# Dependence of18F Production Yield and Radioactive Impurities on Proton Irradiation Dose

Authors: Imam Kambali; Parwanto; Hari Suryanto; Nur Huda; Ferdi D. Listiawadi; Herta Astarina; Ratu R. Ismuha; Kardinah
Journal: Physics Research International
 (2017)

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## Abstract

Radiation safety for patients during positron emission tomography (PET) procedures is affected by the amount of radioactive impurities generated during production of fluorine-18 (18F) radionuclide. In this investigation, the dependence of 18F production yield and radioactive impurities on proton irradiation dose is discussed. Enriched water (H2O18) target was bombarded perpendicularly by 11-MeV proton beams at various proton doses. Experimental results indicated that the 18F radioactivity yield and the amount of 56Co and Ag110m radioactive impurities depend strongly on the proton dose. In the proton dose range between 2 μAhr and 20 μAhr, the radioactive impurities increased with increasing proton dose. There was no significant difference in the radioactivity yield of both 56Co and Ag110m impurities at low proton dose between 2 and 10 μAhr. However a huge difference was recorded when the dose was increased above 10 μAhr. The experimental data can be used to predict the amount of impurities generated during 18F production at proton dose of higher than 20 μAhr.


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## Body

## 1. Introduction

Current nuclear methods in medical and industrial radioisotope production have been mostly involving nuclear reactors and circular accelerators. Subatomic particles such as neutron, proton, deuteron,3He, 4He, and other heavier particles are generated and then accelerated to certain energies sufficient for production of radioisotopes. At thermal energy, neutrons can be directed into a target to create radioisotopes relevant for nuclear medicine applications, such as 154Sm, 166Ho, 149Pm, 166Ho, 161Tb, and 177Lu [1, 2]. Deuteron particles accelerated in circular accelerators or cyclotrons have been recently employed to produce short-lived medical radioisotopes such as Sc44m, Sc44g, 155Tb, and 161Tb [3, 4], whereas 3He particles have been suggested for production of Sc44m,46m+g,47,48, 48V, and 48Cr radioisotopes [5].Proton beams generated from cyclotrons have been widely employed to produce radionuclides relevant for medical applications [6–8] as well as materials studies [9, 10]. One of the most widely used radionuclides in medical diagnoses for positron emission tomography (PET) modality is fluorine-18 (18F) [11, 12]. Research on theoretical and experimental aspects of 18F production using small cyclotrons has been carried out elsewhere to study the optimum target system and irradiation parameters [13], radioactive by-products in the cyclotron vicinity [14], and identification of radioactive impurities [15].The main parameters affecting the types of radionuclidic impurities found in the enriched water target during18F production include the type of the window separating the cyclotron chamber and the target system. The most common materials used as the window are Havar and titanium (Ti) foils. Moreover, proton beam energy employed in the bombardment also influences the number of impurities that fell in the postirradiated target. Previous studies discovered that several radioactive impurities such as 56Co, 48V, 51Cr, 52Mn, 54Mn, 54Co, and 58Co were found to contaminate the enriched water target when proton beams passed through Havar windows [16]. For Nb window, the most significant impurities detected by Köhler et al. were 89Zr, Nb92m, Mo93m, 95Tc, and 96Tc [15].Most studies on the radionuclide impurities have concentrated on the identification of the impurities without further studying the effect of proton beam current on the amount of the impurities. In the present investigation, the dependence of proton beam dose on the radioactivity yields of18F and the impurities is discussed. A medical cyclotron which accelerates 11-MeV proton beams is used to produce 18F and, in this study, the impurity measurement is performed using a gamma spectroscopy system.


## 2. Materials and Methods

### 2.1. Irradiation

A 97% pure enriched water (H2O18), purchased from Cambridge Isotope Laboratories, Ltd., was set as the target for 18F radionuclide production. As much as 1.8 ml enriched water target was placed in a target system consisting of a Havar window and silver body as described elsewhere [14]. An 11-MeV proton beam was directed into the enriched water target at variable proton doses, ranging from 2 to 20 μAhr. The proton dose was varied by varying the irradiation time while keeping the proton beam at a constant current of 30 μA. Note that a new H2O18 target was prepared for every irradiation, allowing it to be free of contaminations prior to the irradiation. The irradiation procedure was performed using a typical Eclipse 11 cyclotron located at the National Cancer Center (NCC), Dharmais Cancer Hospital in Jakarta, Indonesia, as shown earlier [14].


