1. Production of radioisotopes: where it all begins!
Thomas J. Ruth
TRIUMF
Vancouver, Canada

2. Radiochemical tracers
Probe biochemical systems by labeling
compounds with known biological
behavior.

3. Tracer Principle
Tracer behaves in a similar way to the components of the system to be probed.
Tracer does not alter the system in any measurable fashion.
Tracer concentration can be measured.

4. Specific Activity Radioactivity per mass – MBq/mmole
To maintain tracer priniciple must have the highest SA possible.
GBq /mmole = 1014 molecules

5. Sources of radioisotopes:
Naturally occurring – 235U
Fission – 99Mo mTc
Neutron capture – 186Re
Charged particle – 123I

6. Radioisotope production is truly
Alchemy where you change
one element into another!

7. Choice of method
The best possibility for achieving high SA is through charged particle reactions.

8. Notation
185Re + n = 186Re + g
185Re(n,g)186Re
18O + p = 18F + n
18O(p,n)18F

9. Excitation function

10. R = Ins (1 – e-lt) Where R – production rate I – beam flux
s – cross section
(1 – e-lt) – saturation factor

11. Positron Emitters

12. Production Methods

13. Gas Target

14. Liquid Target

15. Parameters target construction target constituents
irradiation conditions
energy
current
temperature
pressure
dose
optimize yield and specific activity
motherhood and apple pie
cylinder vs cone, volume, reliability
seals, base material, chemical properties, thermal properties, activation
energy deposition in target (make a graph??)
density reduction, dependence on current, pressure, temperature
dose to drive to end product
goal is to optimize yield and get high spec. act.

16. [11C]CO2 small volume aluminum targets O2 may or may not be added
H. J. Ache, A.P. Wolf, Radiochim. Acta Vol 6, p32, 1966
primary products are CN and CO at low dose (<0.1 eV/molecule)
higher doses radiolytically oxidize these to CO2
typical dose 150 eV/molecule
need references
mention of methyliodide production - why make CO2? then why make CH4?
hot atom chemistry, Dubrin et al. J. Inorg. Nucl. Chem. Vol 26, p2113, 1964
and Ache & Wolf, Radiochim. Acta Vol 6, p32, 1966
11C forms CN radicals by abstraction of N2, then CN forms HCN by abstraction of H2 or other hydrocarbons, with enough dose this goes to
CH4
however, oxygen is 10x more effective as a reaction partner than nitrogen,
so presence of oxygen immediately diverts the pathway to CO and with enough dose, on to CO2.
Ache & Wolf (ibid.) say primary products at low doses in N2/O2 systems are CN and CO. These are oxidized at higher doses to CO2.
low dose 10E-3 ev/molecule, higher 0.1 eV/molecule, high

17. [11C]CH4
initial work to produce HCN in target required flow-thru quartz body due to dose dependence and CN reactivity.
large aluminum or small nickel targets reported to work well.
D.R. Christman et al. Int. J. App. Rad. Isot., Vol. 26, p435, 1975.
G.-J. Meyer et al. Radiochimica Acta, Vol. 50, p43, 1990.
need references
mention gas phase CH3I
build from cyanide production to methane
maybe split to two slides with reaction pathway in between
how to incorporate our work, ammonia yield and suspicion of CN on target
wall, gamma detector plot
target large or inert to CN (quartz, nickel)
verbal reports of good yield from small aluminum
since oxygen reacts with carbon so much better than nitrogen, little CN is formed in the N2/O2 target so little is lost to the sink of the target wall.

18. [11C]CH4 Reaction Pathway N2 + H2 11C + N2 + H2 11CN 11CN + H2 HCN HCN
protons
N2 + H2
11C + N2 + H2
11CN
11CN + H2
HCN
HCN
CH4 + NH3
radiolysis
Christman et al. Finn’s Phd thesis
ammonia may be formed by other pathways and consume H2

19. [11C]CH4 at TRIUMF
initial results with cylindrical target, 5% H2 very poor (30% theoretical)
conical target, 10% H2 (50% theoretical)
NH3 in equilibrium & only dependent on amount of H2
residual fields show 11C produced but not extracted in gas phase
Recently have starting using Nb target chamber with excellent yields
nickel plated target in the works,
wash target to extract CN,
maybe try to graph gamma detector data in excel?

