Radionuclide production

Transcription

1 Review article Volume 58 (3) 2011 Radionuclide production GM Currie 1,2 MMedRadSc, MAppMngt, MBA, PhD JM Wheat 1,2 BAppSci(RT), MMedRadSc(NM), MHlthSc(HM), DHlthSc R Davidson 1 BBus, MAppSc(MI), PhD, FIR H Kiat 1,2 MBBS, FRACP, FACP 1 School of Dentistry and Health Sciences, Faculty of Science, Charles Sturt University, Wagga Wagga, New South Wales 2650, Australia. 2 Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales 2109, Australia. Correspondence to gcurrie@csu.edu.au Abstract This article continues from the earlier article An Introduction to Nuclear Medicine where the general principles of nuclear medicine were discussed. Radionuclides are required in both diagnostic and therapeutic nuclear medicine procedures. Naturally occurring radionuclides are generally not suitable for diagnostic and therapeutic procedures due to their typically long half-lives or less than ideal physical or chemical characteristics; therefore appropriate radionuclides need to be produced. The common methods of radionuclide production for nuclear medicine include: fission, neutron activation, cyclotron and generator. Fission occurs in a nuclear reactor where neutrons are used to bombard fission nuclides such as uranium-235 ( 235 U) or plutonium-239 ( 239 Pu). Fission results in the splitting of the large nucleus into smaller fission fragments along with the release of gamma radiation and high energy neutrons. Neutron activation also takes place in a nuclear reactor. The neutrons are used to bombard stable nuclides to form other radionuclides. There are disadvantages with this process so other production means are often preferred. Cyclotrons are used to accelerate charged particles such as protons (p), deuterons (d), triton (t) and alpha (α) particles to high velocities to penetrate the orbital electrons of the target atom and interact with the nucleus. Generators produce the most commonly used radionuclide in nuclear medicine, technetium-m ( m Tc). The radionuclide generator sees the decay of a long half-life parent radionuclide to a short half-life daughter radionuclide. The daughter is the radionuclide used in nuclear medicine. An understanding of radionuclide production will assist in the understanding of both diagnostic and therapeutic nuclear medicine procedures. Keywords: cyclotron, fission, generator, radionuclide production. Introduction Radionuclides are required for nuclear medicine diagnostic and therapeutic procedures. The principle difference between nuclear medicine and x-ray procedures is that nuclear medicine relies on image formation by photon emission from the object while x-ray procedures rely on transmission through the patient. Diagnostic and therapeutic procedures in nuclear medicine utilise radionuclides for this purpose. A radionuclide is simply a radioactive nuclide. The terms isotope and radioisotope are also often used; inappropriately unfortunately. An isotope is a group of variations of the same element; they have the same atomic number (Z) because they have the same number of protons but the mass number (A) is different due to a different number of neutrons. 1 For example, nitrogen is characterised by seven protons but may have between five and 11 neutrons to define nitrogen-12 through to nitrogen-18 (nitrogen-13 [ 13 N] is useful in nuclear medicine). The terms isotope and radioisotope are inappropriate because the most commonly used radionuclide in nuclear medicine is technetium-m ( m Tc) which is exactly the same isotope as technetium- ( Tc). The former is the backbone of nuclear medicine while the latter is of no use at all. The m denotes the nuclide is metastable and, thus, a nuclide is defined by its Table 1: A summary of the production methods of common radionuclides used in nuclear medicine. 1-4 Radionuclide Production method Radionuclide Production method 131 I (iodine) Fission 67 Ga (gallium) Cyclotron Mo (molybdenum) Fission 201 Tl (thallium) Cyclotron 133 Xe (xenon) Fission 111 In (indium) Cyclotron 137 Cs (cesium) Fission 123 I (iodine) Cyclotron 32 P (phosphorus) Neutron activation 57 Co (cobalt) Cyclotron 89 Sr (strontium) Neutron activation 18 F (fl uorine) Cyclotron 153 Sm (samarium) Neutron activation 13 N (nitrogen) Cyclotron 51 Cr (chromium) Neutron activation 11 C (carbon) Cyclotron 125 I (iodine) Neutron activation 15 O (oxygen) Cyclotron m Tc (technetium) Generator Ga (gallium) Generator 81m Kr (krypton) Generator 82 Rb (rubidium) Generator 46 The Radiographer 2011

