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Radioactive nuclei for medical applications

Radioactive nuclei for medical applications The radioisotopes used for labeling the diagnostic and therapeutic radiopharmaceuticals are contemporaneously produced using neutrons in reactors and light charged particles from accelerators (cyclotrons). After the presentation of both methods the commercially available cyclotrons are reviewed. Some examples of the most popular medical radioisotopes are given. The new Radiopharmaceuticals Production and Research Centre at the University of Warsaw is presented. 1. INTRODUCTION The first radioactive nucleus used for medical applications, 226Ra with a 1600 y half-life was extracted by fractional crystallization from barium chloride contained in uranium ore by Maria Sk odowska-Curie and Pierre Curie in Dember 1898 (Barium and Radium belong to the same group in the periodic system)[1]. The gamma radiation of the radioactive series of this isotope was used as the therapeutic agent for cancer cell irradiation from Ra "bombs". In some cases the daughter product of 226Ra, the 222Rn isotope (T1/2=3.8 d) was extracted and placed, similarly to 226Ra in "applicators" in the form of sealed thin tubes and needles used for irradiations [2], ("Curie-therapy", also known as E-mail address: jastj@slcj.uw.edu.pl Jerzy Jastrz bski "brachytherapy"). In all cases the source of the energetic gamma-rays was the 20 min. -day of 214Bi [3]. Besides the U-Ra family indicated above, the thorium radioactive family (alpha-day products of the 1.4.1010 y 232Th) with its gamma-ray emitting 228Ac (T1/2 = 6.1 h) and 208Tl (T1/2 = 3 min) members were also sometimes used for Curie-therapy. With the advent of artificially produced radioelements, the radiation from nuclear reactor produced 60Co sources, placed in "cobalt bombs" successively replaced the gamma-rays of the radium and thorium families. In contemporary cancer therapy with eltromagnetic radiation the eltron bremsstrahng radiation issuing from medical linear accelerators is mainly used. The 60Co gamma-rays are, however, still employed in very spialized brain tumor radiosurgery using the so called Gamma Knife. An historical persptive of medical radioisotope production and a rich bibliography of this subjt can be found in Refs. [3, 4]. 2. RADIOISOTOPES AND RADIOPHARMACEUTICALS The contemporary employment of radioactive nuclei for medical applications is based on two different methods of their production. The first one uses neutron induced reactions with neutrons mainly from nuclear reactors, although accelerator produced neutrons are also considered. The sond one employs s induced by accelerated charged particles, mainly using various types of cyclotron. These two production methods lead to quite different positions of the product on the nuclear chart. The neutron induced reactions produce unstable neutron-rich nuclei, spontaneously approaching the betastability line by the beta-day process ( -emission of an eltron and a neutrino). The cyclotron accelerated charged particles (p, d, 3He, 4He) impinging on stable targets lead, with some exceptions, to neutron-deficient final products, daying by positron and neutrino emission ( +) (two eltron-positron annihilation gamma-quanta of 511 keV energy, emitted in opposite dirtions, promptly follow the nuclear day by positron emission) and/or the eltron capture () process. For heavy nuclei sometimes -particle emission is possible, also eventually leading toward the beta stability line. All these radioactive days may lead to the ground state of the final nucleus or to its excited states which in turn day by gamma-ray emission or eltron internal conversion (IC). The emission of low-energy Auger eltrons accompanies the and IC processes. The nuclear reactor or accelerator produced radioisotopes are used as simple sotions or for labeling various compounds, forming so-called diagnostic or therapeutic radiopharmaceuticals [5]. Radiopharmaceuticals administered to the living organisms of animals or humans seltively search various types of cells, permitting their spatial distribution to be identified, spific physiological processes to be examined or malignant cells to be destroyed. The diagnostic radiopharmaceuticals are also largely used in research, serving as information agents on the behavior of various metabolic processes. They are also employed in testing of new pharmaceutical products. The various biomedical properties of labeled radiopharmaceuticals allow the use of the same radioisotope in many applications. Therefore, practically a number of currently used radioisotopes is rather limited whereas the number of labeled compounds is substantially larger and continuously increasing thanks to the radiochemical research effort all around the world. 3. PRODUCTION METHODS OF MEDICAL ISOTOPES 3.1 NUCLEAR REACTORS FOR RADIOISOTOPE PRODUCTION Currently, the prominent part of nuclear medicine diagnostic and therapeutic interventions are based on radioisotopes produced in nuclear reactors [6]. Between them accounts for more than 80% of all administered radiopharmaceuticals. s are based on the fission process of 235U, an isotope present in natural uranium with only 0.7% abundance. The various types of reactors use natural uranium, low enriched uranium (LEU, up to 20% of 235U) and highly enriched uranium (HEU, above 20% of 235U, sometimes even more than 90%). Fig. 3.1.1 presents a simplified scheme of a nuclear reactor. Thermal neutrons, always present in the U compounds from the spontaneous fission of 238U, generate a chain reaction (multiplication of neutrons after each fission process) in the nuclear fuel rods. The fission process liberates about 200 MeV energy per fission in the form of kinetic energy of (generally) two fission fragments, emitted neutrons, charged particles, gamma rays and neutrinos. Only the neutrino energy (a few MeV) escapes from the reactor core. On the average = 2.4 neutrons are emitted after each thermal neutron induced fission of 235U. Some of them are captured without leading to a con- Jerzy Jastrz bski sutive fission event, whereas =2.1 neutrons interact with 235U, leading to its fission or with 238U, leading to the fuel "briding" (production of 239Pu). The positive neutron balance of the neutron induced fission of 235U is the basis of the nuclear chain reaction and the construction principle of nuclear reactors. Fig. 3.1.1 Simplified scheme of a nuclear reactor. The active zone (1) of the reactor is surrounded by neutron refltor (2). In the active zone are placed rods with U fuel delivering heat (3) and rods with the neutron energy moderators (4). The control rods (5) assume the reactor reactivity regulation and prevention against its accidental increase. The heat generated by the reactor is eliminated by coolant through canals (6). (From Ref. 7). In order to produce consutive fission events with high efficiency the fission neutron kinetic energy (on average about 2 MeV) should be substantially dreased down to thermal energies ( 0.025eV), where the neutron induced