African School of Physics 2010 Radionuclide production Marco

African School of Physics 2010 Radionuclide production Marco Silari CERN, Geneva, Switzerland M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 1 Radionuclide production The use of radionuclides in the physical and biological sciences can be broken down into three general categories: Radiotracers Imaging (95% of medical uses) SPECT (99mTc, 201Tl, 123I) PET (11C, 13N, 15O, 18F) Therapy (5% of medical uses)

Brachytherapy (103Pd) Targeted therapy (211At, 213Bi) Relevant physical parameters (function of the application) Type of emission (, +, , ) Energy of emission Half-life Radiation dose (essentially determined by the parameters above) Radionuclides can be produced by Nuclear reactors Particle accelerators (mainly cyclotrons) M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 2 First practical application (as radiotracer) The first practical application of a radioisotope (as radiotracer) was made by G. de Hevesy (a young Hungarian student working with naturally

radioactive materials) in Manchester in 1911 (99 years ago!) In 1924 de Hevesy, who had become a physician, used radioactive isotopes of lead as tracers in bone studies. M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 3 Brief historical development 1932: the invention of the cyclotron by E. Lawrence makes it possible to produce radioactive isotopes of a number of biologically important elements 1937: Hamilton and Stone use radioactive sodium clinically 1938: Hertz, Roberts and Evans use radioactive iodine in the study of thyroid physiology 1939: J.H. Lawrence, Scott and Tuttle study leukemia with radioactive phosphorus

1940: Hamilton and Soley perform studies of iodine metabolism by the thyroid gland in situ by using radioiodine 1941: first medical cyclotron installed at Washington University, St Louis, for the production of radioactive isotopes of phosphorus, iron, arsenic and sulphur After WWII: following the development of the fission process, most radioisotopes of medical interest begin to be produced in nuclear reactors 1951: Cassen et al. develop the concept of the rectilinear scanner 1957: the 99Mo/99mTc generator system is developed by the Brookhaven National Laboratory 1958: production of the first gamma camera by Anger, later modified to what is now known as the Anger scintillation camera, still in use today M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 4 Emission versus transmission imaging Courtesy P. Kinahan

M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 5 Fundamental decay equation N(t) = N0e-t or A(t) = A(0)e-t where: N(t) = number of radioactive atoms at time t A(t) = activity at time t N0 = initial number of radioactive atoms at t=0 A(0) = initial activity at t=0 e = base of natural logarithm = 2.71828 = decay constant = 1/ = ln 2/T1/2 = 0.693/T1/2 t = time and remembering that: -dN/dt = N A=N M. Silari Radionuclide production

ASP2010 - Stellenbosh (SA) 6 Fundamental decay equation Linear-Linear scale M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 7 Fundamental decay equation Linear-Log scale M. Silari Radionuclide production ASP2010 - Stellenbosh (SA)

8 Generalized decay scheme M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 9 The ideal diagnostics radiopharmaceutical a) Be readily available at a low cost b) Be a pure gamma emitter, i.e. have no particle emission such as alphas and betas (these particles contribute radiation dose to the patient while not providing any diagnostic information) c) Have a short effective biological half-life (so that it is eliminated from the body as quickly as possible) d) Have a high target to non-target ratio so that the resulting image has a high contrast (the object has much more activity than the background)

e) Follow or be trapped by the metabolic process of interest M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 10 Production methods All radionuclides commonly administered to patients in nuclear medicine are artificially produced Three production routes: (n, ) reactions (nuclear reactor): the resulting nuclide has the same chemical properties as those of the target nuclide Fission (nuclear reactor) followed by separation Charged particle induced reaction (cyclotron): the resulting nucleus is usually that of a different element M. Silari Radionuclide production

ASP2010 - Stellenbosh (SA) 11 Production methods M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 12 Reactor versus accelerator produced radionuclides Reactor produced radionuclides The fission process is a source of a number of widely used radioisotopes ( 90Sr, 99Mo, 131I and 133 Xe) Major drawbacks: large quantities of radioactive waste material generated

large amounts of radionuclides produced, including other radioisotopes of the desired species (no carrier free, low specific activity) Accelerator produced radionuclides Advantages more favorable decay characteristics (particle emission, half-life, gamma rays, etc.) in comparison with reactor produced radioisotopes. high specific activities can be obtained through charged particle induced reactions, e.g. (p,xn) and (p,a), which result in the product being a different element than the target fewer radioisotopic impurities are produce by selecting the energy window for irradiation small amount of radioactive waste generated access to accelerators is much easier than to reactors Major drawback: in some cases an enriched (and expensive) target material must be used M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 13 Accelerator production of radionuclides

The binding energy of nucleons in the nucleus is 8 MeV on average If the energy of the incoming projectile is > 8 MeV, the resulting reaction will cause other particles to be ejected from the target nucleus By carefully selecting the target nucleus, the bombarding particle and its energy, it is possible to produce a specific radionuclide The specific activity is a measure of the number of radioactive atoms or molecules as compared with the total number of those atoms or molecules present in the sample (Bq/g or Bq/mol). If the only atoms present in the sample are those of the radionuclide, then the sample is referred to as carrier free M. Silari Radionuclide production

