Cyclotrons and production of radioactive isotopes at Rigshospitalet

Cyclotrons and production of radioactive isotopes at Rigshospitalet Holger Jensen, Cyklotronchef, Fysiker Lic. Scient. PET- og Cyklotronenheden, Afsnit 3982, Rigshospitalet, Blegdamsvej 9, 2100 København Ø. Danmark. Tlf. +45 3545 1866 E-mail: holger.jan.jensen@regionh.dk

Agenda 1. A few words about the PET and Cyclotron unit in numbers and hardware 2. A few words about PET. 3. A few words about cyclotrons in Denmark. 4. A few words about small and big cyclotrons. 5. A few words about cyclotron theory. 6. A few words about isotope production. Side 2

Agenda 1. A few words about the PET and Cyclotron unit in numbers and hardware 2. A few words about PET. Maybe?? 3. A few words about cyclotrons in Denmark. Skip 4. A few words about small and big cyclotrons. Skip 5. A few words about cyclotron theory. YES 6. A few words about isotope production. YES Side 3

1A The PET and Cyclotron unit in numbers and hardware The hospital: 1200 beds, 12.000 employees, 800 M Euro budget, +2000 publications. Department of Clinical Physiology, Nuclear Medicine & PET: 0 beds, 200 employees, 16 (+8) M Euro budget, +165 publications, Equipment for 65 M Euro +120.000 patient investigations, Side 4

1B The PET and Cyclotron unit in numbers and hardware PET and Cyclotron unit: 60-70 employee, 1 PET 5 PET/CT, 1 PET/MR, 1 HRRT brain scanner, 1 µpet 9000 PET- and 1000 RTP scans per year, Radiochemistry unit: 5 radiochemistry GMP labs, 14 hot cells. 10 chemist, 2 radio pharmacist, 5 lab. technicians for chemistry Marketing authorisation for two products: FDG and 81 Rb/ 81m Kr Side 5

1C The PET and Cyclotron unit in numbers and hardware Radiopharmaceuticals Tracers available for human use [ 18 F]FDG [ 18 F]FLT [ 18 F]FET [ 18 F]Altanserin [ 11 C]PIB [ 11 C]DASB [ 11 C]Flumazenil [ 11 C]SB207145 [ 11 C]CUMI-101 [ 13 N]NH 3 [ 15 O]H 2 O [ 68 Ga]DOTATOC [ 64 Cu]DOTATATE (Risø) [ 18 F]Fluoride (Risø) [ 18 F]Choline (Risø) Tracers expected to be available in the near future [ 11 C]Cimbi-36 [ 11 C]AZ10419369 [ 64 Cu]ATSM (Risø) Side 6 New tracers available for preclinical use Apoptosis: [ 18 F] Annexin V Angiogenesis: 64 Cu-NODAGA-cRGDyK 64 Cu-NODAGA-E[cRGDyK] 2 68 Ga-NODAGA-cRGDyK EGFRvIII: [ 18 F]FALGEA upar: Radiolabelled AE105 Brain imaging: 5-HT 7 receptors Nicotinic receptors

1D The PET and Cyclotron unit in numbers and hardware Cyclotron unit: Scanditronix MC32 (1992) and CTI/Siemens RDS Eclipse HP (2005) 2 physicist, 4 cyclotron technicians, 6 physics students (=operators), No service contracts, 18 F, 11 C, ( 13 N) at both cyclotrons (11 and 16 MeV) 15 O, 82 Rb/ 82m Kr, 111m Cd and 211 At only at MC32 (d- and α-beams and 16/32 MeV) 18 F and 11 C our major isotopes. Average success rate since 2006: 99.1% Side 7

Agenda 1. A few words about the PET and Cyclotron unit in numbers and hardware 2. A few words about PET. Maybe?? 3. A few words about cyclotrons in Denmark. Skip 4. A few words about small and big cyclotrons. Skip 5. A few words about cyclotron theory. YES 6. A few words about isotope production GOTO 6A Side 8

2A: A few words about PET (Ref. S. Holm) PET = Positron Emission Tomography PET should really be named ART =Annihilation Radiation Tomography 511 kev p n + e + + ν b + e - 511 kev Result: Two photons on an almost straight line that nearly contains the point of decay Side 9

