Handbook of Radiopharmaceuticals
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Handbook of Radiopharmaceuticals Radiochemistry and Applications
Editors MICHAEL J. WELCH The Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, USA
CAROL S. REDVANLY Department of Chemistry, Brookhaven National Laboratory Associated Universities Ltd, Upton, New York, USA
WILEY
Copyright © 2003
John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone ( + 44) 1243 779777
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ISBN 0 471 49560 3
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Contents Contributors
ix
Preface
xiii
1
Production of Radionuclides in Accelerators David J. Schlyer
1
2
Accelerators Available for Isotope Production Thomas J. Ruth
71
3
Reactor Production of Radionuclides Leonard F. Mausner and Saed Mirzadeh
87
4
Chemistry of Nitrogen-13 and Oxygen-15 John C. Clark and Franklin I. Aigbirhio
119
5
Aspects on the Synthesis of 11C-Labelled Compounds Gunnar Antoni, Tor Kihlberg and Bengt Langstrom
141
6
Chemistry of Fluorine-18 Radiopharmaceuticals Scott E. Snyder and Michael R. Kilbourn
195
1
Production and Application of Synthetic Precursors Labeled with Carbon-11 and Fluorine-18 Richard A. Ferrieri
.,
229
8
Automation for the Synthesis and Application of PET Radiopharmaceuticals David L. Alexoff
283
9
Design and Synthesis of 2-Deoxy-2-[18F]Fluoro-D-Glucose Joanna S. Fowler and Tatsuo Ido
307
(18FDG)
vi
CONTENTS
10 Technetium Radiopharmaceuticals Ashfaq Mahmood and Alun G. Jones
323
11 Chemistry of Gallium and Indium Radiopharmaceuticals Ronald E. Weiner and Mathew L. Thakur
363
12
401
Chemistry of Copper Radionuclides and Radiopharmaceutical Products Carolyn J. Anderson, Mark A. Green and Yasuhisa Fujibayashi
13 Chemistry Applied to Iodine Radionuclides Ronald Finn
423
14 Radiobromine for Imaging and Therapy Douglas J. Rowland, Timothy J. McCarthy and Michael J. Welch
441
15
Development of Radiolabeled Probes to Monitor Gene Therapy Chyng- Yann Shiue and Stephen L. Eck
467
16
Mechanism of Target Specific Uptake Using Examples of Muscarinic Receptor Binding Radiotracers William C. Eckelman
487
17 Strategies for Quantifying PET Imaging Data from Tracer Studies of Brain Receptors and Enzymes Jean Logan
501
18
529
Radiopharmaceuticals for Studying the Heart Dah-Ren Hwang and Steven R. Bergmann
19 PET Imaging Studies in Drug Abuse Research Joanna S. Fowler, Nora D. Volkow, Yu-Shin Ding, Jean Logan and Gene-Jack Wang
557
20
Research and Clinical Application of Neuroreceptor Imaging Henry N. Wagner, Jr. and Zsolt Szabo
581
21
Dynamic Neurotransmitter Interactions Measured with PET Wynne K. Schiffer and Stephen L. Dewey
603
22
Tumor Imaging Roland Hustinx and Abass Alavi
629
23
Radiolabeled Peptides for Tumor Imaging Linda C. Knight
643
CONTENTS 24
Radiolabeled Antibodies for Tumor Imaging and Therapy Michael R. Zalutsky and Jason S. Lewis
25
Receptor Imaging of Tumors (Non-Peptide) John A. Katzenellenbogen
715
26
Pulmonary Function Imaging with PET Radiopharmaceuticals P. H. Elsinga and W. Vaalburg
751
21
Considerations in the Selection of Radionuclides for Cancer Therapy Amin I. Kassis and S. James Adelstein
767
28
Radiopharmaceuticals for the Study of Liver and Renal Function David R. Vera, Carl K. Hoh, Robert C. Stadalnik and Kenneth A. Krohn
795
Index
823
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Contributors S. JAMES ADELSTEIN
Harvard Medical School Boston, Goldenson Building, 220 Longwood Avenue, Boston, MA, USA
FRANKLIN I. AIGBIRHIO
Wolfson Brain Imaging Centre, University of Cambridge, Box 65, Addenbrooke's Hospital, Cambridge, CB2 2QQ, United Kingdom
ABASS ALAVI
Division of Nuclear Medicine, Hospital of the University of Pennsylvania, Donner Bldg. Room 109, 3400 Spruce St, Philadelphia, PA, USA
DAVID L. ALEXOFF
Department of Chemistry, Brookhaven National Laboratory, Upton, NY, USA
CAROLYN J. ANDERSON
Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, Campus Box 8225, St. Louis, MO, USA
GUNNAR ANTONI
Uppsala University PET Centre, Uppsala University S-757 85 Uppsala, Sweden
STEVEN R. BERGMANN
Division of Cardiology, Department of Medicine; Department of Radiology, Columbia University, New York, NY, USA
JOHN C. CLARK
Wolfson Brain Imaging Centre, University of Cambridge, Box 65, Addenbrooke's Hospital, Cambridge, CB2 2QQ, United Kingdom
STEPHEN L. DEWEY
NYU School of Medicine, Department of Psychiatry, New York, NY, USA; Brookhaven National Laboratory, Chemistry Department, Upton, NY, USA
YU-SHIN DING STEPHEN L. ECK
Brookhaven National Laboratory, Upton, NY, USA
WILLIAM C. ECKELMAN
Warren Grant Magnuson Clinical Center, PET Department, 10 Center Drive, Bethesda, MD, USA
P. H. ELSINGA
Groningen University Hospital, PET-center, P.O. Box 30001, 9700 RB Groningen, The Netherlands
RICHARD A, FERRIERI
Brookhaven National Laboratory, Department of Chemistry, Upton, NY, USA
RONALD FINN
Cyclotron Core Facility, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, USA
Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA
CONTRIBUTORS JOANNA S. FOWLER
Chemistry Department, Brookhaven National Laboratory, Upton, NY, USA
YASUHISA FUJIBAYASHI
Biomedical Imaging Research Center, Fukui Medical University, 23-3, Shimoaizuki, Matsuoka, Yoshida, Fukui, Japan
MARK A. GREEN
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA
CARL K. HOH
Department of Radiology, University of California, San Diego School of Medicine, 200 West Arbor Drive, San Diego, CA, USA
ROLAND HUSTINX
Division of Nuclear Medicine, University Hospital of Liege, Sart Tilman B35, 4000 Liege, Belgium
DAH REN HWANG
Department of Psychiatry, Columbia University, New York, NY, USA
TATSUO IDO ALUN G. JONES
Tohoku University, Sendai, Japan Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, 220 Longwood Avenue, Boston MA, USA
AMIN I. KASSIS
Harvard Medical School Boston, Goldenson Building, 220 Longwood Avenue, Boston, MA, USA
JOHN A. KATZENELLENBOGEN
Department of Chemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL, USA
TOR KIHLBERG