ASP2010 - Stellenbosh (SA) 14 The essential steps in accelerator r.n. production 1. 2. 3. 4. 5. 6. Acceleration of charged particles in a cyclotron Beam transport (or not) to the irradiation station via a transfer line Irradiation of target (solid, liquid, gas) internal or external Nuclear reaction occurring in the target (e.g. AXZ(p,n)AYz-1) Target processing and material recovering Labeling of radiopharmaceuticals and quality control a = bombarding particle

b, c = emitted particles A, B, D = nuclei M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 15 Example: d + 14N O* 16 Q values and thresholds of nuclear decomposition for the reaction of a deuteron with a 14N nucleus after forming the compound nucleus 16O M. Silari Radionuclide production

ASP2010 - Stellenbosh (SA) 16 Production rate and cross section E0 dn (E) t R nI (1 e ) dE dt dE / dx Es R = the number of nuclei formed per second n = the target thickness in nuclei per cm2 I = incident particle flux per second (related to the beam current) = decay constant = (ln 2)/T1/2 t = irradiation time in seconds

= reaction cross-section, or probability of interaction (cm2), function of E E = energy of the incident particles x = distance travelled by the particle and the integral is from the initial to final energy of the incident particle along its path M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 17 Energy dependence of the cross section Excitation function of the 18O(p,n)18F reaction M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 18

Experimental measurement of cross section Ri Inx i where Ri = number of processes of type i in the target per unit time I = number of incident particles per unit time n = number of target nuclei per cm3 of target = NNA/A i = cross-section for the specified process in cm2 x = the target thickness in cm and assuming that 1. The beam current is constant over the course of the irradiation 2. The target nuclei are uniformly distributed in the target material 3. The cross-section is independent of energy over the energy range used M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 19 Saturation factor, SF = 1 e-t

Tirr = 1 half-life results in a saturation of 50% 2 half-lives 75% 3 half-lives 90% The practical production limits of a given radionuclide are determined by the half-life of the isotope, e.g. O, T1/2 = 2 minutes 18 F, T1/2 = almost 2 hours 15 1 e-tt For long lived species, the production rates are usually expressed in terms of integrated dose or total beam flux (Ah) M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 20

Competing nuclear reactions, example of 201Tl The nuclear reaction used for production of 201Tl is the 203Tl(p,3n)201Pb 201 201 Pb (T1/2 = 9.33 h) Tl (T1/2 = 76.03 h) Cross-section versus energy plot for the 203Tl(p,2n)202Pb, 203Tl(p,3n)201Pb and 203Tl(p,4n)200Pb reactions Below 20 MeV, production of 201 Tl drops to very low level (http://www.nndc.bnl.gov/index.jsp) Around threshold, production of 201 Tl is comparable to that of 202Pb M. Silari Radionuclide production Above 30 MeV, production of 200

Pb becomes significant ASP2010 - Stellenbosh (SA) 21 Targets Internal (beam is not extracted from the cyclotron) External (extracted beam + beam transport to target) Simultaneous irradiation of more than one target (H cyclotrons) The target can be Solid Liquid Gaseous Principal constraints on gas targets removal of heat from the gas (gases are not very good heat conductors) the targets must be quite large in comparison with solid or liquid targets in order to hold the necessary amount of material. M. Silari Radionuclide production

ASP2010 - Stellenbosh (SA) 22 Targets 18 Solid powder target used at BNL O water target Target powder Cover foil Solid Liquid Gaseous

Gas target used for production of 123I from 124Xe Gas inlet Cold finger M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 23 Targets A major concern in target design is the generation and dissipation of heat during irradiation target cooling Efficient target cooling: ensures that the target material will remain in the target allows the target to be irradiated at higher beam currents, which in turn allows production of more radioisotopes in a given time

Factors to be considered in relation to thermodynamics include: Interactions of charged particles with matter Stopping power and ranges Energy straggling Small angle multiple scattering Distribution of beam energy when protons are degraded from an initial energy of 200, 70 or 30 MeV to a final energy of 15 MeV M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 24 Inclined target for better heat dissipation Example of an inclined plane external target used for solid materials either pressed or melted in the depression in the target plane

M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 25 Circular wobbling of the beam during irradiation Rw = radius of wobbler circle (mm) R = radius of cylindrical collimator (mm) r = distance Current density distribution for a wobbled beam M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 26 Target processing and material recovering Schematic diagram of a processing system for the production of [ 15O]CO2

M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 27 Target processing and material recovering Example of a gas handling system for production of 81mKr. Vs and Ps are mechanical pressure gauges and NRVs are one way valves to prevent backflow M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 28 Target processing and material recovering Manifolds used for: (a) precipitation of 201Pb and (b) filtration of the final solution.

