Nucl.Med. 26: 155-64, 1996. 18. Brucer M. Nuclear medicine begins with a boa constrictor. J Nucl Med.19: 581-98, 1978.

Table 1. Physical characteristics of 99m Tc and 131 I

99m Tc 131 I Atomic number (Z) 43 53 Mass number (A) 99 131 Physical half-life 6 hours 8 days Radiation emitted range gamma and beta range = 364, 337, 284 keV Energy of the emitted 140 keV beta = 610 keV radiation

Figure 1: Text of the work that announce the discovery of iodine 131 and technetium 99m [10, 11]. 1