KIVI 9 Oct 2015 Fysische Beeldtechnieken 18 feb

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4 Dutch Isotopes Valley Stable Isotopes 4

5 Patient-hospital: how to recognize the disorder? How to find a targeting molecule? How to make new radionuclides? How to combine? How to test stability? How to assess distribution? How to bring the result to the market? 5

6 Hospital Disorder recognition Selectivity Sensitivity Treatment volume Production site Purity Yield Specific Activity Range Chain products Half life Type and Energy 6

7 Aspects of Specific Activity Physics Radiochemistry Reactor physics Specific activity Nuclear Medicine 7

8 Internal radio Isotopes: Endo-Radiotherapy or -diagnostics Targeting Diseased site Free compound Targeted compound Targeted distribution Disorder Distribution after non-targeted injection 8 8

9 Radionuclide Target organ carrier linker Targeting compound 9

10 External Radiation Source α β Anatomical CT/X-ray imaging, radiotherapy γ Internal Radiation Source Funktional PET, SPECT imaging Skin surface α β Endo-radiotherapy γ 10

11 Most important radionuclides for nuclear medicine Reactor-produced 64 Cu 67 Cu 90 Sr 90 Y 99 Mo 103 Pd 114m In 117m Sn 125 I 131 I 153 Sm 166 Ho 169 Yb 177 Lu 186 Re 188 Re 188 W 191m Ir 194 Ir 195m Pt 199 Au Accelerator-produced 11 C 13 N 15 O 18 F 22 Na 26 Al 28 Mg 38 K 44 Ti 57 Co 67 Ga 67 Cu 68 Ge 72 As Se Br 81 Rb ( 81 Kr) 82 Sr 111 In I 140 Nd 201 Tl 11

12 Some Reactor-radionuclides for endo-therapy Nuclide Range Radiation 90 Y, 188 Re > mm high-energetic β 153 Sm, 186 Re mm medium-energetic β 177 Lu, 131 I < mm low-energetic β 212,213 Bi, 211 At <<mm α-radiation 103m Rh 195m Pt subcellulair low-energetic Auger-electrons 12

13 Radionuclide production Replacing the number of target nuclei N 0 by (N Av θw)/m we get the 'activation formula': N θ w A = σ ( 1 - M with Av -λ Φ th eff e t N Av = Avogadro's number, mol -1 Θ =isotopic abundance of the target isotope N 0 W =mass of the irradiated element, g M =atomic mass, g.mol -1 Φ =particle density cm -2.sec -1 σ =cross section cm 2 (1 barn = cm 2 ) ir ) 13

14 Signal strength in imaging Radiation dose in radio-therapy Highest possible specific activity 14

15 Breeman et al. Nucl Med and Biol. 35, (2008) 250 MBq 99m Tc per nanomol Demogastrin

16 117m Sn for palliative bone tumor therapy 16

17 117m Sn for palliative bone tumor therapy To be coupled to bone (tumor)-seeking phosphate-compounds Why 117m Sn? Auger electrons mm range Less bone marrow damage than from 153 Sm or 166 Ho (beta ranges 0.55 mm and 2.7 mm respectively) 17

18 DIVA URENCO Sn enrichment RID production research NRG/PALLAS industrial scale up 18

19 Reduce the mass? Szilard & Chalmers Szilard-Chalmers reaction (1934) Leo Szilard ( ) Ethyl-iodide 127 I (n,γ) 128 I Recoil-energy is usually larger than the binding energy The recoil nuclei come free from their environment 19

20 Recoil energy E R LOG Recoil energy E R = ( E ) γ A Mass number (A) Prompt Photon energy E R in MeV E γ in MeV A in a.m.u. E R(average) 99 Mo ± 190 ev Binding energy e.g. Mo-O: ~ 6 ev 20

21 The mass problem Szilard-Chalmers reactions Take 99 Mo, leave target Take target, leave 99 Mo The yield problem 21

22 Szilard-Chalmers reactions Theory and practice Mass and yield Metal compounds (target) Escape of recoil isotopes Catcher-media Irradiation conditions Waiting time with off-line produktion Target integrity problems Annealing-effects Target recovery 22