Uppsala University PET Centre; Institute of Chemistry, Uppsala University 5-757 85 Uppsala, Sweden
MICHAEL R. KILBOURN
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA
LINDA C. KNIGHT
Nuclear Medicine Division, Diagnostic Imaging Department, Temple University School of Medicine, 3401 N. Broad Street, Philadelphia, PA, USA
KENNETH A. KROHN
Department of Radiology, University of Washington School of Medicine, Seattle, WA, USA
BENGT LANGSTROM
Uppsala University PET Centre; Institute of Chemistry, Uppsala University 5-757 85 Uppsala, Sweden
JASON S. LEWIS
Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Boulevard, Campus Box 8225, St. Louis, MO, USA
JEAN LOGAN
Chemistry Department, Brookhaven National Laboratory, Upton, NY, USA
ASHFAQ MAHMOOD
Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, 220 Longwood Avenue, Boston MA, USA
LEONARD F. MAUSNER
Medical Department, Brookhaven National Laboratory, Upton, NY
TIMOTHY J. MCCARTHY
Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 S. Kingshighway Boulevard, Campus Box 8225, St. Louis, MO, USA
SAED MIRZADEH
Oak Ridge National Laboratory, Oak Ridge, TN, USA
CONTRIBUTORS
X1
DOUGLAS J. ROWLAND
Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 S. Kingshighway Boulevard, Campus Box 8225, St. Louis, MO, USA
THOMAS J. RUTH WYNNE K. SCHIFFER
TRIUMF, Vancouver, Canada NYU School of Medicine, Department of Psychiatry, New York, NY, USA; Brookhaven National Laboratory, Chemistry Department, Upton, NY, USA
DAVID J. SCHLYER
Department of Chemistry, Brookhaven National Laboratory, Upton, NY, USA
CHYNG-YANN SHIUE
Department of Radiology, University of Pennsylvania Medical Center, Philadelphia, PA, USA
SCOTT E. SNYDER
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA
ROBERT C. STADALNIK
Department of Radiology, University of California, Davis School of Medicine, 4860 Y Street, Sacramento, CA, USA
ZSOLT SZABO MATHEW L. THAKUR
Johns Hopkins Medical Institutions, Baltimore, MD, USA
W. VAALBURG
Groningen University Hospital, PET-center, P.O. Box 30001, 9700 RB Groningen, The Netherlands
DAVID R. VERA
Department of Radiology, University of California, San Diego School of Medicine, 200 West Arbor Drive, San Diego, CA, USA
Department of Radiology, Thomas Jefferson Philadelphia, PA, USA
University Hospital,
Brookhaven National Laboratory, Upton, NY, USA NORA D. VOLKOW HENRY N. WAGNER, JR. Johns Hopkins Medical Institutions, Baltimore, MD, USA Brookhaven National Laboratory, Upton, NY, USA GENE-JACK WANG RONALD E. WEINER Division of Nuclear Medicine, University of Connecticut Health Center, Farmington, CT, USA
MICHAEL J. WELCH
Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 S. Kingshighway Boulevard, Campus Box 8225, St. Louis, MO, USA
MICHAEL R. ZALUTSKY
Duke University Medical Center, Box 3808, Durham, NC, USA
Alfred P. Wolf
Preface This book is dedicated to Alfred P. Wolf whose career in radiochemistry and radiopharmaceutical chemistry spanned almost 50 years. Al's entire professional career was spent in the Chemistry Department at Brookhaven National Laboratory which led to research in accelerator production of carbon-11, fluorine-18 and other positron-emitting radionuclides to be used with nuclear imaging devices. In 1976, under his leadership, the Brookhaven group first synthesized the PET tracer 2fluoro-2-deoxyglucose (FDG) which to date is the most frequently used PET radiopharmaceutical. PET's utility for the non-invasive measurement of regional cerebral glucose metabolism was demonstrated through a collaborative effort of scientists at the University of Pennsylvania, the National Institutes of Health and Brookhaven National Laboratory. This radiopharmaceutical has stimulated advanced basic research studies in neuroscience, neurology, psychiatry, cardiology and cancer for more than 25 years. Over the past several years the use of FDG has increased through its clinical utility in the diagnosis and staging of cancer. In the late summer of 1997 Al Wolf traveled to Philadelphia to attend the International Isotope Society meeting at which he was the recipient of the Melvin Calvin Award. There Al met with Sally Betteridge, Life Science Publishing Editor at John Wiley & Sons, Ltd., and they discussed the possibility of him editing a textbook on radiopharmaceuticals for PET. Unfortunately, the state of Al's health did not allow him to proceed with this project and he died on December 17, 1998, without further discussions with the publisher. At the memorial symposium for Al held at Brookhaven, Michael Welch and Carol Redvanly discussed the book Al had planned and agreed to co-editor the book and dedicate it to the memory of Al. The aim of the book is to provide a resource text for students and new participants in the field of radiopharmaceuticals, for postdoctoral fellows and for research scientists at drug companies interested in utilizing radiopharmaceuticals and PET to evaluate their compounds. The radiopharmaceutical and PET field has been expanding exponentially in recent years with the opening of many new imaging centers world-wide. These new centers will require more trained radiopharmaceutical chemists. Over the past 50 years many radiochemists and radiopharmaceutical scientists have spent time at Brookhaven National Laboratory. Others have interacted with Al through meetings and committees. Many of Al's friends were asked to contribute to the present volume. The volume ranges from accelerator technology, basic radiolabeling as well as the applications of radiopharmaceuticals. Although he spent his career working with radionuclides, Al was always very proud that he was
xiv
PREFACE