### 2.2. Impurity Analysis and Radioactivity Yield

A portable gamma ray spectroscopy system which has been described elsewhere [14, 17] was used to detect and quantify the radionuclidic impurities. The Amptek-USA made spectrometer included a pocket MCA (Type MCA8000A) with the serial number 2278. The pocket MCA was connected to a NaI(Tl) detector. The impurities were recognized from their gamma ray energies as well as half lives.Theoretical calculations of the end of bombardment (EOB) yield of18F radionuclide were performed using the widely used equation [18] and the calculated results were compared with the experimental data by taking into account the radioactivity decays. Moreover, a computerized program was developed [19] using Visual Basic Language. While the 18F radioactivity was relatively easy to predict using the developed program, the impurity yields were not theoretically calculated in this investigation due to complex irradiation parameters.


## 2.1. Irradiation

A 97% pure enriched water (H2O18), purchased from Cambridge Isotope Laboratories, Ltd., was set as the target for 18F radionuclide production. As much as 1.8 ml enriched water target was placed in a target system consisting of a Havar window and silver body as described elsewhere [14]. An 11-MeV proton beam was directed into the enriched water target at variable proton doses, ranging from 2 to 20 μAhr. The proton dose was varied by varying the irradiation time while keeping the proton beam at a constant current of 30 μA. Note that a new H2O18 target was prepared for every irradiation, allowing it to be free of contaminations prior to the irradiation. The irradiation procedure was performed using a typical Eclipse 11 cyclotron located at the National Cancer Center (NCC), Dharmais Cancer Hospital in Jakarta, Indonesia, as shown earlier [14].


## 2.2. Impurity Analysis and Radioactivity Yield

A portable gamma ray spectroscopy system which has been described elsewhere [14, 17] was used to detect and quantify the radionuclidic impurities. The Amptek-USA made spectrometer included a pocket MCA (Type MCA8000A) with the serial number 2278. The pocket MCA was connected to a NaI(Tl) detector. The impurities were recognized from their gamma ray energies as well as half lives.Theoretical calculations of the end of bombardment (EOB) yield of18F radionuclide were performed using the widely used equation [18] and the calculated results were compared with the experimental data by taking into account the radioactivity decays. Moreover, a computerized program was developed [19] using Visual Basic Language. While the 18F radioactivity was relatively easy to predict using the developed program, the impurity yields were not theoretically calculated in this investigation due to complex irradiation parameters.


## 3. Results and Discussion

### 3.1. Radioactivity Yield of18F

The gamma ray spectrum of18F observed at different integrated beam currents, ranging from 2 μAhr to 20 μAhr, is shown in Figure 1. The figure indicates that the gamma ray peak at 0.511 MeV increases with increasing proton dose. The experimental radioactivity hikes proportionally with increasing integrated proton beam current, which clearly agrees with the calculated radioactivity yield as seen in Figure 1 (inset).Figure 1
Recorded18F spectrum at various proton doses observed 1 hour after the end of bombardment. The experimental radioactivity (circles) and calculated radioactivity (line) are shown in the inset.At low proton dose of 2μAhr, the experimental radioactivity yield recorded in the gamma ray spectroscopy system is 3.8073±0.3737 GBq as shown in Table 1. The intensity trend follows linear line of Y=1.81X-0.50 with R2=0.9961 (in which Y is the 18F radioactivity and X is the proton dose). As the proton dose is increased to 20 μAhr, the 18F radioactivity yield also goes up to 36.53±1.16 GBq. The linear regression equation derived in this experiment may be used to predict future 18F production when the proton beam is increased further above 20 μAhr, presumably the proton energy is kept at 11 MeV, and the radioactivity is measured one hour after irradiation. For example, a proton dose of 50 μAhr is required to produce 85.10 GBq of 18F radionuclide, whereas up to 107 μAhr proton dose is needed to obtain nearly 185.00 GBq of 18F.Table 1
Production yield of18F following 1-hour decay.
Proton dose (µAhr)
18F yield (GBq)
Experiments
Theory
2
3.81
±
0.37
3.60
2.5
4.42
±
0.40
4.32
6.5
11.01
±
0.64
11.23
10
16.52
±
0.78
17.28
11
18.87
±
0.84
19.01
20
36.53
±
1.16
36.01In general, our experimental results agree with previous investigations by Nye et al. [20] and Wieland et al. [21], in which the radioactivity yield of 18F increases with increasing proton dose. For example, at proton dose of 3.34 μAhr, our experiment results in 18F yield of 5.79 GBq compared to 5.25 GBq by Wieland et al. [21].


