Radioisotopes in Diagnostics and Therapy Ulli Kster, Jean-Franois - - PowerPoint PPT Presentation

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Radioisotopes in Diagnostics and Therapy Ulli Kster, Jean-Franois - - PowerPoint PPT Presentation

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Summary of Session 2: Radioisotopes in Diagnostics and Therapy Ulli

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SLIDE 1

Summary of Session 2:

Radioisotopes in Diagnostics and Therapy

Ulli Köster, Jean-François Chatal 29 February 2012



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SLIDE 2
  • M. de Jong, O. Ratib, D. Thers, S. Ziegler
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SLIDE 3
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SLIDE 4

Don’t forget the fuel!

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SLIDE 5

Radioisotopes: the “fuel” for nuclear medicine

  • 1. What is the optimum fuel for an application ?
  • 2. Are we using today the optimum fuel ?
  • 3. Is there sufficient supply of fuel

at reasonable cost?

  • 4. How reliable is the fuel supply ?
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SLIDE 6

The quest for the optimum isotope

N Z

Over 3000 radioisotopes known:

  • half-life
  • decay properties
  • chemical properties
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SLIDE 7

PET isotopes

Radio- nuclide Half- life (h) Branching ratio + (%) E mean (MeV) Range (mm) F-18 1.83 96.7 0.25 0.7 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 Ga-68 1.13 89.1 0.83 3.8 Rb-82 0.02 95.4 3.38 20 Sc-44 3.97 94.3 0.63 2.5

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SLIDE 8

PET isotopes

Radio- nuclide Half- life (h) Branching ratio + (%) E mean (MeV) Range (mm) F-18 1.83 96.7 0.25 0.7 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 Ga-68 1.13 89.1 0.83 3.8 Rb-82 0.02 95.4 3.38 20 Sc-44 3.97 94.3 0.63 2.5

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SLIDE 9

Diagnostic Accuracy: PET vs SPECT

Bateman et al, J Nucl Cardiol 2006 Bateman et al, J Nucl Cardiol 2006

81 66 76 86 100 91 20 40 60 80 100 Sensitivity Specificity Accuracy SPECT PET

* * *p<0.001

p<0.001

%

#64: D. Le Guludec

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SLIDE 10

PET isotopes

Radio- nuclide Half- life (h) Branching ratio + (%) E mean (MeV) Range (mm) F-18 1.83 96.7 0.25 0.7 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 Ga-68 1.13 89.1 0.83 3.8 Rb-82 0.02 95.4 3.38 20 Sc-44 3.97 94.3 0.63 2.5

Mother isotope: 271 d 25 d 60 y

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SLIDE 11

Transport of short Transport of short-

  • lived radioisotopes

lived radioisotopes

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SLIDE 12

Small cyclotrons

#340: D. Lewis

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SLIDE 13

Longer-lived PET isotopes

Radio- nuclide Half- life (h) Branching ratio + (%) 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 Y-86 14.7 31.9 0.66 2.6 Zr-89 78.4 22.7 0.40 1.4 I-124 100.2 22.8 0.82 3.8 Tb-152 17.5 17 1.08 5

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SLIDE 14

Nanoparticle PET-CT Imaging of Macrophages in Inflammatory Atherosclerosis

Nahrendorf M et al, Circulation 2008, 117(3) 379-387

64Cu-TNP

#64: D. Le Guludec

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SLIDE 15

Longer-lived PET isotopes

Radio- nuclide Half- life (h) Branching ratio + (%) Branching ratio  (%) h10 (mSv/h/GBq) Sc-44 3.97 94.3 101 0.324 Cu-64 12.7 17.6 0.5 0.03 Y-86 14.7 31.9 320 0.515 Zr-89 78.4 22.7 100 0.182 I-124 100.2 22.8 99 0.17 Tb-152 17.5 17 142

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SLIDE 16

Longer-lived PET isotopes

Radio- nuclide Half- life (h) Branching ratio + (%) Branching ratio  (%) h10 (mSv/h/GBq) Sc-44 3.97 94.3 101 0.324 Cu-64 12.7 17.6 0.5 0.03 Y-86 14.7 31.9 320 0.515 Zr-89 78.4 22.7 100 0.182 I-124 100.2 22.8 99 0.17 Tb-152 17.5 17 142

44Sc production: #275 F. Haddad, #268 M. Bunka, #276 E. Garrido

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SLIDE 17

Scandium-44: image reconstruction

F-18 AC Sc-44 NAC

Sc-44 AC/BG-SUB 0.9 Sc-44 AC/BG-SUB 1.3

Sc-44 NAC Sc-44 BG-SUB

T air W

Sc-44 AC/BG-SUB 0.5 Sc-44 AC/BG-SUB 1.7

#339: M. Miederer

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SLIDE 18

3-photon-cameras

#168: D. Thers

20 10 x106

x [mm]