trained as a synthetic organic chemist in the group of William Doering at Columbia University. Several of the chapters in the book show the sophistication of organic synthesis currently being utilized in radiopharmaceutical research and development. Al was elected to the National Academy of Sciences in 1988 and was the recipient of many scientific awards and honors. These awards and honors include: American Chemical Society Nuclear Chemistry Award (1971); Society of Nuclear Medicine Aebersold Award (1981), Hevesy Nuclear Medicine Pioneer Award (1991), American Chemical Society Northeast Region Esselen Award, Institute for Clinical PET Distinguished Scientist Award (1996), International Isotope Society Melvin Calvin Award (1997) and the American Chemical Society Honorary Symposium (1998). He received honorary degrees from Uppsala University, Sweden (1983) and the University of Rome in Italy (1989). Al Wolf was one of the four founding editors for the Journal of Labelled Compounds and Radiopharmaceuticals and served in that capacity for 33 years. He was also an editor for Radiochimica Acta for more than 20 years. He was the founder of the International Symposium on Radiopharmaceutical Chemistry which has met every two years since 1976 and brings chemists together to discuss the myriad problems of working with short-lived radioisotopes at the submicromolar reaction scale. Al was a consultant for the International Atomic Energy Agency for many years and served as a consultant for the National Research Council of Italy and as a member of the Visiting Committee for the KFA in Julich, Germany. Parallel with his career at Brookhaven, he was an Adjunct Professor of Organic Chemistry at Columbia University's School of General Studies. Teaching was one of his great passions and he derived much satisfaction from interactions with his students. Throughout the years, Al's laboratory at Brookhaven attracted many scientists who were stimulated and challenged under his rigorous tutelage. Today, many of these scientists hold key positions at Cyclotron-PET Centers all over the world. Al Wolf was a mentor, colleague and friend to many in the radiopharmaceutical sciences. He is remembered for his vision, energy, intellect, pride of craft, passion for knowledge, humanity and generosity. Acknowledgements:
We are fully cognizant that we invited some of the best, brightest and busiest scientists to participate in this volume and it was no small feat for them to fit this into their already "over-booked" schedules. We are tremendously grateful to the chapter authors for their thoughtful and detailed contributions. In addition, we wish to thank Laurie Bourisaw and Debbie Hesse at Washington University and Lois Caligiuri at Brookhaven for their able assistance in the formatting of the final versions of the chapters and general administration and coordination of this project. Publication of this book has been delayed due to a corruption of the most of the chapters caused by a computer problem. The reformatting was possible through careful proof reading by many members of the Washington University radiochemistry group. Their assistance is greatly appreciated.
1.
PRODUCTION OF RADIONUCLIDES IN ACCELERATORS
DAVID J. SCHLYER Department of Chemistry, Brookhaven National Laboratory, Upton, NY 11973 INTRODUCTION Radioisotopes can be classified into two basic groups, those that are neutron rich and those that are neutron deficient. Although there are ambiguities in this classification, for our purposes it serves to separate the radioisotopes which are usually made in a reactor (neutron rich) from those that are made with a particle accelerator (neutron deficient). Particle accelerators and in particular cyclotrons, were very important in the preparation of radioisotopes during the years of 1935 to the end of World War Two (WWII). Nuclear fission was yet to be controlled and the amount of radioactive material which could be produced in an accelerator was many times greater than the amount which could be produced using the alpha particles from naturally occurring radioactive elements. After WWII, reactors were used to produce radioactive elements and the use of accelerators for this purpose became less common. However, as the techniques for using radiotracers became more sophisticated, it became clear that reactor produced radionuclides could not satisfy the growing demands and the need for radioisotopes with different decay characteristics. Dedicated accelerators were needed to produce new radioisotopes which could be used in new ways. There are three major reasons the accelerator produced radioisotopes may be used rather than reactor produced radionuclides. These are: 1). The radioisotopes produced in a reactor may have unfavorable decay characteristics (particle emission, half-life, gamma rays, etc.) for a particular application, 2). The radioisotope cannot be produced in a reactor with high specific activity and perhaps most importantly, 3). Access to a reactor is limited. The number of reactors available for radioisotope production has become smaller than the number of cyclotrons available to the scientific community. This reduction in the number of available reactors is a problem which will probably become more severe over the next decade (Helus & Colombetti, 1983). There are a wide variety of nuclear reactions which are used in an accelerator to produce the artificial radioactivity. The bombarding particles are usually protons, deuterons, or helium particles. The energies which are used range from a few MeV to hundreds of MeV (Gandarias-Cruz & Okamoto, 1988). One of the most useful models for nuclear reactions is the compound nucleus model original introduced by Bohr in 1936. In this model, the incident particle is absorbed into the nucleus of the target materials and the energy is distributed throughout the compound nucleus. In essence the nucleus comes to some form of equilibrium before decomposing with the emission of particles. These two steps are considered to be independent of one another. It doesn't matter how the compound nucleus got to the high energy state, the evaporation of the Handbook of Radiopliarmaceuticals. Edited by M. J. Welch and C. S. Redvanly, ©2003 John Wiley & Sons, Ltd
2
HANDBOOK OF RADIOPHARMACEUTICALS
particles will be independent of the way in which it was formed. The total amount of excitation energy contained in the nucleus will be given by the equation:
U =M
M.
