Chapter III: Radioisotope Production Marie-Claire Cantone, Italy – convener Ferid Haddad, France Sotirios Harissopoulos, Greece Mikael Jensen, Denmark Ari Jokinen, Finland – NuPECC liaison Itzhak Kelson, Israel Ulli Köster, France – convener Ondrej Lebeda, Czech Republic Bernard Ponsard, Belgium Uli Ratzinger, Germany Thierry Stora, Switzerland Ferenc Tarkanyi, Hungary Piet Van Duppen, Belgium – NuPECC liaison
Chapter III: Radioisotope Production Valuable Input from: Paul Beasley (Siemens Healthcare) JosĂŠ Benlliure (Univ. Santiago) David Brasse (IPHC Strasbourg) Marc Garland (Department of Energy) Jean-Michel Geets (IBA Louvain-la-Neuve) Tom Ruth (TRIUMF Vancouver) Lucia Sarchiapone (LNL Legnaro) Paul Schaffer (TRIUMF Vancouver) Peter Thirolf (LMU Munich) Nick van der Meulen (PSI Villigen) Eric Van Lier (ACSI Richmond) Etienne Vermeulen (iThemba labs)
Don’t forget the fuel!
Chapter III: Radioisotope Production Introduction 1. Properties of radioisotopes for nuclear medicine
2. Production methods and facilities
3. Examples and specific topics 50000
40000
30000
20000
production (for generator)
235U(n ,f) th 238U(n fast,f) 238U(,f)
Other 111In 67Ga 123I 131I 201Tl 99mTc PET
direct 99mTc production
2013: 99Mo production capacity and demand
100Mo(p,2n) natMo(,x)
Europe
238U(p,f) 98Mo(d,n) 98Mo(n,) natMo(n,)
USA+CAN
Japan
99Ru(n,p)
100Mo(d,p) 100Mo(n,2n) 100Mo(p,np)
10000
96Zr(,n)
EUR JP CA US
0
AT BE BG CH CY CZ DE DK EE ES FI FR GR HR HU IE IS IT LT LU LV MD ME MK MT NL NO PL PT RO RS SE SI SK UA UK
Procedures per million inhabitants and year
99Mo
102Ru(n,)
Other
The nuclear medicine alphabet 500x
gamma rays
5x
cancer cells
SPECT camera
tumor
alpha rays chromosome
beta rays
50000x
Auger electrons
Ideal gamma ray energy for SPECT
Detectectab le fraction (%)
20%
15%
10%
5%
0% 0
100
200 300 400 Photon energy (keV)
500
600
SPECT isotopes Radionuclide
Half-life (h)
E (keV)
I (%)
78
93 185
42 21
EC
Kr-81m
0.004
190
64
IT
Tc-99m
6
141
89
IT
In-111
67
171 245
91 94
EC
I-123
13
159
83
EC
Xe-133
126
81
38
-
Tl-201
73
70 167
59 10
EC
I-131
192
364
82
-
Lu-177
161
113 208
6 10
-
Ga-67
Decay type
Even-Sapir E et al., J Nucl Med 2006; 47: 287. 99mTc-MDP
planar
99mTc-MDP
SPECT
18F-
PET
PET isotopes Halflife (h)
Intensity β+ (%)
E mean (MeV)
Range (mm)
C-11
0.34
99.8
0.39
1.3
N-13
0.17
99.8
0.49
1.8
O-15
0.03
99.9
0.74
3.2
F-18
1.83
96.7
0.25
0.7
Ga-68
1.13
89.1
0.83
3.8
Rb-82
0.02
95.4
3.38
20
Radionuclide
Longer-lived PET isotopes Radionuclide
Half-life (h)
Intensity β+ (%)
E mean (MeV)
Range (mm)
Sc-44
3.97
94.3
0.63
2.5
Cu-64
12.7
17.6
0.28
0.8
Br-76
16.2
55
1.18
6