20. [18F]HF
first water target was Kilbourn et al. Int. J. Appl. Rad. Isot. Vol. 35, p599, 1984.
target materials, titanium, silver, nickel, gold, plated
A.D. Roberts et al. NIM B99, p797, 1995.
C. E. Gonzalez Lepara & B. Dembowski, Appl. Rad. Isot. Vol. 48, p613, 1997.
need references
what is the chemical mechanism to go from forming 18F to HF
I either leave this out or I look it up!
load/empty schema??
experiences?
why F-?
nucleophilic flouride for high specific activity tracers, more difficult chemistry though
small volume
good heat conduction
clean!
sealed or overpressure operation
radiolytic decomposition of water results in pressure buildup
contaminants can affect recovery

21. [18F]F2 An 18O2 Target for the Production of [18F]F2
R. J. Nickles, M.E. Daube, and T.J. Ruth,
Int. J. Appl. Radiat. Isot. Vol. 35, p117, 1984
experience with 20Ne(d,a)18F + carrier 19F2
subsequent irradiations > theoretical
target wall acting as a holding pool for F
NiF2 on target walls is not passive
proton-only accelerators & 3x yield
do I want to draw Nickles 4 compartment model??

22. Nickles’ 4 Compartment Model
Non-reactive gases
(CF4, NF3,…) k6 k7
Atomic
flourine F k2
Molecular
flourine F2 k1 k3 k4 k5
NiF2 target surface

23. Two-shot Method target evacuated O2 released to target and irradiated
O2 cryotrapped out
target evacuated with mech. pump
target loaded with umole F2 + inert gas (Ne, Ar, Kr, Xe)
18F2 released from target via isotopic exchange
(passivation not necessary with aluminum)
along with some flourinated species

24. 18O2 Gas Handling system

25. [18F]F2
several reports of single and double shot production methods implemented
reported use of aluminum target bodies in 1991 by Bida et al.
Proc. of IVth Int. Workshop on Targetry and Target Chemistry.
Development of an improved target for [18F]F2 production.
A.D. Roberts, T.R. Oakes, and R.J. Nickles
Applied Rad. Isot. Vol. 46, p87, 1995
various targets, nickel, gold, aluminum
two-shoot production method
18O2 irradiated, cryotrapped
19F2 + inert gas irradiated
isotopic exchange driven by beam
not inert gas dependent
carrier dependent
multiple recoveries possible

26. [18F]F2 advantages of aluminum: stability passivation activation
machinability
cost

27. [18F]F2 yield vs. 19F2 conc. mmol 19F2
Electrophilic 18F from a Siemens 11MeV Proton-only Cyclotron
Chirakal et al. Nucl. Med. Biol. Vol. 22, p111, 1994.

28. [18F]F2 yield vs. Irradiation time
A.D. Roberts, T.R. Oakes, R.J. Nickles
Development of an improved target for [18F]F2 production.
App. Rad. Isot. Vol. 46, p87, 1995.

29. [18F]F2
Proton Irradiation of [18O]O2: Production of [18F]F2 and [18F]F2 + [18F]OF2
A. Bishop, N. Satyamurthy, G. Bida, G. Hendry, M. Phelps, J.R. Barrio
Nucl. Med. Biol. Vol. 23, p189, 1996
targets of aluminum, copper, gold plated copper, nickel, cone and cylinders
single and two shot
multiple recoveries

30. Multiple Recoveries
recovers about 10% of F18 activity with the oxygen in step 1
likely as CF4 and some as OF2 and FONO2
both bishop and chirakal report the presence of OF2 and FONO2
step 2, 3, and 4 are inert gas/F2 recovery shots
we see similar results, good enough to exploit for tracer preparation
A. Bishop et al., Nucl. Med. Biol. Vol. 23, p189, 1996

31. Choice of Production Method
the threshold energy for initiating the reaction
the energy where the maximum cross section is found
the physical properties of the target material
the physical properties of the product

32. Choice of Production Method -continued
the chemical properties of the target
the chemical properties of the product
the ease of separation of the product and target
and the ability of converting the product into a useful labeling form.