Where: U = Excitation Energy MA = mass of the target nucleus M, = mass of the incident particle T» = kinetic energy of the incident particle Sa = binding energy of the incident particle in the compound nucleus The nucleus can decompose along several channels as shown here in Figure 1
Figure 1. Possible decay channels for the compound nucleus model of nuclear reactions When the compound nucleus decomposes, the kinetic energy of all the products may be either greater or less than the total kinetic energy of all the reactants. If the energy of the products is greater, then the reaction is said to be exoergic. If the kinetic energy of the products is less than the reactants, then the reaction is endoergic. The magnitude of this difference is called the Q value. If the reaction is exoergic, Q values are positive. An energy level diagram of a typical reaction is shown in Figure 2.
Excited Compound Nucleus 14
N + 2H Reactants Q = 8.6 MeV
N + 1H Products
15
Figure 2. Energy level diagram for a nuclear reaction. The Q-value is the difference in the energy levels of the reactants and the products The nuclear reaction cross-section represents the total probability that a compound nucleus will be formed and that it will decompose in a particular channel. There is a minimum energy below which a nuclear reaction will not occur except by tunneling effects. The incident particle energy must be sufficient to overcome the Coulomb barrier and to overcome a negative Q of the reaction. Particles with energies below this barrier have a very low probability of reacting. The energy required to induce a nuclear reaction increases as the Z of the target material increases. For many low Z materials it is possible to use a low energy accelerator, but for high Z materials, it is necessary to increase the particle energy (Deconninick, 1978). The number of reactions occurring in one second is given by the relation (Deconninick, 1978):
dn = L Where: dn is the number of reactions occurring in one second I0 is the number of particles incident on the target in one second NA is the number of target nuclei per gram ds is the thickness of the material in grams per cm2 erab is the parameter called the cross-section expressed in units of cm2 In practical applications, the thickness ds of the material can be represented by a slab of thickness As thin enough that the cross-section can be considered as constant. NA ds is then the number of target atoms in a 1 cm2 area of thickness As. If the target material is a compound rather than a pure element, then the number of nuclei per unit area is given by the expression: NA =
FAC3 AA
HANDBOOK OF RADIOPHARMACEUTICALS Where: NA FA C 3 AA
is the number of target nuclei per gram is the fractional isotopic abundance is the concentration in weight is Avogadro's Number is the atomic mass number of nucleus A
This leads to one of the basic facts of life in radioisotope production. It is not always possible to eliminate the radionuclidic impurities even with the highest isotopic enrichment and the widest energy selection. An example of this is given below in Figure 3 for the production of Iodine-123 with a minimum of I-124 impurity (Guillaume et al., 1975; Lambrecht & Wolf, 1973; Clem & Lambrecht, 1991; Qaim & Stocklin, 1983).
Production of 1-123 vs 1-124
1000
10
15 20 25 Proton Energy (MeV)
Figure 3. Reaction cross-sections for the production of 1-123 and 1-124 as a function of the proton energy. As can be seen from this graph, it is not possible to eliminate the I-124 impurity from the I-123 because the I124 is being made at the same energy. All that can be done is to minimize the I-124 impurity by choosing an energy where the production of I-124 is near a minimum. In this case a proton energy higher than about 20 MeV will give a minimum of I-124 impurity.
PRODUCTION OF RADIONUCLIDES IN ACCELERATORS
5
GENERAL CONSTRAINTS Power deposition One of the main concerns in targets is the deposition of power in the material during irradiation. If the power deposited exceeds the ability of the target to remove the heat, the target will eventually be destroyed or the target material will be melted, volatilized or reduced in density to the point where the yield will be drastically reduced. In liquid targets the material may boil and thereby reduce the average density. In gaseous targets, the density of the gas is reduced in the beam strike area. All these effects are a result of the increased temperature in the beam strike area and this in turn is a result of the power deposited by the beam as it passes through matter. The power deposited in the material is the beam current in microamps multiplied by the energy loss in MeV and the result is the number of watts deposited.
Power(watts) = l(microamp$t±E(MeV} The exact position of the heat deposition will depend on the dE/dx (stopping power) of the beam in the target material with most of the heat being deposited near the end of the particle range in the Bragg peak. A simple approximation for the stopping power is given by the relation:
dE
dx
4m2e4 3Z , 2mnV -In m,V2 A I
Where: dE/dx = energy loss per unit length z = the atomic number of the projectile e = elementary charge 4.803 x 10-10 (erg-cm)1/2 m0 = the electron rest mass V = relativistic projectile velocity 3 = Avogadro's number I = adjusted ionization potential of the target material Z = atomic number of the target material
6
HANDBOOK OF RADIOPHARMACEUTICALS
Some additional helpful approximations are that the relativistic velocity is given by the relation:
V =\3>u]-\tfcm -sec'1 Vffl Where: E = particle energy in MeV m = particle atomic mass number
The other useful approximations for the adjusted ionization potential are: I=13ZeV I = 9.76 Z + 58.8 Z°19
ifZ>13 ifZ>13
The stopping power of particles other than protons are given by the relationships: deuterons tritons 3 He 4 He
Sd(E) = Sp(E/2) St(E) = Sp(E/3) St(E) = 4Sp(E/3) Sa(E) = 4Sp(E/4)
Heat transfer In order to have a useful accelerator target for the production of a radionuclide, it is necessary to effectively remove the heat generated by the passage of the beam. There are three modes of heat transfer which are active in targets. These are conduction, convection and radiation. Radiation is only a significant mode of heat loss at high temperatures (>500°C). Gases and liquids can transfer heat via convection and conduction. In most targets, the final removal of the heat will be from a backing plate to a flowing water stream. Heat transfer in solids is somewhat simpler than in other media since the heat usually flows through the target matrix mainly by conduction. Once the heat has been transferred to the cooled surface of the target, the heat will usually be removed by a fluid such as water flowing against the back of the target. This convective heat transfer is another topic which will not be discussed. The transfer of the heat through the target material and through the backing material are fairly straight forward. The real surprises in designing solid targets comes in the interfaces where the target material meets the backing material. This is where many problems arise and the better the connection one can make at this interface, the better the heat transfer will be and the less likely one is to have problems with loss of target material or damage to the target during the irradiation.