2 Figure 1: Schematic representation of the impact of the radionuclide half-life on cumulative patient dose. It should be noted that for accuracy, the half-life should represent the total half-life; a combination of the physical and biological half-lives. Despite a lower administered dose (50%) for the longer lived radionuclide in this schematic, the total patient radiation dose is higher. This can be calculated as the area under the curve. Since radioactive decay is exponential, the area under the curve (AUC) is simply AUC 0- = Dose 0 / λ where λ is ln2 divided by the half-life. 5 isotopic form in combination with its energy state. Radionuclides decay exponentially according to its half-life. As a result, naturally occurring radionuclides tend to have very long half-lives, often thousands of years, or are stable. 1 A plot of all nuclides and their associated decay schemes demonstrates that unstable or radioactive nuclides decay in a manner that moves towards the line of stability. 1-4 Long half-lives are not useful in nuclear medicine, even for therapy, because the total radiation dose to the patient governs the administered dose. The dose attributed outside the window for imaging or therapy needs to be reduced, very long half-lives will deliver the majority of the dose outside that window, and as a consequence the administered dose would be too low for effective imaging or therapy (Figure 1). Furthermore, the radiation hazard remains long after the procedure and, indeed, well after the patient is deceased. Consequently, there is a need to produce short lived radionuclides for medical use. Generally there are four common methods of radionuclide production for nuclear medicine: fission, neutron activation, cyclotron and generator (Table 1). Fission Fission is one of the processes that can produce radionuclides. Fission is simply splitting the nuclei into two parts; those two parts become new smaller nuclides. Like fission bombs, the fission nuclides are generally uranium-235 ( 235 U) or plutonium-239 ( 239 Pu). 1,2 The neutron is used in a nuclear reactor to create an unstable nucleus. The goal is splitting the atom of a large nucleus. While this can occur spontaneously in unstable nuclei, in the nuclear reactor we add energy by way of a neutron. Given that a neutron has no charge, they can penetrate a target nucleus without being accelerated to high energies. A proton on the other hand, needs to Figure 2: Schematic representation of fi ssion for the Mo / 134 Sn fission pair. A thermalised neutron is produced by slowing down the neutron (lower energy) to increase the probability of interacting. The thermal neutron bombards the 235 U nuclei to produce 236 U which spontaneously undergoes fi ssion to produce Mo and 134 Sn fi ssion fragments. As demonstrated by the fi ssion equation, energy and mass are conserved which results in the emission of gamma photons, 200 MeV of energy and three neutrons. 1,2,6 be accelerated to high energies in order to penetrate the electron clouds of the target. 3 Adding a neutron to 235 U produces the very unstable 236 U which rapidly undergoes fission (Figure 2). The fission fragments move apart rapidly due to high kinetic energy and simultaneously give off gamma emissions and two to five neutrons. 1,2 There is a very wide variety of nuclides that might be produced during fission with mass numbers in the range 70 to 160. While the mean mass number approximates 118 (half of 236), probability dictates that the majority of fission fragments will have an unequal mass number; fission pairs. A fission pair is the two individual atoms produced by the fission and, thus, in the case of 235 U will have a summed mass number equal to 236. In reality, a single fission reaction is uncommon and, thus, a large number of new atoms might be simultaneously produced in a reactor. We know, however, that iodine-131 ( 131 I) and cesium-137 ( 137 Cs) are fission pairs. The neutrons produced as a by-product of fission are fast and energetic but can be slowed down (thermalised or moderated) using scatter reactions in a nuclear reactor. There are a number of low atomic weight materials used as moderators in a nuclear reactor including water and heavy water ( 2 H 2 O). 1,2,3 Once thermalised, the neutrons can be used to initiate subsequent fission reactions with other nuclei. Thus, based on Figure 2, each fission reaction can result in three additional fission reactions. This self sustaining sequence is called a chain reaction (Figure 3). It is easy to see that within a very short time, uncontrolled generation of energy could result. An uncontrolled chain reaction is the principle of atomic weapons and the cause of a reactor meltdown. In a nuclear reactor, control rods made from boron or cadmium are used to absorb the neutrons (Figure 4). 1,2 Inserting more of the control rods slows down and controls a chain reaction (or stops it) while removing some of the control rods will perpetuate fission reactions. Even without control rods, the low enriched fuel rods of less than 5% The Radiographer

