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Hybridised production of technetium-99m and technetium-101 with fluorine-18 on a low-energy biomedical cyclotron


New modes of production and supply of short-lived radioisotopes using accelerators are becoming attractive alternatives to the use of nuclear reactors. In this study, the use of a compact accelerator neutron source (CANS) was implemented to explore the production of 99mTc and 101Tc. Irradiations were performed with neutrons generated from a 16.5 MeV cyclotron utilising the 18O(p, n)18F reaction during routine 18F-fluorodeoxyglucose (FDG) production in a commercial radiopharmacy. Natural molybdenum targets in metal form were employed for the production of several Tc isotopes interest via (n, γ) reactions on 98Mo and 100Mo. The production of 99mTc and 101Tc under these conditions is considered and discussed.

1 Introduction

The capability of non-invasive, internal imaging, static or metabolic, of the various anatomical structures, processes, or the disease and detriment of these, has become the desideratum of diagnostics in the medical community. More than tens of millions of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) procedures are administered every year in the United States of America (U.S.) alone. With the ever-growing demand for these procedures, the pursuit of innovative technologies and processes has become an incessant enterprise for establishing techniques and systems that are more work-efficient, cost-effective, and safety-conscious.

Technetium-99m (99mTc, t\(_{1/2} = 6.007\) h) has been widely used for radiodiagnostic purposes for decades, and it is still one of the most used radioisotopes worldwide constituting approximately 85% of all nuclear medicine procedures conducted. Tc-99m can be produced through various nuclear transmutation methods, but commercially speaking, it is generally derived from molybdenum-99 (99Mo, t\(_{1/2} = 65.925\) h) via 235U targets [1]. However, the current commercial production and distribution of 99mTc rely on a complex supply chain that has proven itself prone to disruptions in years past, which was most recently observed during the SARS-CoV-2 pandemic [2]. Ultimately, this leads to delays in the diagnoses of patients due to postponed imaging procedures as well as the loss of material and capital.

Compact accelerator neutron sources (CANS) have presented themselves in the last few decades as a potential alternative for the decentralised production and distribution of radioisotopes [3]. In this regard, CANS refer to an array of fundamentally different accelerator sources such as cyclotrons, radiofrequency quadrupole (RFQ) accelerators, linear accelerators (LINACs) coupled with a photoneutron converter, electrostatic accelerators, laser-driven sources, and neutron generators. With many of these systems, neutron fluxes upwards of 1012 n/s are achievable [4]. However, an under-utilised source of neutrons is those originating from (p, n) reactions during routine PET radioisotope production, such as for 18F-based radiopharmaceuticals [5].

For example, over the last few decades routine manufacturing of 18F-fluorodeoxyglucose (FDG), the most frequently implemented PET agent, has greatly evolved. From the benchtop synthesis of several doses at a time to hundreds of doses manufactured in a single production run with multiple runs daily, the evolution of 18F[FDG] has become the gold standard for in-house medical radioisotope production. At the present moment, there exists at least one of these facilities with a cyclotron in every single state in the U.S., where states with larger populations, and thus higher demand requirements, may have several. Therefore, the growth in 18F has signified a correlative increase in potentially available neutrons that are effectively not being utilised.

The use of complementary neutrons generated in a biomedical cyclotron employing the 18O(p, n)18F reaction has been proposed for radioisotope production [6], although its application for the production of 99Mo / 99mTc or other Tc isotopes is hardly mentioned in the literature. In one study, 99Mo was implemented as a monitor for neutron flux in a Mo-containing multi-component flux wire measurement, although there was no targeted discussion for its production [7]. In another study, Link and Krohn report using neutrons generated during 13N production, i.e., 16O(p, α)13N, with an 11 MeV Siemens Eclipse at 30 μA over a duration of 0.5 h for producing 99Mo / 99mTc for teaching purposes. Although only small amounts were generated under these circumstances, the authors propose using (p, n) reactions and longer irradiations for higher output [8]. Considering the information provided in the literature pertaining to neutron production rates and energies, it was of interest to determine whether the simultaneous production 99Mo / 99mTc and 101Mo / 101Tc with 18F in a biomedical cyclotron was feasible and if it could be a viable option for production and distribution of these medically relevant radioisotopes.

2 Materials and methodology

Irradiations were performed with complementary neutrons generated on a biomedical cyclotron (Fig. 1) during routine 18F production with a 16.5 MeV proton beam operating between 75 μA and 85 μA. The 18F target material was 18O[H2O] with a purity of >98.0% 18O. High-yield 18F targets (BTI Targetry) were used [9]. The target bodies are made of Al 6061-T6 with a niobium (Nb) insert and implement a Havar alloy foil (0.04 mm) as a target window. Cooling of the target is performed using water and liquid transfer and pressurisation is used with high-purity helium (He) gas. The 18O[H2O] target volume is 3.5 mL.