### 3.2. Experimental Spectrum and Yield of Radioactive Impurities

Following 2 days of cooling (decay) period, the majority of18F radioactivity has decreased which allows better observing the gamma ray spectrum of radioactive impurities. As indicated in Figure 2, two radioisotopes are captured by the gamma ray spectroscopy system, namely, 56Co and Ag110m. The two impurities have been previously discussed in the production of 18F radionuclide [16], despite no further discussion on the radioactivity dependence on the proton beam dose. The identified gamma rays for 56Co are at Eγ=0.847 and 1.238 MeV, whereas, for Ag110m, the strong peaks are recorded at Eγ=0.658, 0.885, and 1.4 MeV. In addition, the annihilation peaks at 0.511 MeV originated from positron emissions of 18F radionuclide and gamma emissions of 56Co and Ag110m impurities with energies over 1.022 MeV are also detected.Figure 2
Gamma ray spectrum of56Co and Ag110m impurities following 2 days of 18F decay period.As can be seen in Figure3, in general the radioactivity of both radioactive impurities (56Co and Ag110m) increases with increasing proton beam dose. For 56Co impurity, the radioactivity yield (Y) matches empirical equation Y=0.0172X2-0.1217X+0.3907 (with R2=0.9978), whereas the radioactivity yield of Ag110m impurity follows equation Y=0.0012X2+0.0505X+0.0088 (with R2=0.9924). Note that, in the equations, X represents proton dose expressed in μAhr. Again, the equations may be applied to calculate the radioactivity yields of both 56Co and Ag110m impurities. For instance, using a 50-μAhr proton dose, the expected impurity yields for 56Co and Ag110m are nearly 37 MBq and 5.55 MBq, respectively.Figure 3
Radioactivity yield of56Co (unfilled squares) and Ag110m (filled circles) following 2 days of decay period.As shown in Figure3 and Table 2, at low proton dose between 2 and 10 μAhr, there is no significant difference in the radioactivity yield of both impurities. For instance at 2 μAhr proton dose, as much as 0.18±0.08 MBq of 56Co is detected, whereas 0.11±0.06 μCi of Ag110m is recorded at the same proton dose. However the difference becomes more apparent and wider as the proton dose increases. At 20 μAhr proton dose, only 1.51±0.24 MBq of Ag110m is observed whereas around 4.86±0.42 MBq of 56Co is measured at the same proton beam dose, meaning that the amount of  56Co impurity is more than 3 times that of the Ag110m.Table 2
Radioactivity yield of56Co and Ag110m impurities following 2 days of decay period.
Proton dose (µAhr)
Impurity yield (MBq)
56Co
A
g
110
m
2
0.18
±
0.08
0.11
±
0.06
2.5
0.18
±
0.08
0.11
±
0.07
6.5
0.42
±
0.12
0.44
±
0.13
10
0.78
±
0.17
0.58
±
0.15
11
1.16
±
0.21
0.71
±
0.16
20
4.86
±
0.42
1.51
±
0.24The much higher increase in the56Co radioactivity yield observed in this experiment is most likely related to the following.(
1) Secondary Neutron Yield Production. During 18F production, secondary neutrons are generated via (p,n) nuclear reaction. While every incoming proton interacts with the atom it passes through, its interaction does not necessarily generate secondary neutrons. Thus the number of secondary neutrons produced in this process is not directly proportional to the number of the incoming protons. As discussed in previous studies [14, 16], 56Co is generated from 56Fe(p,n)56Co nuclear reaction whereas Ag110m is produced via 109Ag(n,γ)Ag110m nuclear reaction. As a result, the number of Ag110m radioisotopes is much less than that of 56Co radionuclides.(
2) Silver Holder Geometry. While the Havar window used in this investigation is perpendicularly hit by the incoming proton beam, the silver body is parallel to the beam as discussed in previous studies [14]. Secondary neutrons generated by the (p,n) reactions are most likely to hit any materials perpendicular to the incoming proton beam as highlighted in earlier similar investigation [17]. As a result, it makes the silver holder harder to be hit by the secondary neutrons and any recoiled atoms originated from the silver window. Thus the Ag110m radioactivity yield detected in the water target is much lower than the 56Co yield.