3 Figure 3: Schematic representation of an uncontrolled chain reaction. Within seconds, a single neutron could produce tens of thousands of fi ssion reactions. The schematic below represents just three generations. A single fi ssion reaction can result in a further 9840 fission reactions in just nine generations. 235 U, means that many neutrons will interact with non fissile material. Critical mass refers to the minimum mass of fissile material ( 235 U) where at least one neutron from each fission reaction causes fission in another 235 U nucleus. The critical mass will depend on the 235 U concentration in the fuel rods, the degree of enrichment, the reactor core geometry, the moderation of neutrons and the control rods. 1,2 Critical mass is usually a term used for nuclear weapons because prompt criticality is desired. Highly enriched fuel or weapons grade uranium contains up to 90% 235 U and can have a critical mass as low as 15 kg. The new nuclear reactor at Lucas Heights in Sydney, Australia specifically operates on low enriched control rods. The Open Pool Australian Lightwater (OPAL) replaced the previous High Flux Australian Reactor (HIFAR) which are both research reactors that do not produce nuclear power. Nonetheless, the steam produced when using water or heavy water as a coolant can be linked to a steam turbine and generate electricity. Despite the political debate, nuclear power is very efficient and a green solution. Uranium is mined as uranium oxide (U 2 O 3 ) which is yellow in colour when purified (yellowcake). The natural abundance of uranium is.3% 238 U and only 0.7% 235 U. 235 U is enriched to 5% or so to increase the fission cross section (fission probability). The major by-product of both enrichment (residual 238 U) and fission (spent fuel rods) is depleted uranium. Indeed, the depleted uranium is a major argument against nuclear power. 239 Pu is a fissile material and can be obtained from the bombardment of 238 U with a neutron which produces 239 U (half-life of 23 minutes) which decays to neptunium-239 ( 239 Np; half-life of 2.4 days) which then decays to 239 Pu. Thus, 239 Pu can be bred from the waste of 235 U fission to produce a more abundant fuel source for either nuclear power or nuclear weapons. 239 Pu has a half-life of 24,000 years and, thus, once sufficient stores of 239 Pu are produced there is little need for the nuclear reactor. The symbolic decommissioning of a reactor is likely to represent an exhaustive stockpile of 239 Pu rather than an end to the pursuit of nuclear weapons. An argument against nuclear power is that 235 U as a natural resource might sustain power requirements for little more than a century or two; non sustainable long term. Breeding 239 Pu from 238 U, remembering.3% of uranium ore is 238 U, will provide several millennia of power. Figure 4: Schematic cross section through a nuclear reactor. The fuel rods (yellow) contain a low percentage of 235 U (black dots), the control rods (brown) absorb neutrons to control the reaction, the moderator (blue) is used to thermalise neutrons and, if it is water or heavy water, acts as a coolant as well. 1,2,4,6 Neutron activation Neutron activation is also undertaken in the nuclear reactor. The high neutron flux associated with the fission reactions in the reactor can be used to bombard other stable nuclides if they are placed in the reactor. Most neutron activation reactions result in the emission of a gamma photon (n, γ). 2,3 Following an (n, γ) reaction (Figure 5) the resulting radionuclide is an isotope of the stable target which produces chemically identical species. It is possible to produce radionuclides that are elementally different from the target using neutron, proton (n, p) and neutron, alpha (n, α) particle reactions. Neutron activation needs port access by which targets can be inserted and removed into the high neutron flux core without interfering with the fission reactions. 1,2,6 Unfortunately, the target is not entirely transformed which means there is carrier, or residual target, present. 