Production of radioisotopes: where it all begins!

Thomas J. Ruth

TRIUMF

Vancouver, Canada

Radiochemical tracers

Probe biochemical systems by labelingcompounds with known biologicalbehavior.

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.

Specific Activity

• Radioactivity per mass – MBq/mole

• To maintain tracer priniciple must have the highest SA possible.

• 370 MBq @ 370 GBq /mole = 1014 molecules

Sources of radioisotopes:

Naturally occurring – 235U

Fission – 99Mo 99mTc

Neutron capture – 186Re

Charged particle – 123I

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

Choice of method

The best possibility for achieving high SA is through charged particle reactions.

185Re + n = 186Re + 185Re(n,)186Re

18O + p = 18F + n18O(p,n)18F

Notation

Excitation function

R = In (1 – e-t)

WhereR – production rateI – beam flux – cross section(1 – e-t) – saturation factor

Positron Emitters

Nuclide T1/2 (mins) Reaction Target Product

11C 20.3 14N(p,) [11C]CO2(gas)[11C]CH4(gas)

13N 9.97 16O(p,)15O 2.03 15N(p,n)

18F 109.7 18O(p,n) [18F]F2 (gas)[18F]HF (aqueous)

Production Methods

Target Target Material Product Form

Gas 14N2, 1% O2 [11C]CO2

Gas 14N2, 1% H2 10% [11C]CH4

Gas [18O]O2 (95-98%) [18F]F2

Liquid [18O]H2O (88-98%) [18F]HF

Gas Target

Liquid Target

Parameters

• target construction• target constituents• irradiation conditions

– energy

– current

– temperature

– pressure

– dose

• optimize yield and specific activity

[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

[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.

[11C]CH4

• Reaction Pathway

N2 + H211C + N2 + H2

11CN

11CN + H2 HCN

HCN CH4 + NH3

protons

radiolysis

[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

[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.

[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,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

Nickles’ 4 Compartment Model

Non-reactive gases(CF4, NF3,…)

Atomic flourineF

MolecularflourineF2

NiF2 target surface

k1

k2

k3 k4 k5

k6 k7

Two-shot Method

• target evacuated

• O2 released to target and irradiated

• O2 cryotrapped out

• target evacuated with mech. pump

• target loaded with 20-200umole F2 + inert gas (Ne, Ar, Kr, Xe)

• 18F2 released from target via isotopic exchange

18O2 Gas Handling system

[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

[18F]F2

• advantages of aluminum:– stability

– passivation

– activation

– machinability

– cost

010203040506070

%18F2

[18F]F2 yield vs. 19F2 conc.

mol 19F2

Electrophilic 18F from a Siemens 11MeV Proton-only CyclotronChirakal et al. Nucl. Med. Biol. Vol. 22, p111, 1994.

[18F]F2 yield vs. Irradiation time

0

20

40

60

80

100

0 5 10 15 20 25

Recovery Irradiation (mins)

% y

ield

A.D. Roberts, T.R. Oakes, R.J. NicklesDevelopment of an improved target for [18F]F2 production.App. Rad. Isot. Vol. 46, p87, 1995.

[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

Multiple Recoveries

A. Bishop et al., Nucl. Med. Biol. Vol. 23, p189, 1996

0

10

20

30

40

50

60

1 2 3 4

Step

%[1

8F]

Rec

over

ed

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

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.

Confounding issues

In Target Chemistry?

For a 15 cm target at 10 atm N2 and a 10.5 MeVproton beam..

Heselius, Abo Akademi

Ep= 13.0 MeV

P0= 300 psi

Havar window

90% Thick

Ep= 13.0 MeV

P0= 300 psi

Havar window

75% Thick

Ep= 13.0 MeV

P0= 300 psi

Havar window

50% Thick

Ep= 13.0 MeV

P0= 300 psi

4.2 MeVHavar window

He cooling foil from TR13 Target

Note heat mark

Courtesy of John Lenz

Courtesy of John Lenz

Simulation Experiments

Test jig:

• Ø 10 mm copper rod with imbedded heater

• Low heat conductive isolation (Vespel)

• Thermocouple at window center

Data measurement:

• Record He flow

• Record temperature during heat/cooling cycle: Activate heat load, when T equilibrates (15 min) deactivate heat load

Performance of "Ideal" & Original Helium Windows

0

20

40

60

80

100

120

0 5 10 15 20 25

Time (minutes)

Te

mp

era

ture

(d

eg

. C)

Ideal 1mm nozzle (flow 39)

Ideal 1.3mm nozzle (flow 73)

Ideal 1.5mm nozzle (flow 90)

Original window (flow 108)

Water Cooled Grid Target

Roberts & Barnhart, U. Wisc.

Yield Comparisons

00.10.20.30.40.50.60.70.80.9

0 10 20 30 40

Irradiation Time (min.)

Rat

io (%

theo

r;

11C

H4/11

CO

2)

Al Cone

Ni cone

SS cyl.

Al cyl.