fission process is the most probable; (compare Fig. 3.1.2). The fission neutron energy drease is achieved during a very short time (of the order of 10-4 s.) by collisions with moderator atoms: regular, light water (H2O); solid graphite (C); heavy water (D2O) or some other material. Actually about 75% of the operating so called "thermal" nuclear rtors use light water, 20% solid graphite and 5% heavy water as moderator. Although light water has the highest "slowing down power" (mass of the hydrogen atom almost equal to the neutron mass) the "moderating ratio" which takes into account the moderator density, collision cross-stion and neutron absorption probability is largest for heavy water (360 times larger than for light water). This is the reason why heavy water is used as moderator for natural uranium based thermal nuclear reactors. Fig. 3.1.2. Neutron induced fission cross ­ stion for 235U vs. neutron kinetic energy (thermal neutrons 0.025 eV). (From Ref. 8). Steady reactor running is obtained thanks to the action of control rods. Control rods are made from strongly neutron absorbing material (such as boron or cadmium) and are inserted into the reactor core to keep the reactivity of the reactor close to zero. The reactivity is defined as =(k-1)/k, where k is the "multiplication factor", the number of fissions in one generation to their number in the previous one. The reactor state having =0 is called "critical". Due to the short fission neutron "life-time" the critical state would be quite unstable if it were not for the existence of delayed neutrons with a yield of 0.65% of all fission neutrons and half-life from a part of a sond to minutes. These neutrons originate from the beta day of the fission products. Taking into account the delayed neutrons, the steady reactor power is made subcritical on prompt fission neutrons and bomes just critical when the delayed neutrons are incded in the neutron fx balance. Fig. 3.1.3 shows the shape of a typical thermal reactor neutron fx. During radioisotope production these neutrons interact with the target material, introduced close to the reactor core in spially designed irradiation capsules. Jerzy Jastrz bski Fig. 3.1.3. Neutron Fx Sptra for Thermal Reactor. (Adapted from Ref. 9). 3.2 ACCELERATORS FOR RADIOISOTOPE PRODUCTION Practically at present cyclotrons are the only accelerators used for medical isotope production. The principle of particle acceleration in a cyclotron is presented in Fig. 3.2.1. It consists in the simultaneous action of a stable magnetic field B and a rapidly varying eltric field E, forcing the particle circular motion and increasing the particle energy at each crossing of the border of the eltric field. The magnetic field generated by the eltromagnet in the form of "hills" and "valleys" assures orbital stability. Particles to be accelerated are introduced into the ion source, an eltrical arc device in a gas for negative ions or a more complex, so called R (eltron cyclotron resonance) ion source for positive ions. Particles are injted into the center of the cyclotron and accelerated by the eltric field, applied to the "dees" ­ the hollow metallic eltrodes, placed on the particle trajtories. With increasing particle energy the radius of its almost circular orbit increases but the revotion period remains independent of this radius. Therefore, the frequency of the rapidly varying eltric field may remain constant. This frequency is a multiple of the particle revotion frequency ("harmonics"). The particle relativistic mass increase with energy is compensated by the shape of the magnetic field, increasing with orbit radius. At the end of the acceleration process negatively charged ions may be extracted from the cyclotron by "stripping" their eltron(s) when passing through a thin foil. Magnetic and/or eltrostatic defltion is used for positive ion extraction. Fig. 3.2.2 shows the structure of a cyclotron. Fig. 3.2.1. Simplified scheme of the cyclotron principle. Magnetic field increasing with radius, generated by eltromagnet in form of "hills" and "valleys"assures the particle orbit stability. The rapidly varying eltric field accelerates particles when approaching or leaving the "dees", A and B. (From. Ref. 10). Dee Structure Hills Valleys Hills Magnet Valleys RF Input Ion Source Dee Structure Fig. 3.2.2. Structure of a cyklotron showing the magnet, ,,dee" structure and ion source. (From Ref. 11). Jerzy Jastrz bski Table I gives the updated [12] classification of cyclotrons used in medical applications. Table I Classification of accelerators. (Adapted from Ref. 12). Accelerator class Characteristics Proton energy (MeV) Class I Single particle (p b d) Class II Single or multiple particle p,d Class III Single, two or three particles p,d, 20?Ep<70 11< Ep <20 Comments Example ?11 PET Siemens lipse He, He not usually available GE PETtrace IBA CYCLONE 18/9 PET, SPT He and He can be available SPT and PET IBA CYCLONE 30 IBA CYCLONE 30XP IBA CYCLONE 70 (Arronax) IBA CYCLONE 230 Triumf Ca Class IV Usually p only 70 - 500 CYCLONE 230 for proton therapy Many hundreds of Class I and Class II cyclotrons are presently operating all round the world, producing mainly diagnostic but also some therapeutic radioisotopes. An example of a Class II cyclotron, a General Eltric (GE) PETtrace accelerator is shown in Fig. 3.2.3 and its cut is displayed in Fig. 3.2.4. The accelerated particles impinge on a cooled target holder, activating the target material. This may be done inside the cyclotron, before the beam extraction (mainly for positively charged ions) as well as after the beam extraction for negatively charged ions. Gaseous, liquid or solid target materials are used. In Fig. 3.2.5 a schematic diagram of a gas target is shown. Fig. 3.2.3. The GE Healthcare PETtrace cyclotron, accelerating protons with energy of 16.5 MeV and deuterons with energy of 8.4 MeV with proton current up to 100 A. This type of cyclotron will be operational at the end of 2011 in the Radiofarmaceuticals Production and Research Centre of the Heavy Ion Laboratory, University of Warsaw (Courtesy of GE). Fig. 3.2.4. Interior of the PETtrace cyclotron (Courtesy of GE). Jerzy Jastrz bski Table II gives the list of main manufacturers of Class I and Class II cyclotrons, used mainly for the production of PET radioisotopes. Table II. Cyclotrons with Ep 20 MeV for PET radioisotope production. (Adapted from Ref. 11) Manufacturer Feature Factory localisation Knoxville, TN (USA) Years of operation 27 27 Uppsala (Sw) 26 26 Louvain-LaNeuve, (Be) 24 Accelerated particles p p p,d p p,d Ep (MeV) 11 11 16.5 9.6 18 Siemens lipse HP lipse RD GE Healthcare PETtrace Minitrace Ion Beam Applic. (IBA) Cyclone 18/9 Cyclone 10/5 p,d Sumitomo Heavy Ind. HM-18 HM-12 Tokio, (Jp.) p,d p,d p,d p Advanced Cycl. Syst. TR-19/9 TR-14 Vancouver, (Ca) Fig. 3.2.5. Schematic diagram of a typical cyclotron target used with gases. (From Ref. 13). The currently commercially available cyclotrons with proton energies below 20 MeV are, however, generally unable to produce radioisotopes in a reasonable quantity via two