23 Szilard-Chalmers reactions Theory and practice Mass and yield Enrichment Factor EF (target T en catcher C) [* X C ] [ ] [ ] [ X ] [* ] [ ] [ ] [ ] X X X EF = =. * X * X X C C T T T T C But concentrations include volume effects, so towards absolute data: * X EF = * X C T X. X T C Boundary conditions Target isotope mass transfer: not more than allowed Product isotope yield: not less than necessary 23

24 Nuclear Reactions: Energetics Po Pb He Mass 212 Po amu Mass 208 Pb+ 4 He amu m amu Q MeV mhe But E He is 8.78 MeV E : E = m : m thus E =. E m He Pb Pb He Pb He Pb mhe Q = EHe + EPb = EHe(1 + ) = 8.95MeV m E He 4 = 8.95/(1 + ) = 8.78MeV 208 October 10, 2015 Pb 24

25 117m Sn for palliative bone tumor therapy 117 Sn(n,n ) 117m Sn SA = 23 MBq/mmol available inelastic neutron scattering high energy neutrons very high neutron flux necessary highly enriched 117 Sn few reactors (o.a. Dimitrograd) 116 Cd(α,3n) 117m Sn 25

26 Recoil approach 118 Sn(γ,n) 117m Sn Target Sn = Sn 4+ Product Sn = Sn 2+ MT-25 microtron JINR Dubna solvent extraction anion exchange chromatography electrolysis 3 kbq.µa -1.h -1.mg kev γ 26

27 Recoil approach 116 Sn(n,γ) 117m Sn SnO and SnO 2 targets σ=0.14 barns carbon/graphite catchers 10 h HOR RID/TUDelft HCl extraction EF= 34 SA=2.5 MBq/mmol 27

28 Reactor-production via (γ,n) Target 2 for (γ,n) reaction n-beam γ from target 1 Target 1 n-absorber 28

29 166 Ho for (liver) tumor therapy 29

30 166 Ho for (liver) tumor therapy DIVA RID production research NRG/PALLAS industrial scale up 30

31 166 Ho production 31

32 166 Ho for (liver) tumor therapy 32

33 microspheres 166 Ho Treatment procedure Liver: 70% portal vein 30% hepatic artery Tumor: 99% hepatic artery Original figure and animation adapted from and

34 Radiochemistry 166 Ho production Direct (n, γ) method: 165 Ho + 1 n 166 Ho t 1/2 = 26 h max. 0.3% of the 165 Ho atoms absorb a neutron to change into 166 Ho: this is not enough for receptor-targeting compounds ( no problem for microspheres or liposomes ) Indirect method: 164 Dy (2n,γ) 166 Dy 166 Ho + β - 166Dy (t 1/2 = 81.6 h). Separation with column of lanthanides-specific resin. Szilard-Chalmers method: Ho-acetylacetonate Ho 2 (C 5 H 7 O 2 ) 3 34

35 Paramagnetic Holmium poly(l-lactic acid) microsphere γ 81 kev neutron Ho Accumulation of MS in and around tumor β 1.84 MeV 35

36 usable Delft 6 h, n.cm -2.s -1 not usable Petten 1 h, n.cm -2.s -1 Petten 2 h, n.cm -2.s -1 Petten 1 h, n.cm -2.s -1 36

37 h Ho-microspheres microspheres 37

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39 Delft new facility Gamma-H 2 O lead facility diameter ~ 30 cm Gamma-Pb n-pb n-h2o Factor 100 decrease in gamma Factor 10 increase in neutrons 39

40 Pb-shielded Irradiation facility 40

41 Shielded facility Reducing E deposition in targets (reducing γ) increase in target mass decrease in damage Increasing ϕ th neutrons increase in yield per unit of mass 41

42 FLEXBeBe semi-permanent facility sample removable plates support cooling Removable sheets composed of: Cd, Pb, Sc etc depending on the needs 42

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