PRODUCTION OF RADIONUCLIDES IN ACCELERATORS Table 1 - Partial List of Radionuclides Produced with a Cyclotron
Product
Half
Nuclear
Nominal
Other Reactions
Impurity
Nuclide
Life
Reaction
Energy
for Impurities
Half-life
Be-7
53.3 d
C-ll
20.4m
I4
N-13
9.98 m
16
O(p,a)13N
15
O-15
2.03 m
14
N(d,n)15O
10
F-18
109.8 m
18
Na-22
2.6 y
27
73,000 y
7
Li(p,n)
20
N(P,a)11C
15
O(p,n)18F
15
22
Ne(p,n)
15
25
Mg(p,a)
20
27
Al(a,3p)
45
Mg-28
21 h
Cl-34m
38 m
34
S(p,n)
20
V-48
16d
48
Ti(p,n)
11
Al(g,n)26Al
49
Ti(p,a)46Sc
49
Ti(p,n)49V
337 d
Ti(p,a)44mSc
2.44 d
47
47
10
Ti(d,n)*
Fe-55
2.73 y
55
Mn(p,n)
20
Co-55
17.5 h
56
Fe(p,2n)
25
83.8 d
50
Ti(p,a)47Sc
3.3 d
48
Ti(d,n)49V
337 d
Mn(p,pn)54Mn
312d
56
77.3 d
55
Fe(p,n)56Co
HANDBOOK OF RADIOPHARMACEUTICALS
Product
Half
Nuclear
Nominal
Other Reactions
Impurity
Nuclide
Life
Reaction
Energy
for Impurities
Half-life
Co-57
271 d
60
Ni(p.a)
25
Mn(3He,n)
40
61
Ni(p,n)*
12
64
Zn(p,a)*
22
67
20
55
Cu-61
Cu-64
3.35 h
12.7 h
Zn(p,a)*
61
Ni(p,a)58mCo
Zn(p,n)67Ga
67
3.3d
66
9.5 h
66
Zn(d,n)67Ga
3.3d
Zn(d,2n)66Ga
9.5 h
Zn(p,n)66Ga
^ZnCd.a)*
20
9.1 h
66
Cu-67
Zn-62
9.2 h
63
Cu(p,2n)
22
65
Cu(p,n)65Zn
244 d
Cu(p,pn)64Cu
12.7 h
65
Ge-68
272 d
69
30
71
As-73
80.3 d
74
11
74
As-74
17.8 d
Br-75
97 m
Br-76
16.2 h
76
Se(p,n)
25
Br-77
2.37 d
78
Se(p,2n)
20
Y-88
106.6 d
Ga(p,2n)*
Ge(p,2n)*
74
Ge(p,n)*
15
Se(p,2n)
16
76
88
Sr(p,n)
11
Ga(p,n)71Ge
11.4 d
Ge(prn)74As
17.8 d
Ge(p,2n)73As
80.3 d
74
76
Se(p,n)76Br
80
Se(p,a)77As
38.6 h
77
Se(p,a)74As
17.8 d
88
Sr(p,2n)87Sr
3.3 d
PRODUCTION OF RADIONUCLIDES IN ACCELERATORS
Product
Half
Nuclear
Nominal
Other Reactions
Impurity
Nuclide
Life
Reaction
Energy
for Impurities
Half-life
Zr-89
3.27 d
Tc-94m
52 m
Tc-95m
61 d
Tc-96
4.3 d
Ru-97
2.89 d
Cd-109
89
Y(p,n)
15
Mo(p,n)
15
Mo(p,2n)*
25
94
96
96
Mo(p,n)*
15
Mo(3He,n)
45
462 d
109
In-110
69 m
110
20 15
In-111
2.8 d
111
I-120g
1.35 h
1-121
2.12 h
1-123
13.1 h
95
Ag(p,n) Cd(p,n) Cd(p,n)
20
Te(p,n)
25
Te(p,2n)
30
Te(p,2n)*
30
120
122
124
124
1-124
4.2 d
Xe-122
20.1 h
Xe-127
36.4 d
Ba-128
2.43 d
Ce-139
137.6 d
Ta-179
1.8 y
89
Y(p,2n)88Zr
83.4 d
96
Mo(p,n)96Tc
4.3 d
Mo(P)2n)95raTc
61 d
124
Te(p,n)I24I
4.2 d
Xe(p,2n)125I
59.4 d
96
30
126
124
Te(p,n)*
26
124
12I
Sb(a,n)*
30
Te(3He,3n)*
50
Xe(p,2n)
122
127
Kp,n)
20
Xe(3He,n)*
30
!39
La(p,n)
11
Hf(p,2n)*
22
126
!80
Te(p,2n)123I
123
13.1 h
Sb(a,n)125I
13.0 d
Te(3He,2n)123Xe
2.0 h
122
127
Kp,pn)126I
13.0d
Hf(p,4n)177Ta
2.4 d
180
HANDBOOK OF RADIOPHARMACEUTICALS
10
Product
Half
Nuclear
Nominal
Other Reactions
Impurity
Nuclide
Life
Reaction
Energy
for Impurities
Half-life
W-178
21.6 d
Pt-195m
4.02 d
Hg-195m
1.67 d
181
Ta(p,4n)
192
Os(a,n)
40
Au(p,3n)
30
Pt(3He,2n)*
40
203
Tl(P,n)
20
Pb(p,3n)*
30
197
194
Pb-203
2.2 d
Bi-205
15.3 d
Bi-206
6.2 d
207
206
Pb(p,2n)*
22
207
Pb(p,2n)*
22
206
Pb(p,n)*
At-211 Pu-237
7.2 h
38
15
209
Bi(a,2n)
46
237
Np(p,n)*
25
* Uses isotopically enriched materials
197
Au(p,n)197Hg
'94Pt(3He,a)193mPt
2.7 d
4.3d
PRODUCTION OF RADIONUCLIDES IN ACCELERATORS
11
RADIONUCLIDES Among all the radionuclides being produced around the world, only a few combine the favorable characteristics of physical decay with desirable biological characteristics to become a useful medical radioisotope. While these constitute a very large number, only a small subset will be examined here. The radioisotopes which are in common use for medical applications and which will be described here are listed in Table 1. It is possible to subdivide these radioisotopes into categories. The first of these is the radiohalogens.