0.2 0.4 0.6

  • 0.2
  • 0.4
  • 0.6

30

0.4 0.2

  • 0.2
  • 0.4
  • 0.6

0.6

z [mm]

#82: C. Lang

Applications:

34mCl 44Sc 52mMn 86Y 94(m)Tc 124I 152Tb

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SLIDE 19

SPECT isotopes

Radio- nuclide Half-life (h) Eγ γ γ γ (keV) Branching ratio γ γ γ γ (%) Decay type Ga-67 78 93 42 EC Kr-81m 0.004 190 64 IT Tc-99m 6 141 89 IT In-111 67 171 245 90 94 EC I-123 13 159 83 EC Xe-133 126 81 38 β- Tl-201 73 69-82 59 EC Lu-177 161 113 208 6.2 10.4 β β β β- Additional SPECT tracers needed for preclinical studies and for tracing specific elements (e.g. 155Tb, 195mPt).

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SLIDE 20

Imaging Studies Using PET and SPECT

KB Tumor-Bearing Nude Mice

152Tb-folate: 9 MBq

Scan Start: 24 h p.i. Scan Time: 4 h

155Tb-folate: 4 MBq

Scan Start: 24 h p.i. Scan Time: 1 h

161Tb-folate: 30 MBq

Scan Start: 24 h p.i. Scan Time: 20 min

PET SPECT SPECT #177: C. Müller

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SLIDE 21

Immunology approach

Roelf Valkema, EANM-2008. Target (antigen) Antibody

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SLIDE 22

Targeted radionuclide therapy

Roelf Valkema, EANM-2008.

Immunology Structural biology Coordination chemistry Nuclear physics and radiochemistry

Target Receptor Radionuclide Linker Peptide, antibody, etc.

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SLIDE 23
  • M. Zalutsky
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SLIDE 24
  • M. Zalutsky
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SLIDE 25

Potential therapy isotopes ?

“In-cell heavy ion accelerator”: 2 fission products per decay 2 x 100 MeV deposited over 25 µ µ µ µm LET 4000 keV/µ µ µ µm on average 38 keV average beta energy plus 1.6/decay conv. elect. 28-53 keV plus many Auger electrons <7 keV 33/decay Auger electrons

M.T. Azure et al., AAPM Symp. 8 (1992) 336. J.D. Willins, G. Sgouros, JNM 36 (1995) 315. production: #207 M.M. Günther, #319 U. Köster

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SLIDE 26

Some interesting isotopes just cannot be produced well.

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SLIDE 27
  • M. Zalutsky
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SLIDE 28
  • M. Zalutsky

More on alpha therapy: #301 F. Davodeau #294 I. Kelson

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SLIDE 29

Targeted Alpha Radionuclide Therapy

KB Tumor-Bearing Mice Treated with 149Tb-Folate

A: control B: treated

32 d < 56 d

control

149Tb-folate

X X

  • therapy

α

#177: C. Müller

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SLIDE 30

Folic acid

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SLIDE 31

Targeted Beta Radionuclide Therapy

KB Tumor-Bearing Mice Treated with 161Tb-Folate

C: control D: treated

28 d < ? d

  • therapy

control

161Tb-folate

X X X X

β

#177: C. Müller

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SLIDE 32

Radionuclides for RIT and PRRT

Radio- nuclide Half- life E mean (keV) E (B.R.) (keV) Range

Y-90

64 h 934 

  • 12 mm

I-131

8 days 182  364 (82%)

3 mm Lu-177

7 days 134  208 (10%) 113 (6%)

2 mm Tb-161

7 days 154  5, 17, 40 e- 75 (10%)

2 mm 1-30 m Tb-149

4.1 h 3967  165,..

25 m Ge-71

11 days 8 e-

  • 1.7 m

Er-165

10.3 h 5.3 e-

  • 0.6 m

localized cross-fire Modern, better targeted bioconjugates require shorter-range radiation     need for adequate (R&D) radioisotope supply.

Estab- lished isotopes Emerging isotopes R&D isotopes: supply- limited!

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SLIDE 33

LET of Auger electrons

A.I. Kassis, Rad. Prot. Dosimetry 143 (2011) 241.