nucleon emission (reactions such as p,2n , d,2n or p,pn). Similarly, the often very useful He induced reactions are not accessible in these accelerators. The higher proton energies as well as He beams are presently available in Europe and the US on old Class III Scanditronix accelerators, no longer commercialized. Fortunately, quite rently IBA (Ion Beam Applications) Company launched a new CYCLONE 30XP accelerator delivering protons of variable energy 18-30 MeV, deuterons of energy 9-15 MeV and He++ particles of energy 29 MeV. Fig. 3.2.6 shows the schematic and cross-stional view of this cyclotron. Two external ion sources are employed: the multicusp eltrical arc device delivering negatively charged protons and deuterons and an R ion source for doubly charged He++ particles. The negative beams are extracted by stripping and He++ by an eltrostatic device. The accelerating eltric field frequency is also different for these two types of accelerated particles. Fig. 3.2.6. Schematic and cross ­ stional view of the IBA CYCLONE XP 30. Two ion sources (multicusp and R) are shown on the top of the cyclotron (Courtesy of IBA). Jerzy Jastrz bski At the upper end of Class III accelerators a currently commercially available cyclotron is again produced by the IBA Company ­ the CYCLONE 70XP, delivering protons of energy 30-70 MeV, deuterons of energy 15-35 MeV and He++ particles of energy 70 MeV. Such a cyclotron was rently put into service at Nantes (France) ­ ARRONAX facility [14]. 4. S 4.1 NEUTRON INDUCED REACTIONS Two quite different nuclear processes are employed to produce medical radioisotopes by neutron interaction with materials introduced into the reactor core: the fission route and the activation route. About 40 radioisotopes are produced by the activation route and 5 are separated from the fission products, incding the most used o generator. In the fission route, after the splitting of the 235U nucleus under the slow neutron capture process two fragments with masses around A 95 and A 140 are produced (see Fig. 4.1.1). By chemical extraction from the irradiated material (often performed in spialized, large separation facilities) the medical radioisotopes are prepared. Currently, highly enriched uranium targets (HEU) are used preferentially, at least for the o fission product. Table III lists the world producers of the o radioisotope. In the activation route the compound nuclei, formed after neutron absorption by the irradiated target nuclei, day via various paths producing final radioactive products. The most common consists of the absorption of the thermal or epithermal neutron with a subsequent emission of rays: the (n, ) reaction. The production of the famous therapeutic 60Co isotope using neutron absorption by the natural 59Co isotope (100% abundance) is an example. The final reaction product is the same element as the target isotope and cannot be chemically separated. A high neutron fx is, therefore, nessary to produce the final product with high spific activity. In the high neutron fx two consutive (n, ) reactions (two neutron captures) on the same target nucleus can also give a reasonable final product activity of the same element two mass units heavier than the target. The neutron absorption reaction of the (n, ) type may be, however, sometimes employed to produce different element than the target one. If the irradiation products are short-lived beta emitters a final isotope of higher atomic Z number may be formed by day. Finally, the (n,p) or (n, ) reactions are also sometimes used employing more energetic (above particle emission threshold) neutrons in the reactor neutron fx. Some examples of medical radioisotopes formed by fission and activation routes are presented in Table IV. Ref. 17 gives a list of currently operating high fx nuclear reactors as well as a more exhaustive list of therapeutic emitters. Fig. 4.1.1. Fission product mass yield curve for the fission of 235U induced with fission sptrum neutrons. (From Ref. 15). Table III. World producers of o. (From Ref. 16) Jerzy Jastrz bski Table IV. Examples of Reactor produced medical isotopes Isotopes T1/2 6.0 h Production route U(n,fission) Mo 99 Day characteristics Applications Imaging, scintigraphy and SPT Therapy, Co bombs, Gamma - Knife Mo( ,66h) 142 keV (95%) 1173 keV (100%) 1333 keV Co 5.3 y Co(n, ) Co 8.0 d Te(n, ) 131m Te 131m Te( ,30h) 364 keV (89%) Imaging and therapy, thyroid, carcinomas, 6.7 d a) b) (2.6%,n, ) Yb(13%,n, ) Yb( ,1.9h) 90 - 498 keV (79%) 208 keV (11%) Short range , Targeted cancer therapy Therapy, long range part Yb 2.7 d a) b) Y(n, ) Y U (n,fission) Y 2.28 MeV (99%) Ir 73 d Ir(n, ) Ir and 296 keV (29%) 308 keV (31%) High dose rate brachytherapy Re 3.7 d Re(n, ) Re , 1077 keV (93%) Therapy with imaging 137 keV (9%) 4.2 CHARGED PARTICLE INDUCED REACTIONS Three mhanisms are of importance when medical radioisotope production with charged particles is considered. For low bombarding particle energies (Class I and Class II cyclotrons) similarly as with thermal or low energy neutrons the compound nucleus (CN) is formed after the fusion of the projtile and target nuclei. Its excitation energy depends mainly on the projtile kinetic energy and the mass difference of the final and initial reaction partners. About 8 MeV excitation energy is nessary to evaporate one nucleon and less than 3 MeV to evaporate an alpha-particle. With increasing projtile kinetic energy dirt reaction processes contribute to the reaction cross-stion. Fig. 4.2.1 ilstrates the cross-stion behavior of a typical CN reaction followed by dirt reaction processes. Finally, at even higher bombarding energies (Class IV cyclotrons) spallation reactions appear with the emission of a substantial proton and neutron number from the target nucleus. Fig. 4.2.1. Excitation function for the 14N(p, )11C reaction. Reaction cross ­ stion is plotted s incident proton energy. The mass difference of the final ( and 11C) reaction products and the initial reaction partners (p and 14N) is 3.6 MeV, reflted by the reaction threshold. (From Ref. 13). Similarly as for the reactor produced radioisotopes, the medical radioactive nuclei produced with accelerators can be divided into diagnostic and therapeutic ones. Radioisotopic imaging in contemporary nuclear medicine uses two different approaches. The first one is based on the dettion of a single gammaray line from the appropriate radiotracer. The planar 2D scintigraphy (gamma-cameras) and 3D SPT scanners represent this approach. The sond approach is based on the + radioactive day consisting of a successive posi- Jerzy Jastrz bski tron emission and annihilation followed by the simultaneous production of two annihilation quanta (511 keV energy). The sensitivity of 3D Positron Emission Tomography (PET) significantly exceeds the SPT sensitivity due to the auto-collimation of the coincident annihilation quanta emitted almost antiparallelly. Currently more and more SPT and PET scanners are equipped with X-ray CT devices giving, during the same examination, anatomic images with increased contrast-enhancement. Rently, nuclear