Requirements for R&D isotopes

Transcription

1 Requirements for R&D isotopes Ulli Köster Institut Laue Langevin, Grenoble 1 The quest for the optimum isotope About 3000 radioisotopes known: half-life chemical element decay properties Z N 2

2 The chart of nuclides nuclear medicine perspective SPECT PET Therapy 111 In 99m Tc 68 Ga Ga Y 89 Sr 123 I 133 Xe 131 I 153 Sm 201 Tl 186,188 Re 177 Lu 18 F 11 C exotic isotopes 3 Radionuclide Halflife (h) PET Tracer Branching ratio β + (%) E mean (MeV) C N O F Cu Ga Rb Zr Range (mm) Some longer-lived (trivalent) PET tracer(s) needed, mainly for preclinical use. 4

3 Radionuclide Half-life (h) SPECT Tracer Eγ (kev) Branching ratio γ (%) Decay type Ga EC Kr-81m IT Tc-99m IT In EC I EC Xe β - Tl , 59 EC I β - Lu β - 5 Multi-Isotope SPECT 99m Tc 123 I 111 In 201 Tl 6

4 TUMOR to LIVER RATIO Lu Tm Dy Sm In Yb Y Gd Pm Ce Ac DTPA-mab Citrate Tb Octreotide EDTMP ionic radius in [pm] Comparison of the bio-distribution of different tumor seeking tracers labeled with radio-lanthanides, 225 Ac and 111 In free chelates: Citrate EDTMP specific tracers: Octreotide and Mab Linker: Aminobenzyl-DTPA G.J.Beyer, Hyperfine Interactions 129 (2000) Radionuclide Half-life (h) SPECT Tracer Eγ (kev) Branching ratio γ (%) Decay type Ga EC Kr-81m IT Tc-99m IT In EC I EC Xe β - Tl , 59 EC Some additional SPECT tracers needed for preclinical studies and for tracing specific elements (e.g. 195m Pt). 8

5 Thallium for patients? MBq to GBq activities correspond to ng to µg no chemical toxicity at this level provided stable isotopes are absent ( carrier-free ) or relatively low abundant ( non-carrier-added ) high specific activity is frequently a decisive quality criterion for nuclear medicine applications! 9 The death and the radiologist. Bad news: you are going to die soon. From diagnostics Oh my God! Where did you find all these nude photos of me? to therapy 10

6 Cancer and efficiency of treatments At time of diagnosis Primary tumor With metastases Total Diagnosed 58% 42% 100% Cured by: Surgery 22% Radiation therapy 12% Surgery+radiation therapy 6% All other treatments and combinations incl. chemotherapy 5% Total cured 40% 5% 45% Fraction cured 69% 12% 45% Per year over one million cancer deaths in the EU. improve early diagnosis improve systemic treatments 11 Immunology approach Target (antigen) Antibody Roelf Valkema, EANM

7 Multidisciplinary collaboration to fight cancer Target Peptide, antibody, etc. Linker Receptor Immunology Structural biology Coordination chemistry Radionuclide Nuclear physics and radiochemistry Roelf Valkema, EANM ,4,7,10-tetraazacyclododecantetraacetate Helmut Maecke, EANM

8 Roelf Valkema, EANM Roelf Valkema, EANM

9 Activity (GBq) Radiotherapy nuclides in Switzerland I 90Y 177Lu Year 1. The demand for radioisotopes is rising. 2. Demand for innovative isotopes ( 177 Lu) is rising disproportionately. 17 The rising star for therapy 18

10 Radionuclides for RIT and PRRT E mean (kev) Eγ (B.R.) (kev) Range Y h 934 β - 12 mm I days 182 β 364 (82%) 3 mm Lu days 134β 208 (10%) 113 (6%) 2 mm Tb days 154 β 75 (10%) 2 mm 5, 17, 40 e µm Tb h 3967 α 165,.. 25 µm Ge days 8 e µm cross-fire Radionuclide Halflife Established isotopes Emerging isotopes R&D isotopes: supplylimited! Er h 5.3 e µm localized Modern, better targeted bioconjugates require shorter-range radiation need for adequate (R&D) radioisotope supply. 19 Ways to high specific activity 1. Nuclear reaction changing Z [(p,xn), (p,α), (α,xn), etc.] plus chemical separation 2. Generator : 99 Mo/ 99m Tc, 188 W/ 188 Re, 68 Ge/ 68 Ga, 82 Sr/ 82 Rb, 3. Favorable cross-section plus high flux : 176 Lu(n,γ) 20

11 Production of 177 Lu Waste problem for hospitals! R. Henkelmann et al., Eur. J. Nucl. Med. Mol. Imag. 36 (2009) S European neutron sources for irradiation Neutron source Lab Position Location Flux Operation cm -2 s -1 (d/year) RHF ILL V4 Grenoble, France BR2 SCK-CEN H1 (access only during reactor stop) Mol, Belgium BR2 SCK-CEN F46 (loading and unloading any time) Mol, Belgium HFR NRG Petten, Netherlands OSIRIS CEA Saclay, France TRIGA II SCN XC-1 Pitesti, Romania 2.6 <150 Maria Polatom Świerk-Otwock, Poland BRR KFKI Budapest, Hungary 1.7 <150 BER II HZB DBVK Berlin, Germany 1.5 <200 FRM2 TUM KBA1 Garching, Bavaria LVR-15 NRI Řež, Czech Republic SINQ PSI PNA1 Villigen, Switzerland Future facilities RJH CEA Cadarache, France ESS ESSS nominal flux Lund, Sweden 3 22

