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Optimization of zirconium-89 production in IBA Cyclone 18/9 cyclotron with COSTIS
solid target system
A. M. Dabkowski, S. J. Paisey, E. Spezi, J. Chester, and C. Marshall
Citation: AIP Conference Proceedings 1845, 020005 (2017);
View online: https://doi.org/10.1063/1.4983536
View Table of Contents: http://aip.scitation.org/toc/apc/1845/1
Published by the American Institute of Physics
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Cyclotron production for the radiometal Zirconium-89 with an IBA cyclone 18/9 and COSTIS solid target system
(STS)
AIP Conference Proceedings 1509, 108 (2012); 10.1063/1.4773950
Optimization of Zirconium-89 Production in IBA
Cyclone 18/9 Cyclotron with COSTIS Solid Target System
A. M. Dabkowski1, a) S. J. Paisey1 E. Spezi2 J. Chester3 and C. Marshall1
1
Positron Emission Tomography Imaging Centre (PETIC), School of Medicine, Cardiff University, Cardiff, UK
2
School of Engineering, Cardiff University, Cardiff, UK
3
Wales Cancer Research Centre, Cardiff University, School of Medicine, Cardiff, UK
a)
dabkowskia@cardiff.ac.uk
Abstract. Zirconium-89 is a promising radionuclide in the development of new immuno-PET agents for in vivo imaging
of cancerous tumours and radioimmunotherapy (RIT) planning. Besides the convenient half-life of 78.4 h, 89Zr has a beta
plus emission rate of 23% and a low maximum energy of 0.9 MeV, delivering good spatial resolution as a result of short
positron range in tissue (around 1 mm). Cyclotron production for the radiometal of 89Zr was investigated to find optimal
conditions according to results of FLUKA code Monte Carlo modelling of irradiation processes, nuclear reactions and
target design. This was followed by reasonably detailed experimental validation (making cyclotron productions for
expected high product yield and low impurities levels followed by activity measurements, spectra acquisitions and chemical
separation procedures), in which the strategies developed by computer models were carried out in the IBA Cyclone 18/9
cyclotron, permitting a comparison of the predicted and actual yields of 89Zr and isotopic by-products (impurities). Once
the in silica model was validated experimentally, then optimal method of the radiometal production in the cyclotron was
developed.
INTRODUCTION
The development of biological targeting agents (proteins, peptides, antibodies) and nanoparticles demands the
production of radionuclides with half-lives complementary to these biological processes [1]. Zirconium-89 is a
promising radionuclide for development of new immuno-PET agents [2, 3]. Alongside its’ convenient half-life of
78.4 h, 89Zr has a E+ emission rate of 23% and a low maximum energy of 0.9 MeV, delivering a short range in tissue
(|1mm) and good spatial resolution. In addition, the daughter radionuclide is the stable isotope Yttrium-89.
Zirconium-89 has only one significant J-line of 909 keV emitted during decay. Whilst the method of cyclotron
production using 89Y(p,n)89Zr route is well characterised [4] we have investigated optimization of the process using
an in silica model.
MATERIALS AND METHODS
FLUKA Monte Carlo (MC) code developed in CERN [5-7] was used to model the target geometry and then
simulate proton bombardment of Yttrium solid target disc (foil). The model contains basic beam parameters (Gaussian
shape, 18 MeV energy protons), Al beam line pipe, Nb energy degrader, Al target holder, Y solid target material and
cooling (Fig. 1).
WTTC16
AIP Conf. Proc. 1845, 020005-1–020005-8; doi: 10.1063/1.4983536
Published by AIP Publishing. 978-0-7354-1517-1/$30.00
020005-1
FIGURE 1. Geometry of the computer model used for FLUKA simulation of 89Zr cyclotron productions (3D views in the two
top pictures and 2D general layout in the bottom one).
Between 106 and 108 of primary beam particles (protons) were used in MC simulations to reduce the statistical
uncertainty of generated 89Zr yields to below 2%.