magnetic resonance imaging (MRI) devices have begun to be coupled with PET scanners (barely commercially available) and, most probably, SPT-MRI devices will be also accessible soon on the market. We begin with the enumeration of the radioisotopes used for PET thniques. The most popular and convenient PET radiopharmaceuticals are based on short lived radioactive nuclei, presented in Table V. Their robust representative, forodeoxygcose, besides local production by hospitalowned small cyclotrons, is often produced in spialized centers and transported to distant diagnostic PET cameras. Another sotion for PET radioisotopes is their extraction from the long lived generators also produced with accelerators. Table VI gives some examples. Table V. Short ­ lived radioisotopes for PET Radioisotope T1/2 (min) Emax (MeV) Efftive range + (mm) Target O water O(p,n)18F Ne gas Ne(d, )18F N(p, )11C N2 - gas [10B(d,n)11C] O water O(p, )13N C(d,n)13N N2 - gas N(d,n)15O [15N(p,n)15O] Table VI. Examples of generator radioisotopes for PET Radioisotope Generator Emax + MeV % + Applications Rb Sr(25d)? Rb(1.3 m) Rb(p,4n) Sr Ep ? 60 MeV Optimal diagnosis and management of cardiac diseases, Myocardial perfusion studies and blood flow Ga Ge(275d)? Ga(68 m) proton spallation of nat. Ga Ga(p,2n) Zn( , 2n) A generator based 18 alternative to F ­ radiopharmacy Imaging and simult. therapeutic appl. Attenuation corrtions of PET scanners Finally, in a number of applications it is nessary to follow labeled compounds in slow pharmacokinetic processes in vivo for times substantially longer than the day time of classic, short lived PET radioisotopes. Examples of longer living positron emitters are given in Table VII. Table VII. Long ­ lived radioisotopes for PET Radioisotope T1/2 Emax + MeV + abund. % 19 Target abund. % Applications Cu 12.8 h Ni(p,n) Zn(p, n) Possible PET and therapy good resotion for animal PET 67 dosimetry for Cu radioimmunotherapy tissue hypoxia Possible PET and therapy thyroid cancer dose estimation 4.2 d Te(p,n) Jerzy Jastrz bski Scintigraphic and SPT imaging is dominated by the use of , extracted from the 66h o generators, produced in nuclear reactors. However, a rent "reactor crisis", due to the unexpted shut-down of a few high fx reactors in Europe and Canada prompted the Canadian Government to launch a research program allowing the efficient production of o or by the accelerator route. The considered s are indicated at the top of Table VIII. In the same table other accelerator produced SPT radioisotopes are also shown. Table VIII. Examples of Accelerator produced SPT radioisotopes. Accelerator production of and o is considered by Canadian Government Isotope T1/2 Targ et abu nd. Day charact. Applications / comments 6.0 h 66 h Mo (p,2n) Mo (p,pn) projt generator (projt) projt Tumours imag. (93, 184, 300 keV) Mo Mo Ga 66 h 3.3 d nat U (g,fission) Zn (p,n) Zn (p,2n) In 2.8 d Cd(p,n) Cd(p,2n) Ag( ,2n) Te(p,2n) Xe(p,2n) (nat. Cd comerc. used) Methastases Thyroid functions. Can replace in imaging (171, 245 keV) 13 h 124m 123 Cs Xe (159 keV) Tl 9h ? 73 h Tl(p,3n) Pb 30 Tl Cardiology (167 keV) It is evident that their production as well as the production of o involves s with the emission of more than one nucleon. As discussed previously, the bombarding energies of Class I and Class II cyclotrons are too low for efficient production of these isotopes. Class III accelerators are nessary. Presently, 95% of accelerator produced medical radioisotopes are used for imaging purposes. In the remaining 5% of therapeutic ones [18] a substantial part is still in the prlinical stage of development. We mention here two of them with great therapeutic potential in the new field of so-called Targeted Alpha Therapy (TAT). The alpha particle emitters, if linked to the cancer cells, efficiently destroy the malignant cells by their double strand breaking without great damage to the surrounding healthy cells. The large energy deposited by short range alpha particles is the basis of TAT. Two isotopes are of particular interest 213Bi and 211At; 213 Bi is obtained from the 225 Ac/213Bi generator [19, 20] and 211At is produced by the 28MeV ( ,2n) reaction on a natural Bi target [21]. Their radiopharmaceuticals are based on peptides or monoclonal antibodies, actively investigated in many laboratories. 5. MEDICAL RADIOISOTOPES FROM THE HEAVY ION LABORATORY OF THE UNIVERSITY OF WARSAW The production of radioisotopes and radiopharmaceuticals for Positron Emission Tomography is in the preparatory phase at HIL-UW. Fig. 5.1 and fig. 5.2 show the layout of the Radiopharmaceuticals Production and Research Center of this Laboratory [22]. The Centre will be operational at the end of 2011, with a PETtrace, k=16 cyclotron (see Fig. 3.2.3). Using the large, k=160, heavy ion cyclotron the 211 At isotope (T1/2=7h) is produced and will be used by a large collaboration [23] for applications in Targeted Alpha Therapy (TAT). Jerzy Jastrz bski Heavy Ion cyclotron Fig. 5.1. Layout of the ground floor of the HIL building. Lower part of the layout shows the heavy ion cyclotron, the beam lines and the nuclear physics experimental stations. Upper part shows the Radiopharmaceuticals Production and Research Centre, placed underground (-7m.). (see also www.slcj.uw.edu.pl/pet). Fig. 5.2. Layout of the RPRC. Proton / deuteron cyclotron and its control room is placed on the left part of the figure. Two independent production rooms are placed in the middle of the figure (The first one for the routine production of FDG and the sond one for other radiopharmaceuticals). The Quality Control room is placed in the right part of the figure. Radioactive nuclei for medical applications 6. SUMMARY AND OUTLOOK Radioactive isotopes are currently indispensable in the contemporary health service all around the world. They are produced using nuclear reactors and more and more with particle accelerators. In Poland during the last dade substantial progress in imaging modalities may be noted. To the currently operating about 50 scintigraphic and gamma cameras, 60 SPT and 8 SPT/CT devices the 12 PET-CT scanners were added during last years both in public and private establishments [24]. Two Class I and Class II cyclotrons are operating and three others should be operational at the end of 2011. Whereas the PET radioisotopes seem soon to be adequately provided, the new, less common accelerator produced SPT isotopes are not available in Poland yet, due to the lack of an appropriate accelerator. Some therapeutic radioisotopes produced via the reactor route are available thanks to the high fx research reactor in wierk near Warsaw. Also, some -emitting therapeutic radioisotopes are produced for research purposes at the Heavy Ion Laboratory of the University of Warsaw. However, their current, everyday production needs also a dedicated Class III accelerator. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annales UMCS, Physica de Gruyter

Radioactive nuclei for medical applications

Jastrzębski, Jerzy
Annales UMCS, Physica , Volume 66 – Jan 1, 2011