1,2,6 Similarly, any impurities in the target may result in neutron activation production of other species leaving both radioactive and stable impurities in the product. Removal of carrier and impurities is an expensive process and contributes to the high cost of these products. Furthermore, neutron activation results in a poor specific activity; the radioactivity per unit mass. 1,2,6 Consequently, if a radionuclide can be produced by other means, for example by fission, cyclotron or generator, these are the preferred method. Cyclotron A cyclotron can be thought of as a linear accelerator but using a spiral to overcome the long linear distance that would be required to reach the energies required. The cyclotron bombards a stable nuclei with high energy charged particles; protons (p), deuterons (d), triton (t) and even alpha (α) particles. 1,2 To penetrate the nucleus of the target, the particles must be accelerated to very high energies. A charged particle gains speed and energy when it is attracted to an opposite charge. The cyclotron is comprised of a vacuum contained within semi-circular electrodes ( D s) within a magnetic field. Each D is separated from the other by a narrow gap (Figure 6). A charged particle to be accelerated is introduced in the 48 The Radiographer 2011

4 Figure 5: Schematic representation of neutron activation. The most common neutron activation reactions examples for radionuclide therapy include; 31 P (n, γ) 32 P and 88 Sr (n, γ) 89 Sr. centre and high voltage is applied to the D s using a high frequency oscillator. The charged particle will be attracted across the gap toward the D with the opposite charge. The magnetic field ensures the charged particle travel in a circular path through the D with the radius dependent on the speed. When the charged particle traverses the first D, the charge on the D has been switched so the particle is now repelled from the first D and attracted to the second D ; picking up speed as it accelerates across the gap. The charged particle then traverses the second D in a circular arc with a larger radius because the speed is higher. This process continues until the charged particle reaches the target speed or energy. For example, when a proton is required for the target, a hydrogen ion is introduced at the centre of the cyclotron, accelerated and after reaching peak velocity or energy, the electrons are stripped using a carbon foil. The change in charge alters the orbit of the proton which is directed out of the D and toward the target (Figure 7). The particle bombardment causes nuclear transformation. Some of the more common cyclotron reactions include: 1-4,6 Zn [zinc] (p,2n) 67 Ga 122 Te [tellurium] (d,n) 123 I 201 Hg [mercury] (d,2n) 201 Tl 109 Ag [silver] (α,n) 111 In 14 N (p,α) 11 C 18 O (p,n) 18 F 20 Ne [neon] (d,α) 18 F Cyclotrons are rated based on the energy of the accelerated charged particle. Small cyclotrons (9-11 MeV) are typically limited to producing fluorine-18 ( 18 F) for positron emission tomography (PET). Medium sized Figure 6: Schematic representation of a cyclotron in cross section. cyclotrons (in the order of 15 MeV) can produce a larger array of PET radionuclides ( 13 N, 11 C, 15 O). Larger cyclotrons (30 MeV) are capable of producing other nuclear medicine radionuclides like 67 Ga, 201 Tl, 123 I. In Australia, a 30 MeV cyclotron (Australian National Medical Cyclotron) was commissioned at Royal Prince Alfred Hospital in Sydney, Australia in 10 to be operated as part of the Australian Nuclear Science and Technology Organisation (ANSTO) in tandem with the Lucas Heights reactor. The cyclotron was meant to provide both nuclear medicine and PET radionuclides. Prior to this, Australia imported nuclear medicine radionuclides at high cost and had no PET services. The facility largely failed to meet the dual needs and multiple smaller (9-15 MeV) cyclotrons The Radiographer

5 Table 2: Properties of nuclear medicine generators. 1,2,3,4,6 Generator Parent half-life Daughter half-life Comment / Use Mo / m Tc 67 hours 6 hours Most widely used generator system in nuclear medicine. 81 Rb / 81m Kr 4.6 hours 13 seconds Widely used in lung ventilation studies in the USA because the daughter separates from the parent by gas evolution, bubbling out of the solution. Ge (germanium) / Ga 287 days minutes Emerging as an important PET radionuclide. A single generator can provide Ga for 12 months. 62 Zn / 62 Cu (copper) 9.1 hours 9.7 minutes Decreasing use in PET. 82 Sr / 82 Rb 25 days 76 seconds Provides a popular perfusion agent solution for PET departments without an on site cyclotron to produce 13 N. Decreasing popularity with increased number of cyclotrons and because the positron energy is very high, reducing resolution. 