2B: A few words about PET (Ref. S. Holm) PET radiation detection A PET scanner counts coincidences t 1 t 1 -t 2 <Dt? yes coincidence detector d1 e - e + Tube or Line Of Response (LOR) detector d2 t 2 Dt ~4-12 ns 30 cm/ns Coincidence window Dt d1 d2 time Coincidences 1 2 3 4 5 Side 10

2C: A few words about PET (Ref. S. Holm) Typical resolution 4-6 mm Coincidence events determine sampling paths (Lines Of Response) Side 11 GE Advance PET (1993)

2D: A few words about PET/CT (Ref. T.L. Klausen) CT PET attenuation of photons structure / anatomy Side 12 Annihilation distribution of tracer function / physiology

2E: A few words about PET/CT (Ref. L. Højgaard) CT PET PET/CT PET/CT December 2001 Side 13

2F: A few words about PET (Ref. L. Højgaard) Typical resolution for normal scanners 4-5 mm c = 3 x 10 8 m/s = 30 cm/ns x = 1.2 mm t = 4 ps. PET HRRT brain scanner with 120,000 crystals Resolution 1.2 mm Side 14

Finito, basta, Finito, basta, Side 16

Agenda 1. A few words about the PET and Cyclotron unit in numbers and hardware 2. A few words about PET. 3. A few words about cyclotrons in Denmark. SKIP 4. A few words about small and big cyclotrons. SKIP 5. A few words about cyclotron theory. GOTO 5 6. A few words about isotope production Side 17

3A: Cyclotrons in Denmark 1. 1938-1994, Niels Bohr Instituttet. One of the first cyclotrons in Europe. One of the longest running cyclotrons. 2. 1992-2048+, Rigshospitalet Scanditronix MC32 The John and Birthe Meyer foundation. 3. 1994, Århus PET center. GE, PETtrace 4. 2005, Rigshospitalet. (d. 17/01/2005) CTI/Siemens, RDS Eclipse HP The John and Birthe Meyer foundation. 5. 2005, Risø. (d. 22/01/2005) GE, PETtrace Side 18

3B: Cyclotrons in Denmark 6. 2007, Odense PET center. GE, PETtrace. 7. 2009, Herlev IBA, Cyclone 18/9 8. 2010, Århus PET center. IBA, Cyclone 18/9 9. 2011, Risø. GE, Micro-cyclotron PT600 10. 2019, Dansk Center for Partikelterapi Varian Medical Systems 11. 201?, Aalborg, Herning,??? Side 19

Agenda 1. A few words about the PET and Cyclotron unit in numbers and hardware 2. A few words about PET. 3. A few words about cyclotrons in Denmark. 4. A few words about small and big cyclotrons. 5. A few words about cyclotron theory. 6. A few words about isotope production Side 20

4A: Some history the beginning of it all M.K. Craddock, TRIUMF, Canada.

4B: Some history the beginning of it all M.K. Craddock, TRIUMF, Canada.

4C: Some history the beginning of it all M.K. Craddock, TRIUMF, Canada.

4D: Our cyclotrons at Rigshospitalet. CTI, RDS Eclipse HP, 2005, 11 MeV Scanditronix MC32, 1992, 32 MeV Beam power: 100µA*32MeV = 3,2 kw Total power: 130 kw (EF=40,6) svarer til 26 typiske parcelhuse ( à 5 kw). Side 24

4E: The real big and heavy Indiana UCF, 1975, 220 MeV, 2000 t PSI, Villigen, 1974, 590 MeV, 1990 t, d=9.3 m P=2,4mA * 590 MeV 1.4 MW Beam power 283 houses EF=40 58 MW energy consumption Side 25 or 11500 bungalows 25

4F: Sektor- separeret AVF cyklotron Sektor-separeret cyklotron, H -, TRIUMF, Vancouver, Cananda. 1977 Variabel energi 183-520 MeV, 4000 t, d=18 m, 18500 A til magnet Side 26 26

4G: The world record Side 27 SRC superconducting ring cyclotron, RIKEN, 2006, 2600 MeV, 8300 t, d=12.4 m