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de Gruyter
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0137-6861
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10.2478/v10246-012-0003-8
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Abstract

The radioisotopes used for labeling the diagnostic and therapeutic radiopharmaceuticals are contemporaneously produced using neutrons in reactors and light charged particles from accelerators (cyclotrons). After the presentation of both methods the commercially available cyclotrons are reviewed. Some examples of the most popular medical radioisotopes are given. The new Radiopharmaceuticals Production and Research Centre at the University of Warsaw is presented. 1. INTRODUCTION The first radioactive nucleus used for medical applications, 226Ra with a 1600 y half-life was extracted by fractional crystallization from barium chloride contained in uranium ore by Maria Sk odowska-Curie and Pierre Curie in Dember 1898 (Barium and Radium belong to the same group in the periodic system)[1]. The gamma radiation of the radioactive series of this isotope was used as the therapeutic agent for cancer cell irradiation from Ra "bombs". In some cases the daughter product of 226Ra, the 222Rn isotope (T1/2=3.8 d) was extracted and placed, similarly to 226Ra in "applicators" in the form of sealed thin tubes and needles used for irradiations [2], ("Curie-therapy", also known as E-mail address: jastj@slcj.uw.edu.pl Jerzy Jastrz bski "brachytherapy"). In all cases the source of the energetic gamma-rays was the 20 min. -day of 214Bi [3]. Besides the U-Ra family indicated above, the thorium radioactive family (alpha-day products of the 1.4.1010 y 232Th) with its gamma-ray emitting 228Ac (T1/2 = 6.1 h) and 208Tl (T1/2 = 3 min) members were also sometimes used for Curie-therapy. With the advent of artificially produced radioelements, the radiation from nuclear reactor produced 60Co sources, placed in "cobalt bombs" successively replaced the gamma-rays of the radium and thorium families. In contemporary cancer therapy with eltromagnetic radiation the eltron bremsstrahng radiation issuing from medical linear accelerators is mainly used. The 60Co gamma-rays are, however, still employed in very spialized brain tumor radiosurgery using the so called Gamma Knife. An historical persptive of medical radioisotope production and a rich bibliography of this subjt can be found in Refs. [3, 4]. 2. RADIOISOTOPES AND RADIOPHARMACEUTICALS The contemporary employment of radioactive nuclei for medical applications is based on two different methods of their production. The first one uses neutron induced reactions with neutrons mainly from nuclear reactors, although accelerator produced neutrons are also considered. The sond one employs s induced by accelerated charged particles, mainly using various types of cyclotron. These two production methods lead to quite different positions of the product on the nuclear chart. The neutron induced reactions produce unstable neutron-rich nuclei, spontaneously approaching the betastability line by the beta-day process ( -emission of an eltron and a neutrino). The cyclotron accelerated charged particles (p, d, 3He, 4He) impinging on stable targets lead, with some exceptions, to neutron-deficient final products, daying by positron and neutrino emission ( +) (two eltron-positron annihilation gamma-quanta of 511 keV energy, emitted in opposite dirtions, promptly follow the nuclear day by positron emission) and/or the eltron capture () process. For heavy nuclei sometimes -particle emission is possible, also eventually leading toward the beta stability line. All these radioactive days may lead to the ground state of the final nucleus or to its excited states which in turn day by gamma-ray emission or eltron internal conversion (IC). The emission of low-energy Auger eltrons accompanies the and IC processes. The nuclear reactor or accelerator produced radioisotopes are used as simple sotions or for labeling various compounds, forming so-called diagnostic or therapeutic radiopharmaceuticals [5]. Radiopharmaceuticals administered to the living organisms of animals or humans seltively search various types of cells, permitting their spatial distribution to be identified, spific physiological processes to be examined or malignant cells to be destroyed. The diagnostic radiopharmaceuticals are also largely used in research, serving as information agents on the behavior of various metabolic processes. They are also employed in testing of new pharmaceutical products. The various biomedical properties of labeled radiopharmaceuticals allow the use of the same radioisotope in many applications. Therefore, practically a number of currently used radioisotopes is rather limited whereas the number of labeled compounds is substantially larger and continuously increasing thanks to the radiochemical research effort all around the world. 3. PRODUCTION METHODS OF MEDICAL ISOTOPES 3.1 NUCLEAR REACTORS FOR RADIOISOTOPE PRODUCTION Currently, the prominent part of nuclear medicine diagnostic and therapeutic interventions are based on radioisotopes produced in nuclear reactors [6]. Between them accounts for more than 80% of all administered radiopharmaceuticals. s are based on the fission process of 235U, an isotope present in natural uranium with only 0.7% abundance. The various types of reactors use natural uranium, low enriched uranium (LEU, up to 20% of 235U) and highly enriched uranium (HEU, above 20% of 235U, sometimes even more than 90%). Fig. 3.1.1 presents a simplified scheme of a nuclear reactor. Thermal neutrons, always present in the U compounds from the spontaneous fission of 238U, generate a chain reaction (multiplication of neutrons after each fission process) in the nuclear fuel rods. The fission process liberates about 200 MeV energy per fission in the form of kinetic energy of (generally) two fission fragments, emitted neutrons, charged particles, gamma rays and neutrinos. Only the neutrino energy (a few MeV) escapes from the reactor core. On the average = 2.4 neutrons are emitted after each thermal neutron induced fission of 235U. Some of them are captured without leading to a con- Jerzy Jastrz bski sutive fission event, whereas =2.1 neutrons interact with 235U, leading to its fission or with 238U, leading to the fuel "briding" (production of 239Pu). The positive neutron balance of the neutron induced fission of 235U is the basis of the nuclear chain reaction and the construction principle of nuclear reactors. Fig. 3.1.1 Simplified scheme of a nuclear reactor. The active zone (1) of the reactor is surrounded by neutron refltor (2). In the active zone are placed rods with U fuel delivering heat (3) and rods with the neutron energy moderators (4). The control rods (5) assume the reactor reactivity regulation and prevention against its accidental increase. The heat generated by the reactor is eliminated by coolant through canals (6). (From Ref. 7). In order to produce consutive fission events with high efficiency the fission neutron kinetic energy (on average about 2 MeV) should