Y-86
14.7
31.9
0.66
2.6
Zr-89
78.4
22.7
0.40
1.4
I-124
100
22.8
0.82
3.8
Radionuclide Cl-34m Sc-44 Mn-52
Y-86
Halflife (h) 0.53 3.97 134
14.7
B.R. β+ E mean Range (%) (MeV) (mm) 54.3 0.84 3.9 94.3 0.63 2.5 29.6
31.9
0.24
0.66
E Intensity (keV) 2127
43
1157
100
0.7
744 936 1434
91 95 100
2.6
628 1077 1153
33 83 31
703 850 871
100 96 100
871
94
603
61
Tc-94
4.9
10.5
0.36
1.1
Tc-94m I-124
0.87 100
70.2 22.8
1.07 0.82
5.2 3.8
Isotopes for 3-photon-cameras Radionuclide Cl-34m Sc-44 Mn-52
Y-86
Halflife (h) 0.53 3.97 134
14.7
B.R. β+ E mean Range (%) (MeV) (mm) 54.3 0.84 3.9 94.3 0.63 2.5 29.6
31.9
0.24
0.66
E Intensity (keV) 2127
43
1157
100
0.7
744 936 1434
91 95 100
2.6
628 1077 1153
33 83 31
703 850 871
100 96 100
871
94
603
61
Tc-94
4.9
10.5
0.36
1.1
Tc-94m I-124
0.87 100
70.2 22.8
1.07 0.82
5.2 3.8
What about PET with a ď ˘- emitter?
Th. Carlier et al., EJNMMI Research 2013;3:11
What about PET with a - emitter?
310-5 e+e-
The nuclear medicine alphabet 500x
gamma rays
5x
cancer cells
SPECT camera
tumor
alpha rays chromosome
beta rays
50000x
Auger electrons
Beta therapy isotopes Radionuclide P-32 Sr-89
HalfEβ Range Eβ Range E life mean mean max max (d) (MeV) (mm) (MeV) (mm) (keV) 14.3 0.7 3 1.71 9.1 50.6 0.59 2.3 1.5 7.8
Y-90
2.67
0.93
4.4
2.28
12
I (%) -
284 364 637
6.1 81.5 7.2
103
29.3
81
6.6
113 208
6.2 10.4
I-131
8.03
0.18
0.39
0.81
3.7
Sm-153 Ho-166
1.94 1.12
0.22 0.67
0.55 2.8
0.81 1.85
3.7 10
Lu-177
6.65
0.13
0.23
0.50
1.9
Er-169 Re-186
9.39 3.72
0.10 0.35
0.14 1.1
0.35 1.07
1.1 5.2
137
9.5
Re-188
0.71
0.76
3.3
2.12
12
155
15.6
-
Alpha therapy isotopes
Radionuclide
Halflife
Tb-149
4.1 h
Pb-212
10.6 h
Bi-212 Po-212
Bi-212
1.01 h
Bi-213
At-211 Ra-223
Ra-224
Ac-225
Th-227
Daughters
Halflife
Cumulative E mean Range /decay (MeV) (m) 0.17
3.97
25
1.01 h 0.3 s
1
7.74
65
Po-212
0.3 s
1
7.74
65
0.76 h
Po-213
4 s
1
8.34
75
7.2 h
Po-211
0.5 s
1
6.78
55
11.4 d
Rn-219 Po-215 Pb-211 Bi-211
4s 1.8 ms 0.6 h 130 s
4
6.59
>50
3.66 d
Rn-220 Po-216 Pb-212 Bi-212
56 s 0.15 s 10.6 h 1.01 h
4
6.62
>50
10.0 d
Fr-221 At-217 Bi-213 Po-213
294 s 32 ms 0.76 h 4 s
4
6.88
>50
Ra-223 Rn-219 Po-215 Pb-211
11.4 d 4s 1.8 ms 0.6 h
5
6.45
>50
18.7 d
Metabolic targeting Thyroid cancer 123I- for imaging 131I- for therapy
Bone metastases 1.5 million patients world-wide 99mTc-MDP
for SPECT imaging 18F- for PET imaging Therapy 153Sm-EDTMP (Quadramet) 89Sr2+ (Metastron) 223Ra2+ (Xofigo)
Receptor Targeted Therapies
Target
Peptide, antibody, vitamin,‌
Linker
Receptor
Immunology Structural biology
Radionuclide
Coordination chemistry
Nuclear physics and radiochemistry
Roelf Valkema, EANM-2008.