Agenda 1. A few words about the PET and Cyclotron unit in numbers and hardware. 2. A few words about PET. 3. A few words about cyclotrons in Denmark. 4. A few words about small and big cyclotrons. 5. A few words about cyclotron theory. 6. A few words about isotope production Side 28

4A: The classical cyclotron Beskrivelsen kan let gøres kompliceret og give en hver fysiker tårer i øjnene over den smukke matematik/fysik, men jeg har forsøgt at gøre det så simpelt at alle kan følge med. Page 29

4B: The 5 main components in a cyclotron 1. Ion source til at genere elektrisk ladede partikler, q, m 2. Magnetic field B til at fastholde partiklerne i cirkulære baner 3. Vacuum for at undgå kollisioner med restgas. 4. RF-system til acceleration 5. Exstraction system. Page 30

5C: De 5 hovedbestanddele i en cyklotron - ionkilde 1. Ionkilde til at genere elektrisk ladede partikler Lånt fra IBA, S2C2 design. Side 31

5D: Den klassiske cyklotron - RF De første cyklotroner blev bygget i 1930-32 af E. Lawrence og M.S. Livingston (plus studenter) i Berkeley, USA. Et stærkt homogent magnetisk felt B 0 tvinger elektrisk ladede partikler (ladning q og masse m) til at følge cirkulære baner i en plan vinkelret på B- feltet. Lorentz kraften (F = q v x B 0 ) giver: eller F L = qvb 0 = mv 2 / r (F = q v x B 0 ) p = mv = qb 0 r Revolution time T is given by T = 2 π r / v = 2 π m / qb 0 The revolution frequency f CYK = 1/T is named the cyclotron-frequency or the resonanse frequency f CYK = 1/T = q B 0 / 2 π m 32

5E: Den klassiske cyklotron - RF Revolution time T T = 2 π r / v = 2 π m / qb 0 is independent of radius r (and v) A commen acceleration voltage U dee for the dee s can be used to accelerate all particles. H - D - He ++ q/m 1 ½ ½ h 1 2 2 RF frekvensen skal altså være et multipla af cyklotronfrekvensen: f RF = h f CYK, h = 1, 2, 3, B og f hænger tæt sammen. Ved en justering af faseforskellen mellem AC- spændingerne på cyklotronens duanter og ved at benytte specielle udformninger af disse kan partikler med forskellige q/m forhold accelereres. Det harmoniske nummer h indgår også i disse tricks. 33

5F: Den klassiske cyklotron - RF Eksempel på dee-struktur i vores Scanditronix MC32. Side 34

5H: Den klassiske cyklotron - vacuum Accelererede partikler vil vekselvirke med en eventuel restgas i maskinen. Derved mistes energi og partiklerne spredes (ændrer retning). Beamets fokusering mistes og ekstraktionen bliver dårligere. Der sker en aktivering af cyklotronens indre. Pumper: a) mek. for-pumpe, b) diffusions-pumper, c) kølebaffler Side 36

5G: Den klassiske cyklotron - vacuum Side 37

5G: Den klassiske cyklotron - vacuum Diffusionspumper Side 41

5H: Den klassiske cyklotron - vacuum We are working on having less back streaming. Our CTI RDS Eclipse uses SantoVac and is anyway growing black. But it has no baffles. MC32 has baffles and is growing black too. Expected to affect the ion source performance. Side 45

5H: Den klassiske cyklotron - vacuum Regular service: a) Oil change for MP every ½ year. b) Full service for DP every 2 year. c) Even oil from MP can be seen in Vacuum (Stefan Johansson, Turko) Better oil: a) Replacement of the Baltzer 71A mineral oil with DC 704 silicon oil. b) Pfeiffer+HSR/Balzers promises a factor 10 reduction in back streaming. c) I want to know more about the effect of SantoVac oil. It is also very expensive. Improved cooling of baffles: a) Present cooling water temperature: 12-14ºC. b) Replacement with HSR BFC 400 multi baffles with PCF145-Z refrigerator. c) Both water and refrigerant (R134a) cooled. d) T = -13-17ºC e) Can be cooled with LN 2 too. f) Back streaming down by a factor 10. P46