be substantially dreased down to thermal energies ( 0.025eV), where the neutron induced fission process is the most probable; (compare Fig. 3.1.2). The fission neutron energy drease is achieved during a very short time (of the order of 10-4 s.) by collisions with moderator atoms: regular, light water (H2O); solid graphite (C); heavy water (D2O) or some other material. Actually about 75% of the operating so called "thermal" nuclear rtors use light water, 20% solid graphite and 5% heavy water as moderator. Although light water has the highest "slowing down power" (mass of the hydrogen atom almost equal to the neutron mass) the "moderating ratio" which takes into account the moderator density, collision cross-stion and neutron absorption probability is largest for heavy water (360 times larger than for light water). This is the reason why heavy water is used as moderator for natural uranium based thermal nuclear reactors. Fig. 3.1.2. Neutron induced fission cross ­ stion for 235U vs. neutron kinetic energy (thermal neutrons 0.025 eV). (From Ref. 8). Steady reactor running is obtained thanks to the action of control rods. Control rods are made from strongly neutron absorbing material (such as boron or cadmium) and are inserted into the reactor core to keep the reactivity of the reactor close to zero. The reactivity is defined as =(k-1)/k, where k is the "multiplication factor", the number of fissions in one generation to their number in the previous one. The reactor state having =0 is called "critical". Due to the short fission neutron "life-time" the critical state would be quite unstable if it were not for the existence of delayed neutrons with a yield of 0.65% of all fission neutrons and half-life from a part of a sond to minutes. These neutrons originate from the beta day of the fission products. Taking into account the delayed neutrons, the steady reactor power is made subcritical on prompt fission neutrons and bomes just critical when the delayed neutrons are incded in the neutron fx balance. Fig. 3.1.3 shows the shape of a typical thermal reactor neutron fx. During radioisotope production these neutrons interact with the target material, introduced close to the reactor core in spially designed irradiation capsules. Jerzy Jastrz bski Fig. 3.1.3. Neutron Fx Sptra for Thermal Reactor. (Adapted from Ref. 9). 3.2 ACCELERATORS FOR RADIOISOTOPE PRODUCTION Practically at present cyclotrons are the only accelerators used for medical isotope production. The principle of particle acceleration in a cyclotron is presented in Fig. 3.2.1. It consists in the simultaneous action of a stable magnetic field B and a rapidly varying eltric field E, forcing the particle circular motion and increasing the particle energy at each crossing of the border of the eltric field. The magnetic field generated by the eltromagnet in the form of "hills" and "valleys" assures orbital stability. Particles to be accelerated are introduced into the ion source, an eltrical arc device in a gas for negative ions or a more complex, so called R (eltron cyclotron resonance) ion source for positive ions. Particles are injted into the center of the cyclotron and accelerated by the eltric field, applied to the "dees" ­ the hollow metallic eltrodes, placed on the particle trajtories. With increasing particle energy the radius of its almost circular orbit increases but the revotion period remains independent of this radius. Therefore, the frequency of the rapidly varying eltric field may remain constant. This frequency is a multiple of the particle revotion frequency ("harmonics"). The particle relativistic mass increase with energy is compensated by the shape of the magnetic field, increasing with orbit radius. At the end of the acceleration process negatively charged ions may be extracted from the cyclotron by "stripping" their eltron(s) when passing through a thin foil. Magnetic and/or eltrostatic defltion is used for positive ion extraction. Fig. 3.2.2 shows the structure of a cyclotron. Fig. 3.2.1. Simplified scheme of the cyclotron principle. Magnetic field increasing with radius, generated by eltromagnet in form of "hills" and "valleys"assures the particle orbit stability. The rapidly varying eltric field accelerates particles when approaching or leaving the "dees", A and B. (From. Ref. 10). Dee Structure Hills Valleys Hills Magnet Valleys RF Input Ion Source Dee Structure Fig. 3.2.2. Structure of a cyklotron showing the magnet, ,,dee" structure and ion source. (From Ref. 11). Jerzy Jastrz bski Table I gives the updated [12] classification of cyclotrons used in medical applications. Table I Classification of accelerators. (Adapted from Ref. 12). Accelerator class Characteristics Proton energy (MeV) Class I Single particle (p b d) Class II Single or multiple particle p,d Class III Single, two or three particles p,d, 20?Ep<70 11< Ep <20 Comments Example ?11 PET Siemens lipse He, He not usually available GE PETtrace IBA CYCLONE 18/9 PET, SPT He and He can be available SPT and PET IBA CYCLONE 30 IBA CYCLONE 30XP IBA CYCLONE 70 (Arronax) IBA CYCLONE 230 Triumf Ca Class IV Usually p only 70 - 500 CYCLONE 230 for proton therapy Many hundreds of Class I and Class II cyclotrons are presently operating all round the world, producing mainly diagnostic but also some therapeutic radioisotopes. An example of a Class II cyclotron, a General Eltric (GE) PETtrace accelerator is shown in Fig. 3.2.3 and its cut is displayed in Fig. 3.2.4. The accelerated particles impinge on a cooled target holder, activating the target material. This may be done inside the cyclotron, before the beam extraction (mainly for positively charged ions) as well as after the beam extraction for negatively charged ions. Gaseous, liquid or solid target materials are used. In Fig. 3.2.5 a schematic diagram of a gas target is shown. Fig. 3.2.3. The GE Healthcare PETtrace cyclotron, accelerating protons with energy of 16.5 MeV and deuterons with energy of 8.4 MeV with proton current up to 100 A. This type of cyclotron will be operational at the end of 2011 in the Radiofarmaceuticals Production and Research Centre of the Heavy Ion Laboratory, University of Warsaw (Courtesy of GE). Fig. 3.2.4. Interior of the PETtrace cyclotron (Courtesy of GE). Jerzy Jastrz bski Table II gives the list of main manufacturers of Class I and Class II cyclotrons, used mainly for the production of PET radioisotopes. Table II. Cyclotrons with Ep 20 MeV for PET radioisotope production. (Adapted from Ref. 11) Manufacturer Feature Factory localisation Knoxville, TN (USA) Years of operation 27 27 Uppsala (Sw) 26 26 Louvain-LaNeuve, (Be) 24 Accelerated particles p p p,d p p,d Ep (MeV) 11 11 16.5 9.6 18 Siemens lipse HP lipse RD GE Healthcare PETtrace Minitrace Ion Beam Applic. (IBA) Cyclone 18/9 Cyclone 10/5 p,d Sumitomo Heavy Ind. HM-18 HM-12 Tokio, (Jp.) p,d p,d p,d p Advanced Cycl. Syst. TR-19/9 TR-14 Vancouver, (Ca) Fig. 3.2.5. Schematic diagram of a typical cyclotron target used with gases. (From Ref. 13). The currently commercially available cyclotrons with proton energies below 20 