### 3.3. Impurity-to-18F Yield Ratio

Based on the experimental results as shown in Table3, at the end of bombardment (EOB), the average ratio between each impurity and 18F yield ranges between 1.2 and 6.2%. For Ag110m impurity, proton dose does not significantly influence the impurity-to-18F yield ratio. In contrast, the proton dose has significant impact on 56Co impurity-to-18F yield ratio, particularly when the proton dose is increased above 10 μAhr. In this case, the average on 56Co impurity-to-18F yield ratio jumps from 2.9% to 6.2%. The difference in the impurity-to-18F yield ratio between 56Co and Ag110m corresponds to both secondary neutron yield production and silver holder geometry as discussed in previous section.Table 3
Ratio of56Co and Ag110m impurities to 18F yield at EOB.
Proton dose (µAhr)
Impurity-to-18F yield ratio (%)
56Co
A
g
110
m
2
2.2
±
0.9
1.2
±
0.8
2.5
1.9
±
0.9
1.2
±
0.7
6.5
1.8
±
0.5
1.4
±
0.5
10
2.2
±
0.5
1.6
±
0.4
11
2.9
±
0.5
1.8
±
0.4
20
6.2
±
0.5
1.9
±
0.4


## 3.1. Radioactivity Yield of18F

The gamma ray spectrum of18F observed at different integrated beam currents, ranging from 2 μAhr to 20 μAhr, is shown in Figure 1. The figure indicates that the gamma ray peak at 0.511 MeV increases with increasing proton dose. The experimental radioactivity hikes proportionally with increasing integrated proton beam current, which clearly agrees with the calculated radioactivity yield as seen in Figure 1 (inset).Figure 1
Recorded18F spectrum at various proton doses observed 1 hour after the end of bombardment. The experimental radioactivity (circles) and calculated radioactivity (line) are shown in the inset.At low proton dose of 2μAhr, the experimental radioactivity yield recorded in the gamma ray spectroscopy system is 3.8073±0.3737 GBq as shown in Table 1. The intensity trend follows linear line of Y=1.81X-0.50 with R2=0.9961 (in which Y is the 18F radioactivity and X is the proton dose). As the proton dose is increased to 20 μAhr, the 18F radioactivity yield also goes up to 36.53±1.16 GBq. The linear regression equation derived in this experiment may be used to predict future 18F production when the proton beam is increased further above 20 μAhr, presumably the proton energy is kept at 11 MeV, and the radioactivity is measured one hour after irradiation. For example, a proton dose of 50 μAhr is required to produce 85.10 GBq of 18F radionuclide, whereas up to 107 μAhr proton dose is needed to obtain nearly 185.00 GBq of 18F.Table 1
Production yield of18F following 1-hour decay.
Proton dose (µAhr)
18F yield (GBq)
Experiments
Theory
2
3.81
±
0.37
3.60
2.5
4.42
±
0.40
4.32
6.5
11.01
±
0.64
11.23
10
16.52
±
0.78
17.28
11
18.87
±
0.84
19.01
20
36.53
±
1.16
36.01In general, our experimental results agree with previous investigations by Nye et al. [20] and Wieland et al. [21], in which the radioactivity yield of 18F increases with increasing proton dose. For example, at proton dose of 3.34 μAhr, our experiment results in 18F yield of 5.79 GBq compared to 5.25 GBq by Wieland et al. [21].