3J Vacuum upgrade First question from IS- experts at TRIUMF was what is your vacuum in the central region A good vacuum is essential for negative ion machines. Improving the pumping conductance in the central region by new dummy-deesupport plates is one step in this direction. I want to do Monte Carlo Simulations to predict the effect. New baffles and better oil is another step in this direction. P47

5H: Den klassiske cyklotron - kinematik Maksimal energi, T max, ved maksimal radius R er givet som T ½ m v 2 og da v = qb 0 r/m fås T max = q 2 B 02 R 2 / 2m H - og He ++ har samme værdi for q 2 /m ( = 1) og derfor også for T max For deuteroner D - haves q 2 /m = ½ T max (D - ) ½ T max (H -, He ++ ). Dette giver følgende maksimale energier i vores MC32: T max (H - ) = T max (He ++ ) = 32 MeV og T max (D - ) = 16 MeV H - D - He ++ q/m 1 ½ ½ q 2 /m 1 ½ 1 h 1 2 2 T max 32 16 32 Dette svarer f.eks. til en hastighed på ca. 78.000 km/s for protoner eller ca. 2 gange rundt om ækvator pr. sekund eller 26% af lysets hastighed! Hertil kommer at vi har variable energier 16-32 og 8-16 for h.h.v. H - og D -. Side 48

5I: Den klassiske cyklotron - ekstraktion Positiv ion cyklotroner: Beamet kan ekstraheres ved hjælp af en elektrostatisk deflektor (men giver desværre ofte et meget radioaktivt septum). Dette giver faste energier for det ekstraherede/eksterne beam. Interne bestrålinger på en probe, som kan give variable energier, blev benyttet i begyndelsen. (Selvom vi så at Lawrence allerede havde ideen til en deflektor i 1932.) Vi producerer f.eks. 211 At ved en sådan intern bestråling. Negativ ion cyklotroner: Den nye generation af cyklotroner. Ion kilderne er vanskelige og kræver bedre vakuum. Ekstraktion sker ved hjælp stripper folier, og giver 100% extraktion. Næsten ingen aktivering af cyklotronen bortset fra targets. Variabel energi mulig, men tilbydes desværre kun på få maskiner idag. Side 49

5J: Limitations of the classical cyclotron Det relativistiske tilfælde/problem: H.E. Bethe og M.E. Rose forudsagde allerede i 1937 maksimale beam energier som følge af relativistiske effekter, m = m 0 γ. 32 MeV protoner har f.eks. en -værdi på 1,034! Impulsen p=m 0 v (=qbr) må erstattes med det relativistiske udtryk m 0 v i bevægelsesligningerne! Resonance condition f CYK = 1/T = q B / 2 π m can be obtained for an increasing B-field with radius, which balance out the relativistic mass increase: B(r) = B 0 (r). But but but this gives axial de-focusing and radial focusing effect. Has been a problem ever since 1937. Side 50

5K: Den klassiske cyklotrons begrænsning Faldende B-felt med radius: Radial de-fokuserende effekt Aksial fokuserende effekt Voksende B-felt med radius: B = B 0 (r). Radial fokuserende effekt Aksial de-fokuserende effekt Side 51

5L: Den klassiske cyklotrons begrænsning og løsning Frekvens-modulerede cyklotroner, synchrocyclotrons, 1945, var en løsning på dette problem. RF-frekvensen justeres for hvert beam-puls til at kompensere for den voksende omløbstid med voksende radius/hastighed. Beam Duty-cycle 1000 dårligere, men meget høje energier kan opnås. But the old solution for high energies for nuclear physics research IBA, S2C2 design. Synchrocyclotron with superconducting coils Side 52 Side 52

5M: Axsial focusing in the classical cyclotron Aksial fokusering fra E-feltet: Det elektriske felt giver en aksial fokuserende effekt. a) Statisk felt giver også en fokusering b) RF- giver en fase afhængig effekt. Page 53