90 Sr / 90 Y (yttrium) 28 years 64 hours Useful source of 90 Y for therapeutic applications. 188 W / 188 Re 69 days 17 hours The half-life of the daughter limits its usefulness as a therapy agent. Figure 7: Schematic representation of cyclotron production of 18 F. have emerged (Melbourne, Adelaide, Sydney, Brisbane) to service the needs of PET. The National Medical Cyclotron was decommissioned commercially in It now only operates as a research facility and cyclotron radionuclides for non-pet nuclear medicine are again being imported; ironically more cheaply than local production. Generator Some radionuclides have sufficiently short half-lives that daily manufacture, quality control and shipping is impractical. m Tc is the most widely used radionuclide in nuclear medicine. 1,2,4,6 It has a six hour half-life which allows a daily delivery to provide the needs of some departments from an off-site centralised pharmacy. For other busier departments and those providing a service that sees regular urgent studies added to the daily schedule or after hours, predicting the precise m Tc requirements for the day is difficult. A radionuclide generator is a device that allows a weekly supply of a short lived radionuclide to be available on site. While the Mo / m Tc generator is the most common, there are numerous other types of generators (Table 2). A radionuclide generator is comprised of a parent/daughter radionuclide pair. The short lived daughter (e.g. m Tc) is paired with a longer lived parent (e.g. Mo). Depending on the half-life of each, regular separation and extraction of the daughter from the parent can occur; elution. Elution is also referred to as milking the generator. Elution can be repeated because the parent replenishes the daughter by decay. Separation of the parent and daughter is generally based on different physical or chemical properties. A significant advantage of the generator is the provision of carrier free radionuclide which provides greater radiopharmaceutical stability / integrity. 1,2 The amount of radioactivity available or activity, of the daughter at any given time will vary depending on the activity of the parent and parent half-life, the half-life of the daughter, and the elution efficiency (the percentage of daughter available that is removed upon elution). Elution efficiency is typically 90% or better. 1,2,4,6 Mo has a 67 hour half-life and provides a perfect parent for a radionuclide generator. Mo is produced by fission and loaded onto an aluminium column by adsorption in the generator as ammonium molybdenate (Figure 8). m Tc has different chemical properties to Mo and so, as the parent decays to the daughter, the m Tc is less tightly bound to the aluminium column ( MoO 4 2- versus m TcO 4- ). Consequently, running normal saline, the eluent, across the aluminium column removes the m Tc from the column to produce eluate while leaving the Mo behind on the column until it decays to more m Tc and is subsequently eluted. Generators are classified based on the type of equilibrium that occurs between the parent and daughter. If the generator has a parent with a halflife considerably longer (100 times or more) than that of the daughter, it is referred to secular equilibrium. 1,2,3 Secular equilibrium means that after 5 6 half-lives of the daughter since the previous elution the activity of the parent and the daughter are the same. 1,2 Consequently, after secular equilibrium the daughter appears to decay at the same rate or half-life as the parent (Figure 9). Of course it does not, but the amount of daughter in the generator is in equilibrium with the parent despite it decaying more rapidly. Most of the generators in Table 2 are secular including the 81 Rb 50 The Radiographer 2011

6 Figure 9: Schematic representation of secular and transient equilibrium. Note the daughter activity (green line) slightly exceeds that of the parent (red line). The y axis is logarithmic. Figure 8: Schematic representation of the simple design of a Mo / m Tc generator. The aluminium column is simply connected to an extension tube at either end. One end is the port for connection of an evacuated vial to draw 40 ml of volume across the column. The other end is the port for connection of the saline. Typically a 40 ml vial containing 20 ml of saline and 20 ml of air is used. The upside down vial ensures that the saline is drawn across the column fi rst and the column is subsequently air dried. This produces greater stability over old designs where the saline end was a saline bag that left the apparatus wet between elutions. Higher concentrations can be achieved by removing some of the saline from the vial before elution (eg. removing 10 ml will leave a 10 ml eluate rather than 20 ml). This is important toward the end of the generator life to ensure workable concentrations of activity. The remainder of the device is simply lead shielding and plastic casing. 