Some of the results from the simulated range of values were verified experimentally in the IBA C18/9 cyclotron
and COSTIS Solid Target System (STS) setup. The model enables the identification of parameters which result in the
highest yields of the product whilst remaining free of the radioactive long-lived impurities (88Zr, 88Y, 90Y and 85Sr).
Reactions that result in production of impurities are listed in Table 1.
TABLE 1. By-products of the 89Zr cyclotron production
Impurity
(Half-life)
88
Zr (83.4 d)
90
Y (106.626 d)
Sr (64.849 d)
Energy Range (Yield)
89
Y(p,2n)88Zr
Y (64 h)
88
85
Reaction
>13 MeV
9.8 – 16.6 MeV (<10-3 MBq/μAh)
89
Y(n,J)90Y
89
Y(p,pn)88Y
>11.6 MeV
Y(p,2p3n)85Sr
>16 MeV
89
020005-2
FIGURE 2. Solid target “coin” design – Aluminium 2-pieces holder and Yttrium foil inside
Since naturally occurring Yttrium is isotopically pure with a single isotope, isotopically pure Zirconium-89 can be
manufactured with a low proton beam energy (Ep = 9.8-16.6 MeV), using the 89Y(p,n)89Zr reaction [5]. The target
material 89Y (100% natural abundance) was modelled in form of the LY = 5-1000 Pm thick discs 99.9 % pure (Fig. 2).
(a)
(b)
FIGURE 3. Used Niobium vacuum window for the protons beam energy degradation (note the dark spot – beam trace) (a),
Schematic picture of the relationship between the Niobium foil thickness and the Zirconium 89 production yield (b)
The proton beam of Cyclone 18/9 cyclotron Ep was modelled as reduced from initial 18 MeV down to 16.6-9.8
MeV by the LNb = 0.1-0.5 mm thick Niobium energy degrader foils (Fig. 3) installed in the COSTIS STS. The selection
of the simulated productions to be verified experimentally was based on reasonable optimisation of the product yield
with possibly lowest rates of impurities generated (Fig 3 (b)). Some isotopes like 88Y (t1/2 = 106.6 d), 90Y (t1/2 = 64 h)
and 85Sr (t1/2 = 64.8 d) can be separated by chemical methods [4, 10] from the product and their presence in target after
production is acceptable at low levels. However, the long lived isotope 88Zr (t1/2 = 83.4 d) cannot be chemically purified
and its yield must be minimised.
The model was then validated experimentally (cyclotron productions, activity measurements, spectra acquisitions),
where strategies developed by computer models were carried out in the IBA Cyclone 18/9 cyclotron and comparisons
of the predicted and actual yields of 89Zr radiometal and impurities were possible. Once the computer model was
validated experimentally, the optimal method of the radiometal production in the cyclotron was developed.
The chemical separation and purification was based on well-known methods described in [4, 8]. Yttrium disc
(Special Metals Fabrication) released from Al holder and dissolved in 2 to 6 M HCl and 30% H 2O2 heated to 110 ºC,
then washed with HCl and water through separation column. Hydroxamate functionalized ion exchange resin was
used for separation of 89Zr product from Y target material. The 89Zr was eluted as Zr-oxalate with 1.0 M oxalic acid.
Zr-oxalate was split into fractions of varying volumes to optimize the specific activity for antibody labelling (ideally
100-200 MBq in 200 μL). Eeffectiveness of separation methods was verified using analytical techniques: gamma
spectrometry (Multi Channel Analyser), mass spectrometry and half-life measurements.
020005-3
RESULTS AND CONCLUSION
First attempts have been done to improve the production yield, following the results of FLUKA simulations
(Fig. 4-8). Results validated experimentally so far are shown in Table 2. The aim was to find the highest simulated
product yields with no 88Z impurities generated (at accuracy of 106 – 108 primary protons) using target disc thickness
less than 500 Pm and then validate them by cyclotron productions and postproduction analysis. The 150 Pm thick Y
target, previously used for routine productions of 89Zr in PETIC, has been replaced by one 300 Pm thick one. The
beam energy degradation was reduced from 400 to 350 Pm Nb foil, resulting in an increased yield of more than double
(from 16.6 to 34,6 MBq/PAh), as predicted by the simulations (Table 2). It is important to consider also the yields of
the impurities in the process of possible optimization (Fig. 5-8).