1,4,7,10-tetraazacyclododecantetraacetate
Helmut Maecke, EANM-2007.
2. Radioisotope Production
H218O water (liquid target)
176Yb
2 O3
(powder in quartz ampoule & Al capsule)
Cyclotron irradiation 18O(p,n)18F
Transformation into FDG
produces [18F]fluoride
by automated synthesis modules in shielded hot cell
Reactor irradiation 176Yb(n,ď §)177Yb(ď ˘-)177Lu
Radiochemical separation of Lu from Yb
produces [177Lu/176Yb]oxide
in shielded hot cells
Radioisotope production in nuclear reactors Thermal flux Power (MW) (1014 cm-2 s -1) HFIR ORNL Oak Ridge, USA 25 85 BOR-60 SSC RIAR Dimitrovgrad, Russia 20 (fast) 60 SM-3 SSC RIAR Dimitrovgrad, Russia 19 100 RHF ILL Grenoble, France 15 58 BR2 SCK-CEN Mol, Belgium 10 (tank), 3.6 (pool) 100 HFR NRG Petten, Netherlands 4.5 45 MURR Univ. Missouri Columbia, USA 4.5 10 HANARO KAERI Daejeon, South Korea 4 30 SAFARI NECSA Pelindaba, South Africa 4 20 NRU AECL Chalk River, Canada 4 135 FRM2 TUM Garching, Bavaria 4 (fast), 1.3 (th.) 20 OSIRIS CEA Saclay Saclay, France 2.7 70 OPAL ANSTO Lucas Heights, Australia 2.5 20 Maria Polatom Świerk-Otwock, Poland 2.5 30 RA-3 CNEA Ezeiza, Argentina 2.4 10 BRR KFKI Budapest, Hungary 1.7 10 LVR-15 NRI Řež, Czech Republic 1.4 10 Research Laboratory reactor
Location
188W 188Re
production by 186W(2n,ď §)
is eluted from a long-lived 188W generator.
Achievable
188W
activity ď‚ľ F ! 2
Cyclotrons: the work horses
Number of Cyclotrons
500 400 300
200 100 0 0-10
11-13
14-20
20-30
30-60
>60
Energy Range (MeV)
11 MeV
18 MeV
30 MeV
70 MeV
Alternative Accelerators
LINACs for deuterons and heavier ions
Laser accelerated ions
Targetry
Pressed RbCl pellet
Encapsulated RbCl pellet
69 MeV protons
RbCl in stainless steel capsule
Ga in Nb capsule
3. Examples and specific topics 3.1. Examples of success of nuclear medicine applications 3.2. Statistics of radionuclide use in Europe: evolution & trends 3.3. 99mTc supply issues: reactor vs cyclotron 3.4. Dosimetry 3.5. Theranostics 3.6. 177Lu, a showcase for nuclear physics and radiochemistry 3.7. Synergies of nuclear medicine and nuclear physics 3.8. Joint exploitation of research reactors and accelerators for research and radioisotope production 3.9. Examples of spinoffs from nuclear physics laboratories
Roelf Valkema, EANM-2008.
Roelf Valkema, EANM-2008.