MeV are, however, generally unable to produce radioisotopes in a reasonable quantity via two nucleon emission (reactions such as p,2n , d,2n or p,pn). Similarly, the often very useful He induced reactions are not accessible in these accelerators. The higher proton energies as well as He beams are presently available in Europe and the US on old Class III Scanditronix accelerators, no longer commercialized. Fortunately, quite rently IBA (Ion Beam Applications) Company launched a new CYCLONE 30XP accelerator delivering protons of variable energy 18-30 MeV, deuterons of energy 9-15 MeV and He++ particles of energy 29 MeV. Fig. 3.2.6 shows the schematic and cross-stional view of this cyclotron. Two external ion sources are employed: the multicusp eltrical arc device delivering negatively charged protons and deuterons and an R ion source for doubly charged He++ particles. The negative beams are extracted by stripping and He++ by an eltrostatic device. The accelerating eltric field frequency is also different for these two types of accelerated particles. Fig. 3.2.6. Schematic and cross ­ stional view of the IBA CYCLONE XP 30. Two ion sources (multicusp and R) are shown on the top of the cyclotron (Courtesy of IBA). Jerzy Jastrz bski At the upper end of Class III accelerators a currently commercially available cyclotron is again produced by the IBA Company ­ the CYCLONE 70XP, delivering protons of energy 30-70 MeV, deuterons of energy 15-35 MeV and He++ particles of energy 70 MeV. Such a cyclotron was rently put into service at Nantes (France) ­ ARRONAX facility [14]. 4. S 4.1 NEUTRON INDUCED REACTIONS Two quite different nuclear processes are employed to produce medical radioisotopes by neutron interaction with materials introduced into the reactor core: the fission route and the activation route. About 40 radioisotopes are produced by the activation route and 5 are separated from the fission products, incding the most used o generator. In the fission route, after the splitting of the 235U nucleus under the slow neutron capture process two fragments with masses around A 95 and A 140 are produced (see Fig. 4.1.1). By chemical extraction from the irradiated material (often performed in spialized, large separation facilities) the medical radioisotopes are prepared. Currently, highly enriched uranium targets (HEU) are used preferentially, at least for the o fission product. Table III lists the world producers of the o radioisotope. In the activation route the compound nuclei, formed after neutron absorption by the irradiated target nuclei, day via various paths producing final radioactive products. The most common consists of the absorption of the thermal or epithermal neutron with a subsequent emission of rays: the (n, ) reaction. The production of the famous therapeutic 60Co isotope using neutron absorption by the natural 59Co isotope (100% abundance) is an example. The final reaction product is the same element as the target isotope and cannot be chemically separated. A high neutron fx is, therefore, nessary to produce the final product with high spific activity. In the high neutron fx two consutive (n, ) reactions (two neutron captures) on the same target nucleus can also give a reasonable final product activity of the same element two mass units heavier than the target. The neutron absorption reaction of the (n, ) type may be, however, sometimes employed to produce different element than the target one. If the irradiation products are short-lived beta emitters a final isotope of higher atomic Z number may be formed by day. Finally, the (n,p) or (n, ) reactions are also sometimes used employing more energetic (above particle emission threshold) neutrons in the reactor neutron fx. Some examples of medical radioisotopes formed by fission and activation routes are presented in Table IV. Ref. 17 gives a list of currently operating high fx nuclear reactors as well as a more exhaustive list of therapeutic emitters. Fig. 4.1.1. Fission product mass yield curve for the fission of 235U induced with fission sptrum neutrons. (From Ref. 15). Table III. World producers of o. (From Ref. 16) Jerzy Jastrz bski Table IV. Examples of Reactor produced medical isotopes Isotopes T1/2 6.0 h Production route U(n,fission) Mo 99 Day characteristics Applications Imaging, scintigraphy and SPT Therapy, Co bombs, Gamma - Knife Mo( ,66h) 142 keV (95%) 1173 keV (100%) 1333 keV Co 5.3 y Co(n, ) Co 8.0 d Te(n, ) 131m Te 131m Te( ,30h) 364 keV (89%) Imaging and therapy, thyroid, carcinomas, 6.7 d a) b) (2.6%,n, ) Yb(13%,n, ) Yb( ,1.9h) 90 - 498 keV (79%) 208 keV (11%) Short range , Targeted cancer therapy Therapy, long range part Yb 2.7 d a) b) Y(n, ) Y U (n,fission) Y 2.28 MeV (99%) Ir 73 d Ir(n, ) Ir and 296 keV (29%) 308 keV (31%) High dose rate brachytherapy Re 3.7 d Re(n, ) Re , 1077 keV (93%) Therapy with imaging 137 keV (9%) 4.2 CHARGED PARTICLE INDUCED REACTIONS Three mhanisms are of importance when medical radioisotope production with charged particles is considered. For low bombarding particle energies (Class I and Class II cyclotrons) similarly as with thermal or low energy neutrons the compound nucleus (CN) is formed after the fusion of the projtile and target nuclei. Its excitation energy depends mainly on the projtile kinetic energy and the mass difference of the final and initial reaction partners. About 8 MeV excitation energy is nessary to evaporate one nucleon and less than 3 MeV to evaporate an alpha-particle. With increasing projtile kinetic energy dirt reaction processes contribute to the reaction cross-stion. Fig. 4.2.1 ilstrates the cross-stion behavior of a typical CN reaction followed by dirt reaction processes. Finally, at even higher bombarding energies (Class IV cyclotrons) spallation reactions appear with the emission of a substantial proton and neutron number from the target nucleus. Fig. 4.2.1. Excitation function for the 14N(p, )11C reaction. Reaction cross ­ stion is plotted s incident proton energy. The mass difference of the final ( and 11C) reaction products and the initial reaction partners (p and 14N) is 3.6 MeV, reflted by the reaction threshold. (From Ref. 13). Similarly as for the reactor produced radioisotopes, the medical radioactive nuclei produced with accelerators can be divided into diagnostic and therapeutic ones. Radioisotopic imaging in contemporary nuclear medicine uses two different approaches. The first one is based on the dettion of a single gammaray line from the appropriate radiotracer. The planar 2D scintigraphy (gamma-cameras) and 3D SPT scanners represent this approach. The sond approach is based on the + radioactive day consisting of a successive posi- Jerzy Jastrz bski tron emission and annihilation followed by the simultaneous production of two annihilation quanta (511 keV energy). The sensitivity of 3D Positron Emission Tomography (PET) significantly exceeds the SPT sensitivity due to the auto-collimation of the coincident annihilation quanta emitted almost antiparallelly. Currently more and more SPT and PET scanners are equipped with X-ray CT devices giving, during