FIGURE 4. 89Zr yields for proton beam energy values (9.8 – 16.6 MeV) modelled in FLUKA for the practically achievable
range of thicknesses of Y solid target discs
020005-4
TABLE 2. Examples of the 89Zr yields for experimental cyclotron productions compared to the FLUKA simulation results.
Simulated
LY
LNb [Pm]
Experimental 89Zr Yield
Simulated 89Zr Yield
Yield Error
[MBq/uAh]
[MBq/uAh]
[Pm]
(Ep [MeV])
[%]
500
100
8.83
8.90
1.1
450
200
18.12
18.82
1.64
(10.7)
400
31.68
31.42
0.98
100
9.76
11.55
0.36
150
15.56
16.62
0.22
400
200
23.30
21.88
0.48
(11.7)
300
30.74
30.79
0.68
400
36.83
37.07
0.25
500
40.43
41.73
0.41
100
9.76
12.37
1.32
150
18.68
18.583
2.342
350
200
24.41
23.55
1.75
(12.6)
300
33.68
34.58
0.99
350
36.57
39.515
1.258
400
41.68
43.13
1.05
(9.8)
Results of the FLUKA simulations were generated as the plots of the yields for the isotopes produced in the yttrium
targets of LY = 5-1000 Pm thickness in the available range (9.8 – 16.6 MeV) of proton beam energies irradiating those
targets. First, the most effectively produced isotope is 89Zr with the highest yield between 13.5 and 16.5 MeV
depending on the Y target disc thickness (Fig. 4). Zirconium-89 production yield could be then optimized in that
energy range for the standard target size used in COSTIS STS.
020005-5
Second and most problematic product is the 88Zr which is the impurity that has to be eliminated by the energy and
target thickness choice because cannot be separated using any chemical purification methods. Figure 5 shows that
simulations, as expected, confirm the well identified threshold of 12.6 MeV for the beam energy value, when above
that 88Zr starts to be generated. Following that the optimal Nb beam energy degrader thickness is 350 μm to avoid the
88
Zr completely (Fig. 6).
FIGURE 5. 88Zr impurity generated for proton beam energy values (9.8 – 16.6 MeV) modelled in FLUKA for the practically
achievable range of thicknesses of Y solid target discs
FIGURE 6. 88Zr impurity was generated for Nb beam energy degraders thinner than 350 μm according to the model
simulated in FLUKA
020005-6
FIGURE 7. 88Y impurity generated for proton beam energy values (9.8 – 16.6 MeV) modelled in FLUKA for
the LY = 5-1000 Pm range of Y solid target discs
FIGURE 8. 90Y impurity generated for proton beam energy values (9.8 – 16.6 MeV) modelled in FLUKA for
the LY = 5-1000 Pm range of Y solid target discs
020005-7
It was shown by FLUKA simulations and its experimental validation, that reduction of the Nb degrader thickness
down to 350 Pm enables production of the 89Zr which is still free of the 88Zr and contains minor amounts (less than
10-2 MBq/PAh) of the other (not Zr) impurities (Figure 7 and 8) which can be easily removed by either chemical
separation or physical decay for isotopes with short half-lives.
Experimental and MC simulations’ results demonstrate the accuracy of the FLUKA model for the optimization of
the cyclotron production.
ACKNOWLEDGMENTS
Many thanks to Angelo Infantino (CERN) and Mario Marengo (University of Bologna) for useful discussions about
Monte Carlo modeling of the cyclotrons and targets used in medicine. Stephan Preusche and Martin Walther from
HZDR are greatly acknowledged for explanations about 89Zr target and its post processing methods.
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