HALOGENS The radiohalogens are some of the most widely used compounds in Nuclear Medicine. They are used in both the organic and the inorganic forms for a wide variety of disease states. They are used both to trace the physiological fate of the element itself and as a tag on organic compounds under the assumption that the introduction of the halogen would not seriously alter the physiological properties of the parent compound. In order for this to be a good assumption, two conditions must be exist. These are that the carbon-halogen bond is strong enough to stay intact for longer than the biological half-life of the compound and that the introduction of the halogen does not change the molecular dimensions of the compound in such a way that the physiological pathways are altered or blocked.
Chlorine-34m Chlorine-34m has a half-life of 32.2 minutes and decays via positron emission and electron capture. The ground state of chlorine-34 decays with a 1.5 second half-life to stable sulfur-34. The positron energy is 2.5 MeV and the gamma rays are fairly high in energy (2.1 MeV and 1.2 MeV). There are a number of biomolecules which naturally contain chlorine and therefore this isotope is of interest to the medical community.
Production Reactions There are several reactions which lead to chlorine-34m as a product. These reactions are listed in the following Table 2:
HANDBOOK OF RADIOPHARMACEUTICALS
12 Table 2. Nuclear Reaction
Useful Energy Range (MeV)
%Natural Abundance
References
35
Cl(p,pn)34mCl
20 to 30
75.8
Weinreich et al., 1977; LagunasSolaretal., 1992
34
S(p,n)34mCl
15 to 25
4.21
S(d,2n)34mCl
15 to 25
4.21
Zatolokin et al., 1976; Abrams et al., 1984 Zatolokin et al., 1976; Abrams et al., 1984
S(4He,pn)34mCl
22 to 40 12 to 30
95.0
Zatolokin et al., 1976
100 75.8 95.0
Zatolokin et al., 1976 Zatolokin et al., 1976 Zatolokin et al., 1976
75.8
Zatolokin et al., 1976
34
32
31
4
35
4
34m
P( He,n)
a
4
34m
Cl( He, Hen)
32
3
S( He,p)
35
3
Cl
34m
4
Cl
Cl( He, He)34raCl
28 to 40 10 to 25 15 to 30
Targetry The targetry for these reactions uses volatile solids and compounds of sulphur and phosphorus (Zatolokin et al., 1976). In addition, a gaseous target of hydrogen sulfide has been used to produce Cl-34m (Abrams et al., 1984). Radioisotope Separation In the case of the solid targets, the chlorine can be distilled out of the target matrix or the entire target dissolved and the chloride removed by ion exchange chromatography (Lagunas-Solar et al., 1992). In the gaseous H2S target, the chlorine was removed from the hydrogen sulfide on a anion exchange column (Abrams et al., 1984). The resin was prepared in a dry state and the gas from the target was passed through the column. The chlorine-34m was trapped on the column in the chemical form of chloride. Bromine-75 The half-life of bromine-75 is 97 minutes and it decays with 71% positron emission and 29% electron capture. This makes it a likely candidate for PET. The positron end point energy is 1.7 MeV and there are several gammas with the most prominent at 286.5 keV These emissions, while degrading the image slightly, would not be a serious detriment to PET. This isotope is often considered as the most likely candidate for PET studies as a result of the shorter half-life. It, however, has a problem in that it decays to Se-75 which has a 120 day half-life and several gamma rays in the 100-300 keV range. This contributes to the overall dosimetry of the bromine-75 containing radiotracers. Production Reactions There are several nuclear reactions which lead to the formation of bromine-75. A list of these reactions is given below:
PRODUCTION OF RADIONUCLIDES IN ACCELERATORS
13
Table 3. References
Useful Energy
%Natural
Range (MeV)
Abundance
Se(p,2n)75Br
28 to 18
9.1
Kovacs et al., 1985; Paans et al, 1980
Se(p,3n)75Br
38 to 28
7.7
Paans et al., 1980
Se(p,4n)75Br
55 to 40
23.5
Paans etal, 1980
74
10 to O
0.9
Paans et al., 1980
76
35 to 20
9.1
Paans et al., 1980
77
Se(d,4n)75Br
45 to 30
7.7
Paans et al., 1980
Se(3He,p3n)75Br
36 to 30
9.1
Youfeng et al., 1982
85 to 70
9.1
Paans et al., 1980
35 to 25
100
Blessing et al, 1982; Paans
Nuclear Reaction
76
77
78
Se(d,n)75Br Se(d,3n)75Br
76
76
Se(4He,p4n)75Br
75
As(3He,3n)75Br
et al., 1980; Schlyer et al., 1994 75
78
As(4He,4n)75Br
56 to 48
100
Blessing et al., 1982; Paans et al., 1980
Kr(p,4He)75 Br
30 to 22
0.35
Friedman et al., 1982
The best reactions as far as production rate in this table are the 76Se(d,3n)75Br and the 76Se(p,2n)75Br reactions. The proton reaction is about a factor of two better than the deuteron reaction and the deuteron reaction is about a factor of 5 or 6 better than all the other the reactions with the exception of the 77 Se(p,3n)75Br reaction (Qaim, 1986). Targetry The targetry for the production of Br-75 is similar to those being used for the production of the other bromine radioisotopes. Elemental selenium targets have been used (Vaalburg et al., 1985; Kovacs et al., 1985) as well as copper-arsenic alloys (Blessing et al, 1982; Weinreich et al, 1981; Loc'h & Maziere, 1988), silverarsenic alloys and copper-silver-arsenic alloys (Vaalburg et al, 1985). Elemental arsenic targets have also been used. One of the more novel targets to be developed is the krypton gas target (Zeisler & Caspar, 1999). This target allows the production of pure Br-75 in a automated system. Radioisotope Separation The most widely used method of separation is that of dry distillation (Vaalburg et al, 1985). The apparatus for this distillation is very similar in design to that described for the distillation of iodine from a tellurium matrix. The method of trapping the Br-75 is slightly different in that a platinum wool is used at the exit of
14
HANDBOOK OF RADIOPHARMACEUTICALS