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SLIDE 34

Micro-Injections of 71Ge

Injected volume is 0.05 to 0.3 pL #338: M. Jensen

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SLIDE 35

Nucleus and cytoplasm

Injected volume monitored by Quantum Dots (red) #338: M. Jensen

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SLIDE 36

Radioisotopes: the “fuel” for nuclear medicine

  • 1. What is the optimum fuel for an application ?
  • 2. Are we using today the optimum fuel ?
  • 3. Is there sufficient supply of fuel

at reasonable cost?

  • 4. How reliable is the fuel supply ?
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SLIDE 37
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SLIDE 38

The traditional supply chain of 99Mo/99mTc

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SLIDE 39

L'OCDE s'inquiète des risques de pénurie d'isotopes médicaux

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SLIDE 40

53% demand 23% demand 20% demand

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SLIDE 41

Back to the roots ? Original discovery of Tc in cyclotron-irradiated Mo !

  • C. Perrier, E. Segrè, J. Chem. Phys. 5 (1937) 712.
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SLIDE 42

Sourcing of enriched 98Mo

Non-fission production of 99Mo needs often large quantities of enriched Mo (1 kg 98Mo vs. 4 g 235U). boiling point: UF6 56 ° ° ° °C MoF6 34 ° ° ° °C Cost of enriched 98Mo or 100Mo: few hundred USD per gram for large quantities (kg). Joint production of 98Mo and 100Mo more cost-effective.

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SLIDE 43

Other suppliers?

Natanz, Iran

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SLIDE 44

The producing reactor gets only 0.26 EUR per 99mTc patient dose, similar to the price of a single cheap pill.

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SLIDE 45

Evolution of 82Sr demand in the USA

(source : Department

  • f Energy, USA)

82Rb is used for PET in cardiology

    82Sr/82Rb generator Le Guludec (Paris) - PET-CT in cardio-vascular diseases #275: F. Haddad

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SLIDE 46

Facilities producing Sr-82 in the world

  • LANL, USA –100 MeV, 200µA
  • BNL, USA –200 MeV, 100µA
  • INR, Russia –160 MeV, 120µA
  • iThemba, South Africa –66 MeV, 250µA
  • TRIUMF, Canada –110 MeV, 70 µA

BLIP

5 accelerators – 2 generator manufacturers – 1 generator Mar - Jul 2011:

  • utage of 2 accelerators > 82Sr shortage

Jul ‘11-Feb ‘12: generator recalled

#275: F. Haddad

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SLIDE 47

Problem: Concentration on few players

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SLIDE 48

New players

#275: F. Haddad

Upcoming: 70 MeV cyclotron in Legnaro Two new 82Sr/82Rb generators (Draximage, Quanticardi)

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SLIDE 49

R&D isotopes

149Tb-therapy 152Tb-PET 155Tb-SPECT 161Tb-therapy

& SPECT #177: C. Müller

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SLIDE 50

#146: T. Stora

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SLIDE 51

#146: T. Stora

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SLIDE 52

#220: D. Pauwels

Also possible at: TRIUMF, PSI, ISIS, SNS, LANL, J-PARC, ESS, EURISOL,…

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SLIDE 53

Irradiation Cooling Dissolution Filtering Iodine removal Acidifying

99Mo

separation

99Mo

purification QC, calibration, distribution Intermediate (ILW) and low level liquid waste (LLW) Off-gas treatment Xenon decay Ventilation Precipitate (U, TU, RE, EA, Te, Zr, Nb, etc.) High level solid waste

Extraction of fission-moly

133Xe 131I

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SLIDE 54

Supply issues ?

1.

131I is coproduced with 99Mo by 235U fission

about 1000 kCi 131I producible per year corresponding to about 5 million doses (100 mCi) exceeds demand by far [additional dedicated production via 130Te(n, 131I]

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SLIDE 55

Fission waste recycling with the Purex process

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SLIDE 56

Supply issues ?

1.

131I is coproduced with 99Mo by 235U fission

about 1000 kCi 131I producible per year corresponding to about 5 million doses (100 mCi) exceeds demand by far [additional dedicated production via 130Te(n, 131I] 2.

90Y is obtained from 90Sr/90Y generators

EDF reactors produce 1.4 tons of 90Sr per year corresponding to 200 MCi 90Sr from these 10 GCi of 90Y can be eluted per year, enough to supply one 90Y dose (100 mCi) per year for every human!