33. Confounding issues

34. In Target Chemistry? For a 15 cm target at 10 atm N2 and a 10.5 MeV
proton beam..
Heselius, Abo Akademi

35. Ep= 13.0 MeV
P0= 300 psi
Havar window

36. 90% Thick
Ep= 13.0 MeV
P0= 300 psi
Havar window

37. 75% Thick
Ep= 13.0 MeV
P0= 300 psi
Havar window

38. 50% Thick
Ep= 13.0 MeV
P0= 300 psi
4.2 MeV
Havar window

39. He cooling foil from TR13 Target
Note heat mark

40. Courtesy of John Lenz

41. Courtesy of John Lenz

44. Water Cooled Grid Target
Roberts & Barnhart, U. Wisc.

48. Production of High LET Radioisotopes at
Accelerator Production of High Specific Activity Therapeutic Radionuclides:
Production of High LET Radioisotopes at
TRIUMF-ISAC Thomas J. Ruth UBC/TRIUMF PET Program

49. "It's not for content but for appearance" Pierce

50. Candidate radionuclides for radioimmunotherapy:

51. Accelerator Production
Target Z  Product Z
High Specific Activity
Low Energy - Fewer By-Products

52. Choice of Accelerator Commercial cyclotrons: 30 MeV
University based cyclotrons: MeV
Hospital based PET accelerators: MeV
National Labs: MeV

53. High Energy Facilities
Brookhaven National Lab Lab, US
200 MeV, 145 mA
Los Alamos National
100 MeV, 125 mA
Institute of Nuclear Research, Russia
160 MeV, 100 mA
TRIUMF, Canada
13, 2 x 30, 42, 70, 500 MeV, 50 mA – 1 mA
National Accelerator Centre, South Africa
200 MeV, 100 mA (p & d, HI)

54. Limitations of High Energy Facilities
Availability
Scheduling
Range of products
Sp. Act. affected by co-production of isotopes.
Reliability

57. How is 64Cu made? Reactor Nat Cu ARI Poor Specific Activity
Cyclotron 64Ni(p,n)64Cu Research High Specific Activity
64Ni(d,2n)64Cu Research High Specific Activity
64Ni 0.93 % nat. abund.
Commercially Viable Questionable
68Zn(p,αn)64Cu Research High Specific Activity
Boothe Zn 18.6 % nat abund.
Target for 67Ga
Commercially Viable
SV Smith, ANSTO

58. High Specific Activity 64Cu
68Zn(p,an)64Cu
High Specific Activity 64Cu
> 3000 Ci/g on delivery (> 24 hours EOB)
Half Life 12.7 hr
Positron Emitter
67Cu (1% at EOB)
High Purity (chemical and radionuclidic) 64Cu
Half-life days
Gamma emitter SV Smith, ANSTO
Customers want high specific activity. A deliver value of 3000 Ci/g as considered acceptable. However the Cu-64 is definitely generated from the Zn-68 so in principle it should be produced carrier-free. But we have a copper target that I have modified to reduce copper contamination. This work very effectively.
The presence of 1% Cu-67 was considered of use for both radiopharmaceutical biological studies (over 48 hours monitoring in animals) but also impact of mining on the environment (I.e monitoring acute toxicity in biological systems (crustaciean, and fish). Just published a paper in Aquatic Toxicology.

59. 77Br Production, t1/2 = 2.4 d Possible reactions: Natural abundances:
75As(a,2n) @ 27 MeV
77Se(p,n) @ 13 MeV
78Se(p,2n) @ 24 MeV
79,81Br(p,xn)77Kr @ 45 MeV
natMo(p,spall.) @ >200 MeV
Natural abundances:
77Se = 7.6%; 78Se = 23.6%

60. 124I - Potential Radiotoxic Nuclide
t1/2 = 4.14 d
b+ emitter
Production
124Te(p,n)124I @ 13 MeV
125Te(p,2n)124I @ 25 MeV
Natural abundance:
124Te = 4.79%
125Te = 7.12%