## 3.2. Experimental Spectrum and Yield of Radioactive Impurities

Following 2 days of cooling (decay) period, the majority of18F radioactivity has decreased which allows better observing the gamma ray spectrum of radioactive impurities. As indicated in Figure 2, two radioisotopes are captured by the gamma ray spectroscopy system, namely, 56Co and Ag110m. The two impurities have been previously discussed in the production of 18F radionuclide [16], despite no further discussion on the radioactivity dependence on the proton beam dose. The identified gamma rays for 56Co are at Eγ=0.847 and 1.238 MeV, whereas, for Ag110m, the strong peaks are recorded at Eγ=0.658, 0.885, and 1.4 MeV. In addition, the annihilation peaks at 0.511 MeV originated from positron emissions of 18F radionuclide and gamma emissions of 56Co and Ag110m impurities with energies over 1.022 MeV are also detected.Figure 2
Gamma ray spectrum of56Co and Ag110m impurities following 2 days of 18F decay period.As can be seen in Figure3, in general the radioactivity of both radioactive impurities (56Co and Ag110m) increases with increasing proton beam dose. For 56Co impurity, the radioactivity yield (Y) matches empirical equation Y=0.0172X2-0.1217X+0.3907 (with R2=0.9978), whereas the radioactivity yield of Ag110m impurity follows equation Y=0.0012X2+0.0505X+0.0088 (with R2=0.9924). Note that, in the equations, X represents proton dose expressed in μAhr. Again, the equations may be applied to calculate the radioactivity yields of both 56Co and Ag110m impurities. For instance, using a 50-μAhr proton dose, the expected impurity yields for 56Co and Ag110m are nearly 37 MBq and 5.55 MBq, respectively.Figure 3
Radioactivity yield of56Co (unfilled squares) and Ag110m (filled circles) following 2 days of decay period.As shown in Figure3 and Table 2, at low proton dose between 2 and 10 μAhr, there is no significant difference in the radioactivity yield of both impurities. For instance at 2 μAhr proton dose, as much as 0.18±0.08 MBq of 56Co is detected, whereas 0.11±0.06 μCi of Ag110m is recorded at the same proton dose. However the difference becomes more apparent and wider as the proton dose increases. At 20 μAhr proton dose, only 1.51±0.24 MBq of Ag110m is observed whereas around 4.86±0.42 MBq of 56Co is measured at the same proton beam dose, meaning that the amount of  56Co impurity is more than 3 times that of the Ag110m.Table 2
Radioactivity yield of56Co and Ag110m impurities following 2 days of decay period.
Proton dose (µAhr)
Impurity yield (MBq)
56Co
A
g
110
m
2
0.18
±
0.08
0.11
±
0.06
2.5
0.18
±
0.08
0.11
±
0.07
6.5
0.42
±
0.12
0.44
±
0.13
10
0.78
±
0.17
0.58
±
0.15
11
1.16
±
0.21
0.71
±
0.16
20
4.86
±
0.42
1.51
±
0.24The much higher increase in the56Co radioactivity yield observed in this experiment is most likely related to the following.(
1) Secondary Neutron Yield Production. During 18F production, secondary neutrons are generated via (p,n) nuclear reaction. While every incoming proton interacts with the atom it passes through, its interaction does not necessarily generate secondary neutrons. Thus the number of secondary neutrons produced in this process is not directly proportional to the number of the incoming protons. As discussed in previous studies [14, 16], 56Co is generated from 56Fe(p,n)56Co nuclear reaction whereas Ag110m is produced via 109Ag(n,γ)Ag110m nuclear reaction. As a result, the number of Ag110m radioisotopes is much less than that of 56Co radionuclides.(
2) Silver Holder Geometry. While the Havar window used in this investigation is perpendicularly hit by the incoming proton beam, the silver body is parallel to the beam as discussed in previous studies [14]. Secondary neutrons generated by the (p,n) reactions are most likely to hit any materials perpendicular to the incoming proton beam as highlighted in earlier similar investigation [17]. As a result, it makes the silver holder harder to be hit by the secondary neutrons and any recoiled atoms originated from the silver window. Thus the Ag110m radioactivity yield detected in the water target is much lower than the 56Co yield.


## 3.3. Impurity-to-18F Yield Ratio

Based on the experimental results as shown in Table3, at the end of bombardment (EOB), the average ratio between each impurity and 18F yield ranges between 1.2 and 6.2%. For Ag110m impurity, proton dose does not significantly influence the impurity-to-18F yield ratio. In contrast, the proton dose has significant impact on 56Co impurity-to-18F yield ratio, particularly when the proton dose is increased above 10 μAhr. In this case, the average on 56Co impurity-to-18F yield ratio jumps from 2.9% to 6.2%. The difference in the impurity-to-18F yield ratio between 56Co and Ag110m corresponds to both secondary neutron yield production and silver holder geometry as discussed in previous section.Table 3
Ratio of56Co and Ag110m impurities to 18F yield at EOB.
Proton dose (µAhr)
Impurity-to-18F yield ratio (%)
56Co
A
g
110
m
2
2.2
±
0.9
1.2
±
0.8
2.5
1.9
±
0.9
1.2
±
0.7
6.5
1.8
±
0.5
1.4
±
0.5
10
2.2
±
0.5
1.6
±
0.4
11
2.9
±
0.5
1.8
±
0.4
20
6.2
±
0.5
1.9
±
0.4


## 4. Conclusion

Two radioactive impurities (56Co and Ag110m) found in the postirradiated water target following 18F production have been measured for their radioactivities. Experimental results indicate that the radioactivities depend strongly on the proton beam dose. The higher the proton dose the higher the radioactivities. At low proton dose of up to 10 μAhr, there is no significant difference in the radioactivity of 56Co and Ag110m radionuclides. However the radioactivity difference becomes significant as the proton beam dose is increased above 10 μAhr. At this point, 56Co radioactivity is a lot higher than that of Ag110m, which is presumably due to secondary neutron yield production and silver holder geometry as discussed in the Results and Discussion.



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