12 Ways to high specific activity 1. Nuclear reaction changing Z [(p,xn), (p,α), (α,xn), etc.] plus chemical separation 2. Generator : 99 Mo/ 99m Tc, 188 W/ 188 Re, 68 Ge/ 68 Ga, 82 Sr/ 82 Rb, 3. Favorable cross-section plus high flux : 176 Lu(n,γ) 4. Indirect production + chemical separation : 176 Yb(n,γ) 177 Yb(β - ) 177 Lu 23 Alternative production route to 177 Lu Free of long-lived isomer Non-carrier-added quality Needs high-flux reactor 24

13 Ways to high specific activity 1. Nuclear reaction changing Z [(p,xn), (p,α), (α,xn), etc.] plus chemical separation 2. Generator : 99 Mo/ 99m Tc, 188 W/ 188 Re, 68 Ge/ 68 Ga, 82 Sr/ 82 Rb, 3. Favorable cross-section plus high flux : 176 Lu(n,γ) 4. Indirect production + chemical separation : 176 Yb(n,γ) 177 Yb(β - ) 177 Lu 5. Mass separation 25 First Results with Folic Acid plus Terbium 152 Tb-PET the first in vivo application ISOLDE Tumor Kidney 24 h p.i ISOLDE Tumor Kidney 155 Tb-SPECT the first in vivo application 19 h p.i 26

14 Survival of mice with lymphoma 5 MBq 149 Tb, 5 µg MoAb % of survived mice no MoAb 5 µg MoAb, cold 300 µg MoAb, cold Survival time, days G.J. Beyer et al., Eur. J. Nucl. Med. Molec. Imaging 31 (2004) Terbium: a unique element for nuclear medicine We strongly embrace increasing the choice of available New Terbium isotopes for therapy and diagnosis radioisotopes. We would like to use 161 Tb, the first samples of which were produced by ILL, in clinical therapy. We are A Multi-Purpose Element very delighted about this progress in basic research that will yield a direct outcome for cancer therapy. Prof. Richard Baum, Zentralklinik Bad Berka, 14 April Tb for targeted alpha therapy 28 28

15 Ways to high specific activity 1. Nuclear reaction changing Z [(p,xn), (p,α), (α,xn), etc.] plus chemical separation 2. Generator : 99 Mo/ 99m Tc, 188 W/ 188 Re, 68 Ge/ 68 Ga, 82 Sr/ 82 Rb, 3. Favorable cross-section plus high flux : 176 Lu(n,γ) 4. Indirect production + chemical separation : 176 Yb(n,γ) 177 Yb(β - ) 177 Lu 5. Mass separation 6. Moderate cross-section plus very high particle flux (γ,n) 29 Energy recovery linac (ERL) E γ = MeV E γ = MeV high harmonics laser high flux mode high brilliance mode ultra-fast mode 80 pc, 130 MHz 8 pc, 1.3 GHz 100 fs peak brilliance (s mm 2 mrad 2 0.1%BW) 1 flux s s 1 spot 15 µm 10 µm 15 µm 20% energy spread accepted for recovery; 1 GeV 0.1 A = 100 MW 30

16 Gamma ray beams with enormous peak brilliance 31 Beam properties (I) average flux 32

17 Beam properties (IV) peak brilliance 33 Potential for radioisotope production 226 Ra(γ,n) 225 Ra 1 Ci/day using few mci 226 Ra targets 195 Pt(γ,γ ) 195m Pt 2 Ci/mg 170 Er(γ,n) 169 Er 20 Ci/mg etc. D. Habs and U. Köster, Appl. Phys. B103 (2011) mg Ra-226 M. Harfensteller et al., WTTC

18 small bandwidth source broad bandwidth source 35 Resonant photonuclear reactions high cross-sections for resonant capture of epithermal neutrons with appropriate neutron energy high cross-sections for resonant photonuclear reactions with appropriate gamma ray energy no experimental high resolution data available for (γ,n) since no bright, tunable, monoenergetic gamma ray source was available so far relativistic focusing produces tiny (100 µm diameter) and intense gamma ray beam radioisotope production with very high specific activity achievable in small volume 36

19 Radionuclides for RIT and PRRT E mean (kev) Eγ (B.R.) (kev) Range Y h 934 β - 12 mm I days 182 β 364 (82%) 3 mm Lu days 134β 208 (10%) 113 (6%) 2 mm Tb days 154 β 75 (10%) 2 mm 5, 17, 40 e µm Tb h 3967 α 165,.. 25 µm Ge days 8 e µm cross-fire Radionuclide Halflife Established isotopes Emerging isotopes R&D isotopes: supplylimited! Er h 5.3 e µm localized Modern, better targeted bioconjugates require shorter-range radiation need for adequate (R&D) radioisotope supply. 37 Which radioisotopes will we need in 2030?... 38