M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 29 Most common radionuclides for medical use versus the proton energy required for their production Proton energy (MeV) Radionuclide easily produced 0 10 18 F, 15O 11 16

11 C, 18F, 13N, 15O, 22Na, 48V 17 30 124 30+ 124 M. Silari Radionuclide production I, 123I, 67Ga, 111In, 11C, 18F, 13N, 15O, 22Na, 48V, 201Tl I, 123I, 67Ga, 111In, 11C, 18F, 13N, 15O, 82Sr, 68Ge, 22Na, 48V ASP2010 - Stellenbosh (SA)

30 Nuclear reactions employed to produce some commonly used imaging radionuclides (1) Radionuclide 99m Tc 123 I Use SPECT imaging SPECT imaging Half-life 6h 13.1 h Tl 11

C SPECT imaging PET imaging 73.1 h 20.3 min N PET imaging 9.97 min 201 13 M. Silari Radionuclide production

Reaction 100 Mo(p,2n) 124 Xe(p,n)123Cs 124 Xe(p,pn)123Xe 124 Xe(p,2pn)123I 123 Te(p,n)123I 124 Te(p,2n)123I 203 Tl(p,3n)201Pb 201Tl ASP2010 - Stellenbosh (SA) Energy (MeV) 30

27 N(p,) 11 B(p,n) 15 25 29 1119 10 O(p,) 13 C(p,n) 19 11 14

16 31 Nuclear reactions employed to produce some commonly used imaging radionuclides (2) Radionuclide 15 O Use PET imaging Half-life 2.03 min F PET imaging

110 min Cu PET imaging and radiotherapy 12.7 h I PET imaging and radiotherapy 4.14 d 18

64 124 M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) Reaction 15 N(p,n) 14 N(d,2n) 16 O(p,pn) 18 O(p,n) 20 Ne(d,)

nat Ne(p,X) 64 Ni(p,n) 68 Zn(p,n) nat Zn(d,xn) nat Zn(d,2pxn) 124 Te(p,n) 125 Te(p,2n) Energy (MeV) 11 6 > 26 11-17

8-14 40 15 30 19 19 13 25 32 Decay characteristics and max SA of some r.n. M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 33 Radionuclides for therapy

High LET decay products (Auger electrons, beta particles or alpha particles) Radionuclide linked to a biologically active molecule that can be directed to a tumour site Beta emitting radionuclides are neutron rich they are in general produced in reactors Some of the radionuclides that have been proposed as possible radiotoxic tracers are: M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 34

Radionuclides for therapy Charged particle production routes and decay modes for selected therapy isotopes M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 35 Radionuclide generators Technetium-99m (99mTc) has been the most important radionuclide used in nuclear medicine Short half-life (6 hours) makes it impractical to store even a weekly supply Supply problem overcome by obtaining parent 99 Mo, which has a longer half-life (67 hours) and continually produces 99mTc A system for holding the parent in such a way that

the daughter can be easily separated for clinical use is called a radionuclide generator M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 36 Radionuclide generators M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 37 Transient equilibrium Between elutions, the daughter (99mTc) builds up as

the parent (99Mo) continues to decay After approximately 23 hours the 99mTc activity reaches a maximum, at which time the production rate and the decay rate are equal and the parent and daughter are said to be in transient equilibrium Once transient equilibrium has been reached, the daughter activity decreases, with an apparent halflife equal to the half-life of the parent Transient equilibrium occurs when the half-life of the parent is greater than that of the daughter by a factor of about 10 M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 38 Transient equilibrium M. Silari Radionuclide production

ASP2010 - Stellenbosh (SA) 39 Radionuclide generators M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 40 Positron Emission Tomography (PET) Cyclotron PET camera Radiochemistry

J. Long, The Science Creative Quarterly,scq.ubc.ca M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 41 Positron Emission Tomography (PET) 51 eV 1k 1 51 V ke COVERAGE: ~ 15-20 cm

SPATIAL RESOLUTION: ~ 5 mm SCAN TIME to cover an entire organ: ~ 5 min CONTRAST RESOLUTION: depends on the radiotracer M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) 42 PET functional receptor imaging Normal Subject Parkinsons disease [11C] FE-CIT

M. Silari Radionuclide production ASP2010 - Stellenbosh (SA) Courtesy HSR MILANO 43 Some textbooks Cyclotron Produced Radionuclides: Principles and Practice, IAEA Technical Reports Series No. 465 (2008) (Downloadable from IAEA web site) Targetry and Target Chemistry, Proceedings Publications, TRIUMF, Vancouver (http://trshare.triumf.ca/~buckley/wttc/proceedings.html ) CLARK, J.C., BUCKINGHAM, P.D., Short-Lived Radioactive Gases for Clinical Use, Butterworths, London (1975) M. Silari Radionuclide production

ASP2010 - Stellenbosh (SA) 44

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