5N: Den klassiske cyklotrons begrænsning og løsning Llewellyn Thomas kom med en løsning til det relativistiske (og det aksiale defokuserings) problem allerede i 1938. B = B(r,θ) Variationen i B(θ) giver en netto fokuserende effekt i aksial retning. Samtidig giver B(r) den ønskede radiale fokusering og løser det relativistiske problem. Thomas vinklen κ skal være > 0 og virker i praksis kun for E<45 MeV. Offentligt tilgængelige resultater/løsninger kom først i 1956. Side 54

5P: Scanditronix MC32 Scanditronix, 1992. Negative ions (H - and D - beams). Magnetic field can be reversed for acceleration of positive ions for internal bombardments (i.e. H +, D +, He ++ -beam). Dual beam exit possible. Variable energies 16-32 MeV and 8-16 MeV for H -, He ++ and D - respectively. Sector focused, AVF. Internal ion source, cold cathode Penning source with two chimneys. The main isochronous magnet field is approxi-mately 1.6 T. Resonance frequency 24.3 MHz. Magnet 58 tons. Vacuum 2x10-6 mbar (beam on) and 3x10-7 mbar (beam off). Total power consumption 130 kw. Side 56

5Q: CTI/Siemens RDS Eclipse HP Negative ion (H - ), 11 MeV. Penning type ion source. Deep valley (27:1) magnet design. Peak hill field, 1.9 T. Trimbars. Resonance frequency f CYK =18 MHz. 4 x 30-degree dees. f RF = 72 MHz 10 + 40 ton Total power consumption 25 kw. Dual beam exit. 4 target per port. 18 F, 11 C, 13 N, 15 O, 64 Cu,? 18 F yield, 7 Ci in 2 hours, dual beam, 2x60 µa. 11 C yield, 1.8 Ci in 40 min, Side 57

Agenda 1. A few words about the PET and Cyclotron unit in numbers and hardware. 2. A few words about PET. GOTO 2 3. A few words about cyclotrons in Denmark. SKIP 4. A few words about small and big cyclotrons. SKIP 5. A few words about cyclotron theory. 6. A few words about isotope production Side 58

6A: Short T ½ implies a local production Isotop Halveringstid Isotop Halveringstid 10 C 19.255 S 62 Cu 9.74 M 11 C 20.39 M 13 N 9.965 M 15 O 2.037 M 18 F 109.77 M 64 Cu 12.700 H 81 Rb 4.576 H 124 I 4.15 D 131 Ba 11.5 D 111m Cd 48.54 M 211 At 7.214 H Henfaldsligningen: A t = A 0 e λt = A 0 1 med henfaldskonstanten λ = ln(2) / T ½ 2 t T½ Side 59

6B: Where and how are the isotopes of the universe made? Some people claims that God created everything. Physicists do not always agree! Big-bang? Yes, mainly light isotopes. Super nova explosions? Yes, mainly the heavy isotopes. Nuclear reactors? Yes, fission fracments and neutron activation processes. Massefordeling ved fission af 235 U Neutronindfangningstværsnit Page 60

6D: Where and how are the isotopes of the universe made? Some people claims that God created everything. Physicists do not always agree! Big-bang? Yes, mainly light isotopes. Super nova explosions? Yes, mainly the heavy isotopes. Nuclear reactors? Yes, fission fracments and neutron activation processes. A-bombs? Yeah, gives fission products! We still see the remains from the test explosions. Research in nuclear physics during the last 70-80 years is the basis for all productions of radioisotopes today. Almost all relevant isotopes can be produced with accelerators today. Page 62

6E: Some nuclear physics Z 1 Coulomb force: F Coulomb = (e 2 /4 0 ) (Z 1 Z 2 /r 2 ). Z 2 The strong nuclear forces/interactions between the nucleons - F SI - will be stronger than the Coulomb force for distances of a few fm (= 10-15 m). For the reaction p + 18 O 19 F ex the Coulomb barrier energy is around 2-3 MeV corresponding to a velocity of the projectile/proton of 20-24.000 km/s! A strong accelerator (for example a cyclotron) is necessary. We operates with nuclear reaction cross sections σ 18O(p,n)18F Typically only 1 out of 10000 particles will react. The rest will only deposit heat in the target. Side 63