Lymphoma therapy: RITUXIMAB+177Lu
F. Forrer et al., J Nucl Med 2013;54:1045.
Radioimmunotherapy of advanced prostate cancer
8 Oct 2010: before RIT
28 Jan 2011: after RIT with 177Lu+J591 Massive reduction of the size of metastases
S.T. Tagawa et al., Clin Cancer Res 2013;19:5182. Cornell Univ., ATLAB Pharma Nantes
223Ra:
Alpharadin/Xofigo
Targeted Radionuclide Therapies Thyroid: 131I-
Lymphoma: Zevalin® (90Y-mab) Bexxar® (131I-mab) 131I/177Lu-mabs (I/II) Bone metastases: Metastron® (90SrCl2) Quadramet® (153Sm-EDTMP) Xofigo® (223RaCl2)
Neuroblastoma: 131I-MIBG Neuroendocrine (GEP-NET): 177Lu-peptides (III) 90Y-peptides
Brain: 90Y-mab ,131I-mab (I/II), 211At-mab (I), 213Bi-pept.(I) Leukemia, myeloma: 90Y-mab, 213Bi-mab (II) 225Ac-mab Medullary Thyroid: 131I-mab (II) 90Y-pept. Breast: 90Y-mab, 90Y-pept. Lung (SCLC): 177Lu-mab (II) Pancreas: 90Y-mab (II)
Ovary: Liver (HCC): 212Pb-mab (I) Theraspheres® & 90Y/177Lu-mab 90 SIRspheres® ( Y) 188Re-Lipiodol (II) Colon & rectum: Prostate: Kidneys (RCC): Melamoma: 166Ho-microspheres 131 177Lu-mab (II) 90Y/177Lu-mab (I) 213Bi-mab(I) I-mab (II)
The chart of nuclides – nuclear medicine perspective
SPECT PET Therapy
201Tl
186,188Re
177Lu
133Xe
153Sm
123I131 111In
I
99m 90 Tc
68Ga 67Ga
18F
11C
89Sr
Y
“exotic” isotopes
50000
40000
30000
20000
Other 111In 67Ga 123I 131I 201Tl 99mTc PET
10000
EUR JP CA US
0
AT BE BG CH CY CZ DE DK EE ES FI FR GR HR HU IE IS IT LT LU LV MD ME MK MT NL NO PL PT RO RS SE SI SK UA UK
Procedures per million inhabitants and year
3.2. Statistics of radionuclide use in Europe
Use of diagnostic isotopes in Europe, USA, Canada and Japan
Cumulative use of diagnostic isotopes in Europe
99mTc 201Tl 131I 123I 67Ga 111In PET Other
Evolution of use of therapeutic isotopes in Switzerland 4000 3500 Activity (GBq)
3000
131I 90Y 177Lu
2500
2000 1500 1000
500 0 1994 1996 1998 2000 2002 2004 2006 2008 2010 Year
Statistics data from: Bernard Aubert (IRSN France) Ursula Bär (Federal Statistical Office, Germany) Dieter Cernohorski (Federal Office of Economics and Export Control, Germany) Panicos Demitriades (Department of Labour Inspection, Cyprus) Andrejs Dreimanis (State Environmental Service, Latvia) Marisa España Lopez (H.U. de la Princesa, Madrid) Cécile Etard (IRSN France) Karlheinz Haug (Bavarian State Office for Environment) Jörg Kotzerke (DGN & TU Dresden, Germany) Leszek Krolicki (Medical Univ. of Poland) Reto Linder (Federal Office of Public Health, Bern, Switzerland) Dietmar Noßke (Federal Office for Radiation Protection, Germany) Sigrid Richter (Bavarian State Office for Environment) Anthony Samuel (Mater Dei Hospital, Malta) Elena Shubina (Environmental Board, Estonia) Damijan Škrk (Slovenian Radiation Protection Administration) Pedro Teles (IST/ITN Portugal) Gertrud Vierkant (Federal Statistical Office, Germany) Stavroula Vogiatzi (Greek Atomic Energy Commission) the State Institute for Drug Control Czech Republic the State Institute of Radiation Protection Denmark the Japan Radioisotope Association Consejo de Seguridad Nuclear (Spain)
3.3. 99mTc supply issues: reactor vs cyclotron
All ways lead to Rome; many ways lead to 99mTc 99Mo
production (for generator)
235U(n ,f) th 238U(n fast,f) 238U(,f)
direct 99mTc production 100Mo(p,2n) natMo(,x)
238U(p,f) 98Mo(d,n) 98Mo(n,) natMo(n,) 100Mo(d,p) 100Mo(n,2n) 100Mo(p,np) 96Zr(,n) 102Ru(n,)
99Ru(n,p)
The economy of the aviation industry and of nuclear medicine 19% “Fuel” sourcing Reactor
5% “Fuel” refinement Mo processing Generator
0.11% (0.26€)
0.67% (1.64€) 0.14% (0.34€)
Transport
Radiopharmacy 3.51% (8.62€) 17% Equipment (amortization, maintenance, leasing, chartering) 31% Personal costs Air France KLM, financial reports 2007-2012
Total 245.61€
OECD-NEA, 2008
2013: 99Mo production capacity and demand
Europe USA+CAN
JP
Other
Circle diameter proportional to annual reactor capacity (blue) and demand (red).