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SLIDE 57

1990 1995 2000 2005 2010 10 20 30 40 50

90Y 177Lu

Pub Med Therapeutic Studies

Year

177Lu low energy beta-emitter for therapy

 moderate β--energy

  • low

side effects

  • safe handling

 imageable γ-rays

  • dosimetry
  • therapy control

Lu 177

6.647d β β β β - 160.1 d β β β β -

Hf 177 18.60

#270: K. Zhernosekov

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SLIDE 58

The rising star for therapy

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SLIDE 59

Lu 176 2.59

 3 + 2070

Lu 175 97.41

 8

Yb 176 12.7

 3

Lu 177

6.647d β β β β -

Yb 177 1.9 h

β

160.1 d β β β β -

Yb 175 4.2 d

β

Yb 174 31.8

 68

Hf 177 18.60 Hf 176 5.206

specific activity 20 – 30 Ci/mg (vs. theoretical 110 Ci/mg)

  • nly 25 % of hot 177Lu atoms

75% of cold 175/176Lu atoms

176Lu(n,γ)177Lu

“Carrier-added” c.a. 177Lu

long-lived radioactive impurities: ∼0.01 % of 177mLu waste management; environment exposure #270: K. Zhernosekov

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SLIDE 60

Lu 176 2.59

 3 + 2070

Lu 175 97.41

 8

Yb 176 12.7

 3

Lu 177

6.647d β β β β -

Yb 177 1.9 h

β

160.1 d β β β β -

Yb 175 4.2 d

β

Yb 174 31.8

 68

Hf 177 18.60 Hf 176 5.206

176Yb(n,γ)177Yb  177Lu

“No -carrier-added” n.c.a. 177Lu

highest specific activity > 100 Ci/mg (vs. theoretical 110 Ci/mg) and highest radionuclide purity Yb-target must be quantitatively removed by chemical separtion #270: K. Zhernosekov

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SLIDE 61

2 4 6 8 10 12 14 25 50 75 100 25 50 75 100

Sth = 110 Ci/mg S1/2 = 92 Ci/mg S

1/2 = 16 Ci/mg

Specific Activity [Ci/mg] Days

Shelf-life/ c.a. vs n.c.a. 177Lu

#270: K. Zhernosekov

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SLIDE 62

Physical quantity describing the activity per mass (GBq/mg, Ci/mg), basically the ratio of radioactive atoms to all atoms (including stable ones).

Specific activity

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SLIDE 63

Carrier added vs. non-carrier added

ca

nca

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SLIDE 64

Saturation of selective receptors per cell

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SLIDE 65

SPECT/CT day 1 p.t. Lu-octreotate

NCA 177Lu-octreotate, 2 µg

  • Conv. 177Lu-octreotate, 11 µg

adrenals adrenals tumour tumour

  • M. de Jong
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SLIDE 66

Tumour uptake, based on SPECT quantification

Clearance rate was similar: 67

  • 10 vs. 72
  • 12 h

NCA 177Lu-octreotate: ~2x higher tumour uptake     70 vs. 35 Gy tumour dose

  • M. de Jong
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SLIDE 67

Pumping: power 120 – 130W,  = 510nm, f = 10kHz,  = 20ns.

Output of the system: 3 g/ year Final isotope content:

  • Yb – 168 – 20.21% (only 0.14 % in natural

Yb)

  • Yb – 170 – 2.36%
  • Yb – 171 – 18.38%
  • Yb – 172 – 15.45%
  • Yb – 173 – 12.1%
  • Yb – 175 – 22.38%
  • Yb – 176 – 9.12%

Channel Wavelength, nm Dye Power, W Spectr.band, MHz Pulse width, ns 1 555 R110 5 500 15 2 581 R6G 5 500 15 3 582 R6G 20 3104 20

Parameters of 3 Parameters of 3-

  • Channel Dye

Channel Dye -

  • Laser System

Laser System for AVLIS of Ytterbium for AVLIS of Ytterbium #157: S. Akulinichev

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SLIDE 68



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SLIDE 69



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SLIDE 70

The history of lutetium separation

1878 Separation of Yb in Geneva by Jean-Charles Galissard de Marignac 1907 Separation of Lu from Yb Georges Urbain Carl Auer von Welsbach Charles James 1995- Large-scale separation of Lu for production of LSO crystals by Mark Andreaco (CTI) and George Schweitzer (Univ. Tennessee) 2007 Rapid large-scale separation

  • f n.c.a. 177Lu from irradiated Yb

by ITG Garching

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SLIDE 71

Outlook

The ideal agent for cancer therapy would consist of heavy elements capable of emitting radiations of molecular dimensions, which could be administered to the organism and selectively fixed in the protoplasm of cells one seeks to destroy. While this is perhaps not impossible to achieve, the attempts so far have been unsuccessful.

  • C. Regaud, A. Lacassagne, Radiophysiologie et Radiotherapie 1 (1927) 95.

Translation : A.I. Kassis, Int. J. Radiat. Biol. 80 (2004) 789.

Today we are closer than ever to reach this goal !