2. Radiopharmaceutical Production Radionuclide Production Practical Targets Design and Construction STOP

3. Requirements in Targetry Need to produce radionuclides reliably to meet our research needs Need to produce large quantities to meet current and future demands May need high specific activity for diagnostic or research applications Simple targets which do not degrade in performance Recycle enriched isotopes Minimize the amount of non-radioactive isotope in the final product (high specific activity) Targets which will withstand high power deposition and use favorable nuclear reactions Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP

4. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Basic Principles  Choice of Nuclear Reaction  Choice of the physical state  Gas target  Water target  Solid target  Choice of processing  Gas target - chemical separation  Solid target - distillation or sublimation  Choice of the chemical form  Element or Compound  Target Geometry  What is the best shape for the target  Target Body Material  Chemical Interactions  Thermal Conductivity  Activation  Front Foil Material  Strength  Chemical Interactions There are several decisions which must be made when starting to design a cyclotron target. These include:

5. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Carbon-11 20.4 min Fluorine-18 110 min Nitrogen-13 10 min Oxygen-15 2 min Isotope half-life As an example, let us assume we want to produce carbon-11. There are several potential nuclear reactions which may be used to produce C-11. The possibilities are given in the following slides Carbon-11 Example

6. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Potential Reactions We can explore the potential nuclear reaction pathways by looking at a chart of the nuclides. We want all the reactions to end on carbon-11, but they can start from different stable elements (black squares)

7. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Types of Nuclear Reactions 3 He, n α,2n α,n p,3np,2np,np, γ d,n p,pnTargetd,p p, αp,2p Nuclear Charge Nuclear Mass The radionuclides that can potentially be made from different nuclear reactions are shown in the following diagram. The first letter is the particle in and the letter after the comma is the particle(s) emitted by the excited nucleus. This template can be overlaid on a chart of the nuclides to get the products

8. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Potential Reactions 11 B(p,n) 11 C Proton in Neutron out

9. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Potential Reactions 14 N(p, α ) 11 C Proton in Alpha particle out

10. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Potential Reactions 12 C(p,pn) 11 C Proton in Proton and Neutron out

11. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Carbon-11 Production Three potential nuclear reactions – 14 N(p, α ) 11 C – 11 B(p,n) 11 C – 12 C(p,pn) 11 C The cross sections for these three reactions are given in the table below In terms of the yield of the nuclear reactions, it is clear that the best choice is the 11 B(p,n) 11 C reaction

12. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP PET Radioisotope Production One must choose the chemical form for the target. The best choice is a Solid Phase Target The target is boron oxide which is a solid The 11 B(p,n) 11 C reaction in a boron oxide matrix will produce carbon dioxide An example of a target designed for this reaction is shown on the next slide The difficulty with these type of solid targets is removing the carbon-11 carbon dioxide efficiently from the boron oxide matrix

13. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP protons Helium in 11 CO x in Helium out to flow-through chemistry 11 B + 11 B 2 16 O 3 11 CO x flow-through target Target design features Use of B 2 O 3 to provide oxygen for CO x production Enriched 11 B to increase yield Slanted target material to increase 11 CO x diffusion High temperature to increase 11 CO x diffusion Helium carrier gas to remove 11 CO x from target The actual yields are quite low due to the difficulty of getting the 11 CO 2 out John Clark - circa1975

14. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Carbon-11 Production The next option to be considered is the Nitrogen Gas Target for 14 N(p,α) 11 C reaction. This target has the advantage of using a gas as the target material which makes the extraction of the carbon-11 carbon dioxide much easier. Gas target body is made from polished aluminum Gas inlet Gas outlet Water cooling channels

15. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Carbon-11 Production This is a cutaway drawing of a typical target for the production of carbon-11 from nitrogen-14 in the chemical form of nitrogen gas. Nitrogen Gas Target for 14 N(p,α) 11 C reaction

16. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Range of protons in N 2 Gas at 1 atm EnergyRange (MeV) 4.50277.00 mm 5.00 332.37 mm 5.50 392.20 mm 6.00 456.41 mm 6.50 524.95 mm 7.00 597.76 mm 8.00 755.83 mm 9.00 930.42 mm 10.00 1.12 m 11.00 1.33 m 12.00 1.55 m 13.00 1.79 m 14.00 2.04 m 15.00 2.31 m 16.00 2.59 m The first decision is how long to make the target and what pressure to use. If we want to stop the beam we can calculate the range of the protons in the gas. At 1 atmosphere, the target would need to be 2.6 meters long to stop the beam.

17. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Range of protons in N 2 Gas at 10 atm EnergyRange (MeV) 4.00 22.62 mm 4.50 27.70 mm 5.00 33.24 mm 5.50 39.22 mm 6.00 45.64 mm 6.50 52.50 mm 7.00 59.78 mm 8.00 75.58 mm 9.00 93.04 mm 10.00 112.12 mm 11.00 132.79 mm 12.00 155.03 mm 13.00 178.81 mm 14.00 204.12 mm 15.00 230.92 mm 16.00 259.21 mm At a pressure of 10 atmospheres, the beam will stop in about 26 cm. Which is a much more reasonable target length although most nitrogen targets are shorter than this and operate at higher pressures.

18. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Shape of the Target EnergyStraggling (MeV) 4.00 730.98 um 4.50 885.82 um 5.00 1.05 mm 5.50 1.23 mm 6.00 1.42 mm 6.50 1.63 mm 7.00 1.84 mm 8.00 2.31 mm 9.00 2.82 mm 10.00 3.37 mm 11.00 3.97 mm 12.00 4.61 mm 13.00 5.29 mm 14.00 6.01 mm 15.00 6.78 mm 16.00 7.58 mm 8.0 mm We need to decide the shape of the target. We know that the beam will spread out due to small angle multiple scattering. This straggling can be calculated most easily using a program such as SRIM

19. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Entrance Foil Material Materialdensity (g/cm3) Melt. Pt. (°C) Tensile St. (kpsi) Thermal Cond. (watt/cm-°K) dE/dx (MeV/g/cm 2 ) Carbon2.2>3000---2.5141.08 Aluminiu m 2.71660302.3733.96 Titanium4.516681200.3129.77 316 Stainless 8.0214271200.2928.91 Havar8.314932500.1728.6 Nickel8.914531200.9128.53 Tantalum16.62996700.5318.57 Tungsten19.333875001.818.42 Platinum21.41769200.7218.3 Niobium8.572477400.54 The table below gives the physical characteristics of some common foil materials. The ideal has high strength, low density, good thermal conductivity, a reasonable dE/dx and high melting point. None is perfect but Al, Ti and Havar are common.

20. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Getting High Specific Activity In order to get high specific activity carbon-11, it is necessary to take precautions when fabricating the target. These include: Use Electrical Discharge machining to cut the metal Use only alumina (Al 2 O 3 ) abrasives in polishing the inside surface. Never use oils in the target If organic solvents must be used, follow the use with repeated rinses of ethanol and water Cleaning the target Should never need to be cleaned If it is necessary, then Acetone and Ethanol should be used as they are soluble in water If abrasives are used, they should be alumina The target should be irradiated and the gas discarded after any cleaning procedure and before a production irradiation

21. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Carbon-11 20.4 min Fluorine-18 110 min Nitrogen-13 10 min Oxygen-15 2 min Isotope half-life Fluorine-18 Example

22. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Fluorine-18 Example Proton in Neutron out There is really only one reasonable nuclear reaction with protons as the bombarding particle. This is the 18 O(p,n) 18 F reaction.

23. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP 18 O(p,n) 18 F Reaction The nuclear reaction cross section is shown on the right and it should be noted that the peak of the reaction is about 6 MeV and it tails off rapidly above 11 MeV. The most convenient chemical form of the target material is in the form of oxygen-18 enriched water. This is the reaction that is used by nearly all facilities for the production of FDG

24. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Fluorine-18 Fluoride Production The target is usually a depression cut into a metal block which contains the oxygen-18 enriched water There is a inlet and outlet for the water and the target is deep enough to allow some boiling in the target without loosing yield. The rear of the target is cooled with a high pressure water flow The front foil is made of a material that is strong enough to hold the pressure generated by the boiling water and chemically resistant to the fluoride and the oxygenated species like peroxide generated in the water. Beam Cooling water Target waterFront flange

25. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Fluorine-18 Fluoride Production Typical water target. This particular target is made from solid silver to help in the heat transfer. A more modern water target is typically made from niobium. 18 O(p,n) 18 F Nuclear Reaction in 95% enriched water Volume of the target from 0.3 mL up to 3.0 mL

26. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Water Target Operation Beam Helium push gas Vent To the Chemistry Lab [ 18 O]Water Filling and Irradiation Cycle

27. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Water Target Operation Beam Helium push gas Vent To the Chemistry Lab [ 18 O]Water After Irradiation, pushing the water from the target to the Chemistry Lab

28. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP F-18 transfer line - 60 meters Transfer of the F-18 from the Cyclotron to the Chemistry Laboratory

29. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Initial Fabrication and Cleaning of F-18 targets Fabrication of Fluorine targets Should never use soldering fluxes as they contain fluorine which will reduce specific activity The back wall should be thin to allow good heat transfer A “reflux” volume helps with keeping the target material in the liquid state Cleaning of Fluorine targets Silver targets need to be cleaned fairly frequently Niobium and Titanium can be cleaned much less frequently No cleaning may be necessary if these last two are used Mild abrasive and repeated water rinses are best

30. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Iodine-124 Example As the next example, suppose you wanted to make I-124 on the cyclotron and wanted to design a target for the production

31. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Chart of the Nuclides n p Here we can use the 124 Te(p,n) 124 I nuclear reaction

32. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Cross-section 124 Te(p,n) 124 I This excitation function for the nuclear reaction shows that the best energy interval is from 15 down to about 5 MeV

33. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Tellurium Solid Targets Here we have the option of two different chemical forms of the tellurium to use for the target. We can use tellurium metal as shown on the left or tellurium dioxide as shown on the right Both of these target materials are used for production and the choice depends on ease of chemical processing and target material recovery. Since the target material is isotopically enriched, it is relatively expensive and so must be recovered

34. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Preparation of solid targets by electrodeposition  Requirements  The layer must be homogeneous over the entire surface area to ±5%.  The layer must adhere strongly to the carrier up to the irradiation temperatures.  The layer must be smooth (not spongy), dense (no occlusions nor vacuoles), and stress free.  The layer must be free of any organic plating additives (complexing agents or surfactants). The tellurium metal target may be prepared by electrodeposition. There are several constraints on the targets prepared this way. Some of these are given below.

35. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Electrodeposition Apparatus A diagram of an electrodeposition apparatus is shown on the right This particular apparatus will prepare four targets simultaneously. The composition of the solutions used to prepare these targets are beyond the scope of this presentation, but may be found in the IAEA publication TRS 432TRS 432 A picture of the actual apparatus is shown on the next slide.

36. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Electrodeposition Apparatus

37. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Radioiodine Production The target can be an internal target which can have a very low angle of incidence and high power dissipation The target is mounted inside the vacuum tank of the cyclotron and is irradiated under high vacuum Loss of the I-124 during irradiation is a concern Courtesy of John Clark

38. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Radioiodine Production The idea of an inclined plane can be used as well with the target attached directly to the cyclotron This target attaches to the beam port of the cyclotron Courtesy of Advanced Cyclotron Systems, Inc.

39. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Range of Protons in TeO 2 EnergyRange (MeV) 4.50 204.55 um 5.00 242.96 um 5.50 284.11 um 6.00 327.95 um 6.50 374.42 um 7.00 423.48 um 8.00 529.12 um 9.00 644.68 um 10.00 769.91 um 11.00 904.59 um 12.00 1.05 mm 13.00 1.20 mm 14.00 1.36 mm 15.00 1.53 mm 16.00 1.71 mm 17.00 1.90 mm 18.00 2.10 mm 20.00 2.52 mm The target can also be formed from a tellurium dioxide powder target. This target has the advantage of being able to be reused without extensive processing by distilling the iodine out of the TeO 2.. The target needs to be about 1.5 mm thick

40. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Depth distribution of 124 I yield The yield will vary as a function of depth into the target. In this plot we see the yield as a function of depth into the target. You can see that the yield is very low when the beam has penetrated 0.6 mm into the target. This can be compared to the excitation function as shown on the previous slide. The target is 124 TeO 2, with a incident proton energy of 14.9 MeV)

41. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Initial target preparation To prepare the target, the enriched tellurium dioxide powder is placed in a platinum dish which has a depression of about 1.5 mm deep.

42. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Inserting the target into furnace The platinum dish is placed in the furnace to melt the TeO 2 powder into a glass for irradiation

43. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Supercooled liquid TeO 2 on the Pt disk After melting, the powder has formed a glass and is ready for irradiation

44. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP TeO 2 before and after irradiation After irradiation with IBA Cyclone 18/9 (20 min, 6 μA, 13,5 MeV protons): yield ~1,5 mCi (56 MBq) 124 I After irradiation Before irradiation

45. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Thermochromatographic release of radioiodines The I-124 is distilled out of the TeO 2 target and then the target can be reused °C Solution for trapping radioiodine Air out Air in Al 2 O 3 trap for TeO 2 vapours TeO 2 target melted on a platinum disk HeaterThermocouple

46. Radiopharmaceutical Production Practical Targets Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary STOP Final Summary Here are the steps we must take to design and build useful targets Simple targets can be designed, but the material and method of construction is critical The physical form of the target material often determine the recycling Non-radioactive isotopes have many sources High power targets are being developed There are several characteristics of targets which make them more useful and robust Simple targets which do not degrade in performance Recycle enriched isotopes Minimize the amount of non-radioactive isotope in the final product Targets which will withstand high power deposition and use favorable nuclear reactions

47. Return to Main Menu