61. 211At Production t1/2 = 7.2 h Possible reactions 211Rn t1/2 = 14.6 h
209Bi(a,2n) @ 28 MeV
209Bi(7Li,5n)211Rn @ 60 MeV
232Th(p,spall.)211Rn @ >200 MeV
211Rn t1/2 = 14.6 h

62. Decay of 211Rn and growth of 211At.
Optimal recovery at about 16 hours.

63. Estimated Production of 211Rn
Target - UO2/C g
Yield of 211Rn x 107nuclei/s/mA
Translates to mCi/h
Conclusion - Need at least 3 orders of magnitude improvement to have any clinical utility.

64. 100 mA provides 2 orders of magnitude,
thicker target/beam optics gains a factor of 2 or 3 (or more),
better transport system from target to ECR gains a factor of 2 at most,
better ionization efficiency could provide another factor of 2 or 3.

65. High Specific Activity 186Re
Chemistry of Re similar to that of Tc
t 1/2 = 90.6 h
Ib = 92% Emax = 1.1 MeV
Ig = 9% Eg = 137 keV
Max. Theoretical Sp. Act. –
1.28 X 106 GBq/mmol
Reactor Produced Sp. Act GBq/mmol

66. Accelerator Production of 186Re
186W(p,n) mCi/ 18 MeV
186W(d,2n) MeV
197Au(p,spall.) MeV
natPt(p,spall.) MeV
natIr(p,spall.) 1.6 mCi/ 500 MeV

67. Reactor produced radionuclides that potentially could be prepared via on-line isotope separator system:

68. Production of Selected Isotope

69. ION BEAM II Implantation 60 keV Implantation into
plastic material open channels
metal foils channels closed II
P l a s t i c – f o i l (PE, polyether, MYLAR, KAPTON …)
G-J Beyer, CERN

70. Feasibility of 125Xe Implantation
at TRIUMF for the Preparation of
125I Brachytherapy Sources

71. 125Xe Collection Box at TISOL

72. Critical Factors on 125I Implantation
Production rates of 125Xe
Implant system efficiency
Stability from losses of implanted species
Radiobiological effectiveness

73. Production rates of 125Xe
Based on published data* the yield of 125Xe from a 50 g/cm2 Cs target is 0.7 Ci/hr for a 10 mA proton beam.
The 125Xe is quantitatively released.
Due to half-life differences the yield of 125I is of 125Xe.
* JS Vincent, J. Radioanal. Chem. 65:17-29 (1981)

74. Implant system efficiency
125Xe is ionized via ECR ion source
Implantation potential 12 kV & 22 kV
Mean range in Fe is m
Foils tested include Fe, Ti, Au
Efficiency through the system to implantation was 23%.

75. Stability from Losses of implanted Species
Foils were soaked in saline at room temperature for 3 days.
Soaked in saline at 55 C for 3 days.
Solutions taken to dryness and counted for 125I radioactivity.
All foils tested had quantitative retention of radioactive species..

76. Conclusions System efficiency = 23% Cs target has high production rate
Estimated yields = 2 mCi/hour
Stable implant

77. Many clinically relevant therapeutic nuclides can not be produced in high specific activity from reactors and the accelerators can not produce sufficient quantities for large scale usage.

78. Problem: Reactor production - Low Specific Activity.
National Lab Accelerators - Capacity for large scale production insufficient.

79. Possible Solution: Production in reactors or spallation sources with off-line isotope separation.

80. Conclusions
Many radionuclides can be produced at low energy cyclotrons distributed throughout NA, Europe and Asia.
High Energy facilities can not be relied upon for the bulk of clinically relevant radionuclides.
Alternative methods of production and isolation need to be explored.

81. Acknowledgements
I wish to thank the many colleagues have contributed to the work, ideas and slides presented here, especially Gerd Beyer, Suzanne Smith, ANSTO and Geneva John Vincent, TRIUMF.
TRIUMF is supported through a contribution fom the National Research Council of Canada.

82. TRIUMF, Vancouver, Canada

83. There's nothing left . . . but to get drunk. F. Pierce