the heated tube. Wet chemical separation using an ion exchange resin is also used if the radioisotope is in the chemical form of bromide (Zeisler & Caspar, 1999). Bromine-76 The half-life of bromine-76 is 16.2 hours and it decays with both positron emission (54%) and electron capture. The half-life allows radiotracers to be used that have accumulation times of a day or two. The high end-point energies of the positrons emitted may affect the positron emission image to some extent. Production Reactions The production reactions for Br-76 are similar to those in use for Br-77. As is the case in many nuclear reaction sequences, one chemist's impurity is another chemist's product. This is the case here where the impurity Br-76 now becomes the product. The production reactions for bromine-76 are listed in the table below. Table 4. Nuclear Reaction
Useful Energy Range %Natural (MeV) Abundance
References
76
Se(p,n)76Br
16 tolO
9.1
Tolmachevero/., 1998
77
Se(p,2n)76Br
25 to 16
7.7
Nozakiefa/., 1979b
75
18tolO
100
Nozakie/a/., 1979b
Br(p)xn)76Kr : 76Br
65 to 50
100
Qaim et al., 1977; Sakamoto et al., 1985
'Br(d,xn)76Kr : 76Br
80 to 55
100
Qaim et al., 1977
36 to 30
9.1
Blue & Benjamin, 1971; De Jong et al., 1979
10 to 25
9.1
Paans et al., 1980
As(4He,3n)76Br
nat
na
76
Se(3He,3n)76Kr':
76
Se(d,2n)76Br
76
Br
The pathway through the krypton is viable for bromine-76 although it is necessary to use a higher energy cyclotron and the impurity levels of Br-77 in the Br-76 is rather high (Qaim, 1986; De Jong, 1979). Targetry Most of the targets for the production of bromine-76 have been the elemental targets (Qaim, 1986). Most are of the inclined plane type as is used in the production of bromine-77. Bromine-76 has been made using a copper-selenium alloy (Tolmachev et al., 1998; McCarthy et al., 1999a). In this case, the target is a simple powder target as described previously. Similar targets to those used for the production of bromine-75 could, of course, be used.
PRODUCTION OF RADIONUCLIDES IN ACCELERATORS
15
Radioisotope Separation In the case of the elemental arsenic target, a wet chemical separation technique is commonly used. In the case of the elemental selenium and the copper-selenium alloys, the bromine is liberated from the target matrix by a dry distillation technique (Qaim, 1986; Tolmachev et al., 1998). Bromine-77 There are two radioisotopes of bromine in common use. The most popular of these is bromine-77. Bromine77 has a 56 hour half-life and decays nearly exclusively (99.3%) by electron capture with prominent gamma rays at 239.0 keV and 520.7 keV. There are several other gamma rays varying in energy from 238 to 820 keV, The electron capture mode of decay makes this isotope a likely candidate for radiotherapy applications as well. Many organic molecules can be labeled with bromine and in general the carbon-bromine bond is somewhat stronger than the carbon-iodine bond and this leads to added stability for the molecules labeled with bromine. An additional advantage over iodine is that inorganic bromide, released from the labeled molecule by metabolism, will not accumulate in the thyroid. The organic molecules are somewhat easier to label than with fluorine-18. The longer half-life of bromine-77 makes it a good candidate for long term accumulation studies. Production Reactions Several routes for production and subsequent separation of bromine-77 have been worked out. The most commonly used reactions are the protons on selenium reaction and the alpha on arsenic reaction. The production reactions for bromine-77 are listed in the table below. Table 5. Nuclear Reaction
Useful Energy Range (MeV)
%Natural Abundance
References
77
Se(p,n)77Br
10-20
7.7
Janssen et al., 1980
78
Se(p,2n)77Br
20-30
23.6
Janssen et al., 1980
75
20-30
100
Nozakiefa/., 1979b
As(4He,2n)77Br
80
Se(p,4n)77Br
49.9
82
Se(p,6n)77Br
8.9
79
Br(p,3n)77Kr:77Br
35-50
50.7
Qaim et al., 1977; Sakamoto et al, 1985
79
Br(d,4n)77Kr : 77Br
25-40
50.7
Qaim et al., 1977
The yields from the proton on selenium reaction are higher than those from the alpha on arsenic reaction although the energy of the alpha reaction can be "tuned" to give a bromine-77 with very small impurities of bromine-76.
HANDBOOK OF RADIOPHARMACEUTICALS
16 Targetry
Various target substances have been used for the production of bromine-77. All the elemental substances are rather volatile and considerable efforts must be undertaken to maintain their stability during irradiation. For the protons on selenium reactions, the first substance was elemental selenium. If natural selenium is used, there will be a trade off between the yield of Br-77 and the level of Br-76 and Br-82 impurities. In the case of elemental selenium, the beams often spread over a large area in order to reduce volatilization of the target material and loss of the radiobromine. A typical target holder for this type of target is shown in Figure 4.
c=*--=
?5'
*— 2.0' — -|
:
I
w
'
1
ft
1 - 1.0'
» \r- 7/9\
^^^ i ~~
'"
\
1
\
I
5/8'
Figure 4. Typical inclined plane target for the irradiation of low-melting materials in an external cyclotron beam Oxides or compounds are often used to reduce the loss of material from the targets. For selenium targets, copper selenide, lead selenide, aluminum selenide, and a mixture of oxides (SeO2-B2O3-Na2O) have been used in targets (Nozaki et al., 1979b). In a similar fashion, the arsenic targets can be prepared from the elemental arsenic (Nunn, 1972), but more often a compound of arsenic is used such as As2O3 and Cu-As alloys to increase the maximum beam current which may be put on target (Nunn & Waters, 1975). Of course the yield is reduced by the fraction of the adulterating material in the matrix. One common method to help dissipate the heat from the irradiation is to use a grooved target. The target material (often the oxides) is pressed into the grooves under high pressure to give good contact between the target material and the backing plate (Nunn & Waters, 1975). Elemental arsenic targets can be prepared by a sublimation technique (Nunn, 1972). Another approach which is used for bromine-77 is to make the krypton-77 which will then decay to Br-77. Since the radioisotopes of krypton can be easily distilled from the target matrix and allowed to decay in isolation, the bromine-77 which is made in this manner is usually of higher isotopic purity than the bromine made from the direct reaction (De Jong et al., 1979; Nozaki et al., 1979b).