Performance Ratio (CH4/CO2 Yields)

0

0.2

0.4

0.6

0.8

1

5 20 30

Irradiation Time (min)

Yie

ld R

atio Ni Plated Al

Large Volume Al

Stainless Steel

11CH4 Yield vs Irradiation Time

0

200

400

600

800

1000

1200

1400

1600

1800

0 10 20 30 40 50 60 70

Time (minutes)

Rad

ioac

tivi

ty (

mC

i)

Theoretical @ 92mCi/A

Nb bodied target

Aluminum bodied target

Accelerator Production of High Specific Activity Therapeutic Radionuclides:

Production of High LET Radioisotopes at

TRIUMF-ISAC

Thomas J. RuthUBC/TRIUMF PET Program

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

Candidate radionuclides for radioimmunotherapy:

47Sc 64Cu 67Cu

90Y 105Rh 103Pd

111Ag 124I 142Pr

149Pm 153Sm 159Gd

166Ho 177Lu 186/188Re

194Ir 199Pt 211At

Accelerator Production

• Target Z Product Z

• High Specific Activity

• Low Energy - Fewer By-Products

Choice of Accelerator

• Commercial cyclotrons: 30 MeV• University based cyclotrons: 10 - 50 MeV• Hospital based PET accelerators: 3 - 19 MeV• National Labs: 100 - 500 MeV

High Energy Facilities• Brookhaven National Lab Lab, US

– 200 MeV, 145 A

• Los Alamos National– 100 MeV, 125 A

• Institute of Nuclear Research, Russia– 160 MeV, 100 A

• TRIUMF, Canada– 13, 2 x 30, 42, 70, 500 MeV, 50 A – 1 mA

• National Accelerator Centre, South Africa– 200 MeV, 100 A (p & d, HI)

Limitations of High Energy Facilities

• Availability

• Scheduling

• Range of products

• Sp. Act. affected by co-production of isotopes.

• Reliability

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 Activity64Ni 0.93 % nat. abund.Commercially Viable

Questionable

68Zn(p,αn)64Cu Research High Specific ActivityBoothe 1991 68Zn 18.6 % nat abund.

Target for 67GaCommercially Viable

SV Smith, ANSTO

68Zn(p,n)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 2.580 days

Gamma emitter SV Smith, ANSTO

77Br Production, t1/2 = 2.4 d

• Possible reactions:– 75As(,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%

124I - Potential Radiotoxic Nuclide

• t1/2 = 4.14 d

• + emitter• Production

– 124Te(p,n)124I @ 13 MeV

– 125Te(p,2n)124I @ 25 MeV

• Natural abundance: – 124Te = 4.79%

– 125Te = 7.12%

211At Productiont1/2 = 7.2 h

• Possible reactions– 209Bi(,2n) @ 28 MeV– 209Bi(7Li,5n)211Rn @ 60 MeV– 232Th(p,spall.)211Rn @ >200 MeV

• 211Rn t1/2 = 14.6 h

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

Estimated Production of 211Rn

• Target - UO2/C - 3.4 g

• Yield of 211Rn - 1.5 x 107nuclei/s/A• Translates to 0.027 mCi/h

Conclusion - Need at least 3 orders of magnitude improvement to have any clinical utility.

• 100 A 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.

High Specific Activity 186Re

• Chemistry of Re similar to that of Tc

• t 1/2 = 90.6 h

• I = 92% Emax= 1.1 MeV

• I= 9% E= 137 keV• Max. Theoretical Sp. Act. – • 1.28 X 106 GBq/mmol• Reactor Produced Sp. Act. - 37 GBq/mmol

Accelerator Production of 186Re

• 186W(p,n) 0.05 mCi/ Ah @ 18 MeV

• 186W(d,2n) 0.2 mCi/Ah @ 20 MeV• 197Au(p,spall.) 0.025 mCi/Ah @ 500

MeV• natPt(p,spall.) 0.2 mCi/Ah @ 500 MeV• natIr(p,spall.) 1.6 mCi/ Ah @ 500 MeV

Reactor produced radionuclides that potentially could be prepared via on-line isotope separator

system:

105Rh 109Pd 111Ag

142Pr 149Pm 153Sm

159Gd 166Ho 177Lu

186Re 188Re 194Ir

Production of Selected IsotopeIsotope ISOLDE Yield

(atoms/A /s) Projected ISAC Yield

mCi/100A day 105Rh 1.5 x 108 190 109Pd 2.4 x 109 790 142Pr 1 x 107 23

149Pm 4.3 X 105 0.4 153Sm 8.7 x 107 83

ION BEAM

60 keV

P l a s t i c – f o i l (PE, polyether, MYLAR, KAPTON …)

Implantation

Implantation into plastic material open channelsmetal foils channels closedII

G-J Beyer, CERN

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

125Xe Collection Box at TISOL

Critical Factors on 125I Implantation

• Production rates of 125Xe• Implant system efficiency• Stability from losses of implanted species • Radiobiological effectiveness

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 A proton beam.

• The 125Xe is quantitatively released.• Due to half-life differences the yield of 125I is 0.012 of

125Xe.

* JS Vincent, J. Radioanal. Chem. 65:17-29 (1981)

Implant system efficiency

• 125Xe is ionized via ECR ion source• Implantation potential 12 kV & 22 kV• Mean range in Fe is 0.047 • Foils tested include Fe, Ti, Au• Efficiency through the system to implantation

was 23%.

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..

Conclusions

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

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.

Problem:

• Reactor production - Low Specific Activity.

• National Lab Accelerators - Capacity for large scale production insufficient.

Possible Solution:

Production in reactors or spallation sources with off-line isotope separation.

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.

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.

TRIUMF, Vancouver, Canada

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