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

 Summary of Session 2: Radioisotopes in Diagnostics and Therapy Ulli Köster, Jean-François Chatal 29 February 2012

M. de Jong, O. Ratib, D. Thers, S. Ziegler

Don’t forget the fuel!

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 ?

The quest for the optimum isotope Over 3000 radioisotopes known: • half-life • decay properties • chemical properties Z N

PET isotopes Radio- Half- Branching E mean Range ratio  + (%) nuclide life (h) (MeV) (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

PET isotopes Radio- Half- Branching E mean Range ratio  + (%) nuclide life (h) (MeV) (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

Diagnostic Accuracy: PET vs SPECT * 100 * 100 * p<0.001 91 p<0.001 86 81 76 80 66 60 SPECT % PET 40 20 0 Sensitivity Specificity Accuracy #64: D. Le Guludec Bateman et al, J Nucl Cardiol 2006 Bateman et al, J Nucl Cardiol 2006

PET isotopes Radio- Half- Branching E mean Range ratio  + (%) nuclide life (h) (MeV) (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 Mother isotope: Ga-68 1.13 89.1 0.83 3.8 271 d 25 d Rb-82 0.02 95.4 3.38 20 60 y Sc-44 3.97 94.3 0.63 2.5

Transport of short Transport of short- -lived radioisotopes lived radioisotopes

Small cyclotrons #340: D. Lewis

Longer-lived PET isotopes Radio- Half- Branching E mean Range ratio  + (%) nuclide life (h) (MeV) (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

Nanoparticle PET-CT Imaging of Macrophages in Inflammatory Atherosclerosis 64 Cu-TNP Nahrendorf M et al, Circulation 2008, 117(3) 379-387 #64: D. Le Guludec

Longer-lived PET isotopes Radio- Half- Branching Branching h 10 ratio  + (%) ratio  (%) nuclide life (h) (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

Longer-lived PET isotopes Radio- Half- Branching Branching h 10 ratio  + (%) ratio  (%) nuclide life (h) (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 44 Sc production: #275 F. Haddad, #268 M. Bunka, #276 E. Garrido

Scandium-44: image reconstruction F-18 AC Sc-44 NAC Sc-44 NAC Sc-44 BG-SUB W T air Sc-44 AC/BG-SUB 0.5 Sc-44 AC/BG-SUB 0.9 Sc-44 AC/BG-SUB 1.3 Sc-44 AC/BG-SUB 1.7 #339: M. Miederer

3-photon-cameras x [mm] #82: C. Lang 0.6 0.4 0.2 0 -0.2 -0.4 -0.6 x10 6 30 20 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 10 0 z [mm] Applications: 34m Cl 44 Sc 52m Mn 86 Y 94(m) Tc 124 I 152 Tb #168: D. Thers

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

Imaging Studies Using PET and SPECT KB Tumor-Bearing Nude Mice PET SPECT SPECT 152 Tb-folate: 9 MBq 155 Tb-folate: 4 MBq 161 Tb-folate: 30 MBq Scan Start: 24 h p.i. Scan Start: 24 h p.i. Scan Start: 24 h p.i. Scan Time: 4 h Scan Time: 1 h Scan Time: 20 min #177: C. Müller

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

Targeted radionuclide therapy Peptide, Target antibody, Linker etc. Receptor Radionuclide Immunology Coordination Nuclear physics Structural biology chemistry and radiochemistry Roelf Valkema, EANM-2008.

M. Zalutsky

M. Zalutsky

Potential therapy isotopes ? 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 “In-cell heavy ion accelerator”: 2 fission products per decay 2 x 100 MeV deposited over 25 µ µ m µ µ LET 4000 keV/ µ µ m on average µ µ

Some interesting isotopes just cannot be produced well.

M. Zalutsky

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

Targeted Alpha Radionuclide Therapy KB Tumor-Bearing Mice Treated with 149 Tb-Folate A: control B: treated α - therapy X X 32 d < 56 d 149 Tb-folate control #177: C. Müller

Folic acid

Targeted Beta Radionuclide Therapy KB Tumor-Bearing Mice Treated with 161 Tb-Folate C: control D: treated β - therapy X X X X 28 d < ? d 161 Tb-folate control #177: C. Müller

Radionuclides for RIT and PRRT E  (B.R.) Radio- Half- E mean Range nuclide life (keV) (keV) cross-fire Estab- 934  64 h - Y-90 12 mm lished 182  8 days 364 (82%) I-131 3 mm isotopes 134  7 days 208 (10%) Lu-177 2 mm Emerging 113 (6%) isotopes 154  7 days 75 (10%) Tb-161 2 mm 5, 17, 40 e - 1-30  m R&D 3967  25  m 4.1 h 165,.. Tb-149 isotopes: supply- 1.7  m 8 e - 11 days - Ge-71 limited! 0.6  m 5.3 e - 10.3 h - Er-165 localized Modern, better targeted bioconjugates require shorter-range radiation   need for adequate (R&D) radioisotope supply.  

LET of Auger electrons A.I. Kassis, Rad. Prot. Dosimetry 143 (2011) 241.

Micro-Injections of 71 Ge Injected volume is 0.05 to 0.3 pL #338: M. Jensen

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

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 ?

The traditional supply chain of 99 Mo/ 99m Tc

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

20% demand 53% demand 23% demand

Back to the roots ? Original discovery of Tc in cyclotron-irradiated Mo ! C. Perrier, E. Segrè, J. Chem. Phys. 5 (1937) 712.

Sourcing of enriched 98 Mo Non-fission production of 99 Mo needs often large quantities of enriched Mo (1 kg 98 Mo vs. 4 g 235 U). boiling point: UF 6 56 ° ° C MoF 6 34 ° ° C ° ° ° ° Cost of enriched 98 Mo or 100 Mo: few hundred USD per gram for large quantities (kg). Joint production of 98 Mo and 100 Mo more cost-effective.

Other suppliers? Natanz, Iran

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

82 Rb is used for PET in cardiology   82 Sr/ 82 Rb generator   Le Guludec (Paris) - PET-CT in cardio-vascular diseases Evolution of 82 Sr demand in the USA (source : Department of Energy, USA) #275: F. Haddad

Facilities producing Sr-82 in the world #275: F. Haddad • LANL, USA – 100 MeV, 200µA BLIP • BNL, USA – 200 MeV, 100µA • INR, Russia – 160 MeV, 120µA • iThemba, South Africa – 66 MeV, 250µA • TRIUMF, Canada – 110 MeV, 70 µA 5 accelerators – 2 generator manufacturers – 1 generator outage of 2 accelerators > 82 Sr shortage Mar - Jul 2011: Jul ‘11-Feb ‘12: generator recalled

Problem: Concentration on few players

New players #275: F. Haddad Upcoming: 70 MeV cyclotron in Legnaro Two new 82 Sr/ 82 Rb generators (Draximage, Quanticardi)

R&D isotopes 149 Tb-therapy 152 Tb-PET 161 Tb-therapy 155 Tb-SPECT & SPECT #177: C. Müller

#146: T. Stora

#146: T. Stora

#220: D. Pauwels Also possible at: TRIUMF, PSI, ISIS, SNS, LANL, J-PARC, ESS, EURISOL,…

Extraction of fission-moly Irradiation Ventilation Cooling Off-gas 133 Xe Xenon decay Dissolution treatment Precipitate Filtering (U, TU, RE, EA, Te, Zr, Nb, etc.) 131 I High level Iodine removal solid waste Acidifying QC, 99 Mo 99 Mo calibration, separation purification distribution Intermediate (ILW) and low level liquid waste (LLW)