17
PRODUCTION OF RADIONUCLIDES IN ACCELERATORS Radioisotope Separation
There have been three methods used to separate the radiobromine from the target matrix. The first is distillation from solution, the second is volatilization by melting of the target (dry distillation) and the third is co-precipitation with AgCl followed by dissolution of the precipitate in ammonium hydroxide and removal of cations by ion exchange. The best method seems to be dry distillation as has been used on the radioiodines, Iodine- 120g Iodine- 120g decays with a half-life of 1.35 hours and about 39% positron emission. The beta energy is quite high (4.0 MeV). Despite these limitations, it has been used in PET in certain applications (Herzog et al., 1999). Production Reactions The production reactions for I-120g are shown in the table. Table 6. Nuclear Reaction
Useful Energy Range (MeV)
%Natural Abundance
References
127
l(p,8n)120Xe:120gI
E>65
100
Butement & Qaim, 1965
Te(p,3n)120gI
32 to 38
0.095
Zweitetal., 1995
15 to 25
4.8
Hohn et al., 2000
!22
120
Te(p,n)120«I
Targetry The targetry for this reaction consists of a titanium foil with electro-deposited tellurium on the foil. The foil is irradiated and then dissolved.
Radioisotope Separation Methods of separation will be the same as for other isotopes of iodine separated from tellurium targets (see I123 section).
Iodine-121 Iodine-121 is an isotope of iodine with a 2.12 hour half-life which decays with 94% electron capture and 6% positron emission. There is a prominent gamma ray at 212.2 kev which can be used in gamma camera images. It decays to Te-121 which has a long half-life and decays with the same 212.2 keV gamma ray. This limits the usefulness of the isotope relative to the other radioisotopes of iodine which are available.
18
HANDBOOK OF RADIOPHARMACEUTICALS
Production Reactions The only practical method of production is from the 122Te(p,2n)l2!I nuclear reaction on highly enriched tellurium-122 (Butement & Qaim, 1965). Targetry The targetry is identical to targets described previously for the production of other radioisotopes of iodine from tellurium targets. Radioisotope Separation The separation of 1-121 is accomplished in the same way as described for 1-123. Iodine-123 Probably the most widely used cyclotron produced radiohalogen is 1-123. It has gradually replaced 1-131 as the isotope of choice for diagnostic radiopharmaceuticals containing radioiodine. It gives a much lower radiation dose to the patient and the gamma ray energy of 159 keV is ideally suited for use in a gamma camera. The gamma ray will penetrate tissue very effectively without excessive radiation dose. For this reason, it has in many instances replaced the reactor produced iodine-131 (Lambrecht et al., 1972a; Lambrecht & Wolf, 1973). A great number of radiopharmaceuticals have been labeled using 1-123 and the number is increasing. Production Reactions The major reactions for the production of iodine-123 are given in the following table. As can be seen from this table there are two major routes to 1-123. The first is the direct route and the second is through the Xenon-123 precursor. The advantage of going through the Xe-123 is that the xenon can be separated from the original target material and allowed to decay in isolation which gives an 1-123 with very little contamination from other radioisotopes of iodine.
PRODUCTION OF RADIONUCLIDES IN ACCELERATORS
19
Table 7. References
(MeV)
%Natural Abundance
I
55 +
100
Adilbish et al, 1980; Cuninghame et al., 1976; Jungerman & LagunasSolar, 1981; Zaitseva et al., 1991. Lagunas-Solar et al., 1986
I
83
100
Weinreich et al., 1976
14 to 8
2.4
Zaidi et al., 1983
123
Te(p,n)123I
15 to 8
0.87
Barrall et al., 1981
!24
Te(p,2n)123I
26 to 20
4.6
Dahl & Tilbury, 1972; Clem & Lambrecht, 1991; Hupf et al., 1968
Useful Energy Range
Nuclear Reaction
!27
I(P,5n)123Xe :
127
!22
I(d,6n)123Xe :
123
123
Te(d,n)!23I
122
Te(4He,3n)123Xe:!23I
124
Xe(P,pn)123Xe :
1972b;
15 to 30
0.10
Graham et al,, 1985; Witsenboer et al., 1986; Firouzbakht et al., 1987; Tarkanyi et al., 1991; Kurenkov et al., 1989
Sb(4He,2n)!23I
15 to 25
57.4
Watson et al., 1973
Sb(3He,3n)!23I
20 to 30
42.6
Watson et al., 1973
121
123
123
Lambrecht & Wolf, Silvester et al., 1969
I
The most common reaction for the production of I-123 in the recent past has been the 124Te(p,2n)123I reaction on highly enriched Te-124. The high enrichment is necessary since there is a second source of I-124 contamination and this comes from the 125Te(P,2n)124I nuclear reaction on any Te-125 which may be present in the target material (Guillaume et al., 1975; Kondo et al., 1977b). The reaction on tellurium has been gradually replaced by the 124Xe(p,pn)123Xe : 123I reaction since this gives 1-123 with greatly reduced 1-124 contamination. The dose to the patient is therefore reduced and the image is somewhat clearer. As an example of how the impurity level can be calculated, the following equation can be written which allows calculation at any energy as long as the relevant cross sections are known (Barrall et al., 1981). The percentage of I-124 in I-123 is given by:
h
