Nuclear Physics for Medicine (Nuclear Physics European Collaboration Committee - NuPECC)

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?

310-5 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.”