2016: 99Mo production capacity and demand
Europe USA
JP
Other Diameter of circles proportional to annual reactor capacity and demand.
3.4. Theranostics
Effect
Therapeutic effect Side effects
Acceptable side effects Dose
High selectivity is essential to widen the therapeutic window! Therapeutic effect
Paracelsus (1493-1541) “All things are poison and nothing is without poison. Only the dose makes that a thing is not poisonous.� Septem Defensiones 1538, Vol. 2.
Effect
Side effects
Acceptable side effects Dose
Theranostics
Effect
Therapeutic effect Side effects
Acceptable side effects
Dose Accurate dosimetry is essential for optimum use of the therapeutic window.
Effect
Theranostics
Acceptable side effects
Dose Accurate dosimetry is essential for optimum use of the therapeutic window.
Terbium: a unique element for nuclear medicine
Theranostics with terbium isotopes PET
152Tb-folate:
9 MBq Scan Start: 24 h p.i. Scan Time: 4 h
SPECT
155Tb-folate:
4 MBq Scan Start: 24 h p.i. Scan Time: 1 h
SPECT
161Tb-folate:
30 MBq Scan Start: 24 h p.i. Scan Time: 20 min
C. M端ller et al., J. Nucl. Med. 53 (2012) 1951.
3.5. 177Lu, a showcase for nuclear physics and radiochemistry
Waste problem for hospitals! R. Henkelmann et al., Eur. J. Nucl. Med. Mol. Imag. 36 (2009) S260.
Alternative production route to 177Lu
• Free of long-lived isomer • Non-carrier-added quality • “Needs” high-flux reactor
The rising star for therapy
Nuclear cardiology procedures per capita
2007: 8.54M myocardial perfusion SPECT procedures reimbursed in the USA J.V. Vitola et al., J Nucl Cardiol 2009;16:956.
Diagnostic Accuracy: PET vs SPECT * 100
100 81
* 91
86
*p<0.001
76
80 66
%
60
SPECT PET
40 20 0 Sensitivity
Specificity
Accuracy
Bateman et al, J Nucl Cardiol 2006;13:24.
82Sr
and 68Ge production
68Ge 82Sr
Facilities producing 82Sr LANL, USA – 100 MeV, 200 µA BNL, USA – 200 MeV, 100 µA INR, Russia – 160 MeV, 120 µA
TRIUMF, Canada – 110 MeV, 70 µA iThemba, South Africa – 66 MeV, 250 µA
BLIP
New players
Upcoming: 70 MeV cyclotron in Legnaro Two new 82Sr/82Rb generators (Draximage, Quanticardi)
Facilities producing 82Sr LANL, USA – 100 MeV, 200 µA BNL, USA – 200 MeV, 100 µA INR, Russia – 160 MeV, 120 µA
TRIUMF, Canada – 110 MeV, 70 µA iThemba, South Africa – 66 MeV, 250 µA
ARRONAX, France – 70 MeV, < 750 µA SPES, Italy – 70 MeV, < 1000 µA PSI, Switzerland – 70 MeV, < 2500 µA
BLIP
3.8. Examples of spinoffs from NP laboratories CRC Louvain-la-Neuve
Paracelsus (1493-1541) “Many have said of Alchemy, that it is for the making of gold and silver. For me such is not the aim, but to consider only what virtue and power may lie in medicines.” (Edwardes)
500 years later: “Many have said of nuclear physics, that it is for the making of gold and silver (and other elements’) isotopes. For us such is not the only aim, but also to consider what virtue and power may lie in it for medicine.”