1,2,3,4,6 / 81m Kr generator. Conversely, when the parent half-life is longer but not substantially (in the order of 10 times), transient equilibrium occurs. 1,2,3 Transient equilibrium means that the daughter activity increases as the parent decays and maximal daughter activity is reached about four halflives (daughter) after the previous elution. 1,2 While that represents a maximum amount of activity, the decay of the parent means that actual equilibrium (which occurs closer to 16 half-lives of the daughter) does not yield the highest activity for subsequent elutions. After this actual equilibrium, production and decay of the daughter are equal and the daughter appears to decay at the same rate as the parent. The Mo / m Tc generator is a transient equilibrium generator. Conveniently for daily use, the daughter half-life is six hours which means that the maximum activity post elution (approximately four half-lives) is 24 hours (22.9 hours to be more precise although actual mathematical calculations are beyond the scope of this paper) with equilibrium occurring at approximately 72 hours post elution (Figure 10). Normally, the daughter activity after equilibrium will slightly exceed that of the parent. In the case of the Mo / m Tc generator, however, only about 88% of the Mo decays to m Tc with the remainder decaying directly to Tc. 1,2 This is referred to as the branching fraction and means that the post equilibrium m Tc activity is only about 96% of the parent activity. 1,2 These concepts are important to understand because it has a bearing on daily practice. It is easy to simply focus on the m Tc activity of the generator. Given that both m Tc and Mo decay to Tc, an understanding of the Tc content is important to radiochemical purity. Chemically, Tc and m Tc are identical and these will compete for the same binding sites during radiopharmaceutical reconstitution. If the generator has not been eluted for a long period of time, for example from Friday morning through to Monday morning, the Tc content in the eluate will be far in excess of the m Tc content. Consequently, exploring the boundaries of radiopharmaceutical activity could cause free pertechnetate. Free pertechnetate is unbound m Tc that accumulates in thyroid and stomach in the main, degrading image quality. Indeed, some radiopharmaceuticals have specific requirements for fresh eluate (eluted in the last two to four hours from a generator previously eluted in the last four to 24 hours for example) to minimise Tc competition and subsequent labelling inefficiencies. The Radiographer

7 Conclusion An understanding of the principles of radionuclide production extends translational knowledge to the application of diagnostic and therapeutic nuclear medicine procedures. The production processes are not generally complex and are important to broader applications in research. Figure 10: Schematic representation of m Tc elution profi les with multiple elutions. Note the maximum activity occurs prior to actual equilibrium. The y axis is logarithmic. The red line indicates the decay of the parent Mo. The green line indicates the activity of the daughter m Tc assuming elution at time zero. Maximum activity occurs at 23 and equilibrium occurs at approximately 72 hours. The yellow line shows the activity profi le following a second elution at 24 hours and the blue line a third elution. References 1 Kowalsky R, Falen S. Radiopharmaceuticals in nuclear pharmacy and nuclear medicine (2nd edition). Washington: APhA; Theobald T (editor). Sampson s textbook of radiopharmacy (4th edition). London: Pharmaceutcial Press; Cherry S, Sorenson J, Phelps M. Physics in Nuclear Medicine (3rd edition). Philadelphia: Saunders; Christian PE, Waterstram-Rich KM (editors). Nuclear medicine and PET/CT: technology and techniques (7th edition). Philadelphia: Elsevier Mosby; Tozer TN, Rowland M. Introduction to pharmacokinetics and pharmacodynamics; the quantitative basis of drug therapy. Philadelphia: Lippincott Williams & Wilkins; Busberg JT, Seibert JA, Leidholdt EM, Boone JM. The essential physics of medical imaging (2nd edition). Philadelphia: Lippincott Williams & Wilkins; The Radiographer 2011