the same examination, anatomic images with increased contrast-enhancement. Rently, nuclear magnetic resonance imaging (MRI) devices have begun to be coupled with PET scanners (barely commercially available) and, most probably, SPT-MRI devices will be also accessible soon on the market. We begin with the enumeration of the radioisotopes used for PET thniques. The most popular and convenient PET radiopharmaceuticals are based on short lived radioactive nuclei, presented in Table V. Their robust representative, forodeoxygcose, besides local production by hospitalowned small cyclotrons, is often produced in spialized centers and transported to distant diagnostic PET cameras. Another sotion for PET radioisotopes is their extraction from the long lived generators also produced with accelerators. Table VI gives some examples. Table V. Short ­ lived radioisotopes for PET Radioisotope T1/2 (min) Emax (MeV) Efftive range + (mm) Target O water O(p,n)18F Ne gas Ne(d, )18F N(p, )11C N2 - gas [10B(d,n)11C] O water O(p, )13N C(d,n)13N N2 - gas N(d,n)15O [15N(p,n)15O] Table VI. Examples of generator radioisotopes for PET Radioisotope Generator Emax + MeV % + Applications Rb Sr(25d)? Rb(1.3 m) Rb(p,4n) Sr Ep ? 60 MeV Optimal diagnosis and management of cardiac diseases, Myocardial perfusion studies and blood flow Ga Ge(275d)? Ga(68 m) proton spallation of nat. Ga Ga(p,2n) Zn( , 2n) A generator based 18 alternative to F ­ radiopharmacy Imaging and simult. therapeutic appl. Attenuation corrtions of PET scanners Finally, in a number of applications it is nessary to follow labeled compounds in slow pharmacokinetic processes in vivo for times substantially longer than the day time of classic, short lived PET radioisotopes. Examples of longer living positron emitters are given in Table VII. Table VII. Long ­ lived radioisotopes for PET Radioisotope T1/2 Emax + MeV + abund. % 19 Target abund. % Applications Cu 12.8 h Ni(p,n) Zn(p, n) Possible PET and therapy good resotion for animal PET 67 dosimetry for Cu radioimmunotherapy tissue hypoxia Possible PET and therapy thyroid cancer dose estimation 4.2 d Te(p,n) Jerzy Jastrz bski Scintigraphic and SPT imaging is dominated by the use of , extracted from the 66h o generators, produced in nuclear reactors. However, a rent "reactor crisis", due to the unexpted shut-down of a few high fx reactors in Europe and Canada prompted the Canadian Government to launch a research program allowing the efficient production of o or by the accelerator route. The considered s are indicated at the top of Table VIII. In the same table other accelerator produced SPT radioisotopes are also shown. Table VIII. Examples of Accelerator produced SPT radioisotopes. Accelerator production of and o is considered by Canadian Government Isotope T1/2 Targ et abu nd. Day charact. Applications / comments 6.0 h 66 h Mo (p,2n) Mo (p,pn) projt generator (projt) projt Tumours imag. (93, 184, 300 keV) Mo Mo Ga 66 h 3.3 d nat U (g,fission) Zn (p,n) Zn (p,2n) In 2.8 d Cd(p,n) Cd(p,2n) Ag( ,2n) Te(p,2n) Xe(p,2n) (nat. Cd comerc. used) Methastases Thyroid functions. Can replace in imaging (171, 245 keV) 13 h 124m 123 Cs Xe (159 keV) Tl 9h ? 73 h Tl(p,3n) Pb 30 Tl Cardiology (167 keV) It is evident that their production as well as the production of o involves s with the emission of more than one nucleon. As discussed previously, the bombarding energies of Class I and Class II cyclotrons are too low for efficient production of these isotopes. Class III accelerators are nessary. Presently, 95% of accelerator produced medical radioisotopes are used for imaging purposes. In the remaining 5% of therapeutic ones [18] a substantial part is still in the prlinical stage of development. We mention here two of them with great therapeutic potential in the new field of so-called Targeted Alpha Therapy (TAT). The alpha particle emitters, if linked to the cancer cells, efficiently destroy the malignant cells by their double strand breaking without great damage to the surrounding healthy cells. The large energy deposited by short range alpha particles is the basis of TAT. Two isotopes are of particular interest 213Bi and 211At; 213 Bi is obtained from the 225 Ac/213Bi generator [19, 20] and 211At is produced by the 28MeV ( ,2n) reaction on a natural Bi target [21]. Their radiopharmaceuticals are based on peptides or monoclonal antibodies, actively investigated in many laboratories. 5. MEDICAL RADIOISOTOPES FROM THE HEAVY ION LABORATORY OF THE UNIVERSITY OF WARSAW The production of radioisotopes and radiopharmaceuticals for Positron Emission Tomography is in the preparatory phase at HIL-UW. Fig. 5.1 and fig. 5.2 show the layout of the Radiopharmaceuticals Production and Research Center of this Laboratory [22]. The Centre will be operational at the end of 2011, with a PETtrace, k=16 cyclotron (see Fig. 3.2.3). Using the large, k=160, heavy ion cyclotron the 211 At isotope (T1/2=7h) is produced and will be used by a large collaboration [23] for applications in Targeted Alpha Therapy (TAT). Jerzy Jastrz bski Heavy Ion cyclotron Fig. 5.1. Layout of the ground floor of the HIL building. Lower part of the layout shows the heavy ion cyclotron, the beam lines and the nuclear physics experimental stations. Upper part shows the Radiopharmaceuticals Production and Research Centre, placed underground (-7m.). (see also www.slcj.uw.edu.pl/pet). Fig. 5.2. Layout of the RPRC. Proton / deuteron cyclotron and its control room is placed on the left part of the figure. Two independent production rooms are placed in the middle of the figure (The first one for the routine production of FDG and the sond one for other radiopharmaceuticals). The Quality Control room is placed in the right part of the figure. Radioactive nuclei for medical applications 6. SUMMARY AND OUTLOOK Radioactive isotopes are currently indispensable in the contemporary health service all around the world. They are produced using nuclear reactors and more and more with particle accelerators. In Poland during the last dade substantial progress in imaging modalities may be noted. To the currently operating about 50 scintigraphic and gamma cameras, 60 SPT and 8 SPT/CT devices the 12 PET-CT scanners were added during last years both in public and private establishments [24]. Two Class I and Class II cyclotrons are operating and three others should be operational at the end of 2011. Whereas the PET radioisotopes seem soon to be adequately provided, the new, less common accelerator produced SPT isotopes are not available in Poland yet, due to the lack of an appropriate accelerator. Some therapeutic radioisotopes produced via the reactor route are available thanks to the high fx research reactor in wierk near Warsaw. Also, some -emitting therapeutic radioisotopes are produced for research purposes at the Heavy Ion Laboratory of the University of Warsaw. However, their current, everyday production needs also a dedicated Class III accelerator.

Journal

Annales UMCS, Physica – de Gruyter

Published: Jan 1, 2011

References

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