Sigma [mb] 6F: One example Production of 211 At, for particle therapy of cancers: 209 Bi(,2n) 211 At, E = 28 MeV, I = 18 A Before 209 Bi After 211 At n α Dt 10-21 10-16 s n 209Bi (a,xn/t) At/Po The used reaction channel must be optimized with respect to competing channels. 1,0E+04 1,0E+03 1,0E+02 1,0E+01 211At: W.J. Ramler et al. 211At: R.M. Lambrecht et al. Target- composition, thickness, reaction-energy, irradiation time and chemical separation/purifications is used for this. 1,0E+00 210At: W.J.Ramler et al. 210At: R.M. Lambrecht et al. 1,0E-01 209At: W.J. Ramler et al. 210Po: W.J. Ramler et al. 1,0E-02 15 20 25 30 35 40 45 E_beam [MeV] 64

6G: Renhed og konkurrerende reaktionskanaler Det er svært at finde rene reaktioner! 60 Cu 61 Cu 62 Cu 63 Cu 64 Cu 65 Cu 23.7M 3.333H 9.74M 69.17% 12.70H 30.83% 58 Ni 60 Ni 61 Ni 62 Ni 64 Ni 68.08% 26.22% 1.140% 3.634% 0.926% 57 Co 58 Co 59 Co 60 Co 61 Co E p = 15-20 MeV 271.7D 70.86 H 100.0% 5.271Y 1.650 H p + 64 Ni ( 65 Cu * ) 64 Cu + n 200 mb 61 Co + 20 mb 63 Cu + 2n ( 20 mb?) 1 g 64 Ni, 97.0% berigning koster 200.000 300.000 Dkr. 65

6H: Another example, production of 18 F for FDG, FET, FLT, Bestråling af væske-target til fremstilling af 18 F, til 18 F-FDG: 18 O(p,n) 18 F, E p = 16-18(11) MeV, I p = 35-50(60+) A HAVAR- foil P He-køling/ Grid Ag/Ti/Nb/Ta target body + Kølevand ind Beriget H 2 18 O vand Kølevand ud Vi producerer p.t. 100-300 GBq 18 F 8-10 gange pr. uge med dette target design. Side 66

6I: Produktion af isotoper, væske target, 18F, IBA Kostede 500.000,00 Dkr i 2002 Fungerer stadig. Vi har 2 stk. idag. Side 67

6J: Home made target for 18F Samarbejde mellem Lund, Uppsala og Rigshospitalet. Koster under 100.000,00 Dkr. Plus vi nu har 100% kontrol over alle detailler. Side 68

6O: Typical reactions used Bestråling af væske-target til fremstilling af 18 F, til 18 F-FDG (SCX+CTI): 18 O(p,n) 18 F, E p = 16-18(11) MeV, I p = 20-35(60+) A Bestråling af væske-target til produktion af 13 N, til 13 N-NH 3 (SCX): 16 O(p, ) 13 N, E p = 16 MeV, I p = 23 A Bestråling af gas-target til produktion af 11 C, til 11 C-CH 4 (CO 2 ) (SCX+CTI): 14 N(p, ) 11 C, E p = 16 (11) MeV, I p = 25-30(60+) A Bestråling af gas-target til produktion af 15 O-H 2 O (SCX): 14 N(d,n) 15 O, E d = 8 MeV, I d = 5 A Produktion af 211 At, til alfa-terapi (SCX): 209 Bi(,2n) 211 At, E = 28 MeV, I = 18 A Bestråling af metal-target til fremstilling af 64 Cu, 64 Cu-ATSM (CTI): 64 Ni(p,n) 64 Cu, E p = 11 MeV, I p = 40 A, 5-8 timer. 73

6Q: Our new solid-target for 62 Zn/ 62 Cu Page 75

Agenda 1. A few words about the PET and Cyclotron unit in numbers and hardware. 2. A few words about PET. GOTO 2 3. A few words about cyclotrons in Denmark. Skip 4. A few words about small and big cyclotrons. Skip 5. A few words about cyclotron theory. GOTO 5 6. A few words about isotope production Side 76

Finito, basta, Finito, basta, Side 77