Figure 1
figure 1

(A) Experimental setup for irradiation of Mo metal samples on a biomedical cyclotron (1) using high yield 18F targets from BTI Targetry. White arrows indicate the position of the samples to be irradiated on the primary 18F target (2) located in position 5, vertically located above a second 18F target in position 2 (3). The top arrow is pointing to the Mo metal block attached directly behind the target, and the bottom arrow is the location of the Mo metal foils behind a Styrofoam moderator (4). (B) Close-up view of the 18F target and Mo sample configurations from the perpendicular perspective relative to the incoming beam

Several varying geometries including cubes and foils of Mo metal were used for irradiations to determine the production of 99Mo. The Mo foil (10 cm × 10 cm × 0.01 cm) with ≥ 99.98% Mo was subdivided into 4-square pieces of dimension (5 cm × 5 cm × 0.01 cm) and approximate masses of 2.6–3.0 g. Mo target masses and dimensions are presented in Table 1. Foil samples were positioned underneath the 18F target in position 5 with a piece of Styrofoam moderator placed between the foils and the target. Mo cubes (volume 1 cm3, mass 10.3 g) with 99.95% Mo were used to determine production in thicker targets. Mo cubes were placed in small plastic bags and adhered to either the back of the 18F target directly (Cube 1) or behind the Styrofoam moderator (Cube 2) as shown in Fig. 1.

Table 1 Characteristics of Mo cube and foil samples used in irradiation experiments

Irradiation durations and conditions were logged throughout the course of the workweek. The values generated, such as run time, 18F yield, and beam current, were used to determine relative neutron production rates and relative total neutron output in order to compare with measured values of activity generated in the Mo samples. Scheduled production of 18F in the facility involves at least two to three production runs in a typical working day. The cyclotron is equipped with two 18F targets located in positions 2 and 5 approximately 28 cm apart at the rear of the targets as shown in Fig. 1. For each working day, the two 18F targets were alternated for each corresponding run. Samples were positioned on the back of the 18F target in position 5 with the sample faces oriented perpendicularly to the direction of the incoming proton beam, as well as underneath the 18F target with the sample faces oriented parallel to the beam. Several of the samples underneath the 18F target were also positioned behind two pieces of a Styrofoam moderator to determine the effect of moderation. Although both sample sets were located in the closest proximity to the neutron flux generated on the target in position 5 (Fig. 1), it is acknowledged that the samples were also within the bounds of the irradiation field generated by the 18F target in position 2 during operation, albeit at a lower neutron flux and different energy regime.

Radioactivity in the Mo foils was quantitatively determined using a NaI-type gamma spectrometer, taking measurements at various time intervals after end-of-bombardment (EOB). The NaI spectrometer was calibrated with a 137Cs source from North American Scientific with an activity of 2118 Bq at the time of use. The detector efficiency was determined to be 10.814% for the 661 keV peak. It is acknowledged that at lower γ energies (Eγ) better detector efficiencies are achievable, however, due to time and materials constraints of this study an efficiency plot was not established to determine this. The activities of 99Mo, 99mTc, and 101Tc were determined using the gamma emissions at 181.1 keV (I\(\gamma = 6.05\)%), 140.5 keV (I\(\gamma = 89.4\)%), and 306.8 keV (I\(\gamma = 89.4\)%). The absolute activity (A) of 99Mo in several samples was calculated as a function of integrated counts under the corresponding peaks (C) and adjusted for background counts (B) at the region of interest (ROI), detector efficiency (ε), decay time after EOB until the measurement (\(T_{d}\)), decay during the measurement time (\(T_{c}\)), and the associated γ-ray emission probability (\(I_{\gamma}\)) and decay constant (λ) with each distinct isotope using Eq. (1) [10]. Furthermore, the reaction rate of 99Mo production in the irradiated samples was also calculated considering the irradiation duration (\(T_{i}\)) with Eq. (2) [10].

$$\begin{aligned} &A= \frac{\lambda (C-B)}{\varepsilon \mathrm{I}\gamma e^{-\lambda Td} (1- e^{-\lambda Tc} )}, \end{aligned}$$
$$\begin{aligned} &R_{Mo-99} = \frac{\lambda (C-B)}{\varepsilon \mathrm{I}\gamma ( 1- e^{-\lambda T_{i}} ) e^{-\lambda T_{d}} (1- e^{-\lambda T_{c}} )}. \end{aligned}$$

3 Results and discussion

3.1 Complementary neutron production on a low-energy cyclotron

At the fundamental level, the endoergic nuclear reaction of an impinging proton on 18O for the production of 18F can be represented by the equation:

$$\begin{aligned} ^{18} O + p \rightarrow ^{18} F + n,\qquad Q = -2.44\ \mathrm{MeV}. \end{aligned}$$

The reaction threshold energy is approximately 2.5 MeV with a reaction cross-section maximum of 550 mb occurring around 5 MeV. Although the 18O transmutation proceeds above and below the maximum cross-section energy, the construction of the target is devised so that the beam terminates within the water target, and it does so with a beam energy as close to the maximum cross-section. For a 16.5 MeV incoming proton beam, slowing of the beam, or beam degradation is performed within the Havar alloy window and controlled by its relative thickness. According to Eq. (3), the transmutation of 18O via proton capture is accompanied by the ejection of a neutron from the nucleus. Therefore, for every atom of 18F formed, a neutron is also generated. Thus, the degree of transmutation is dependent upon the number of impinging protons on the target, which can be calculated using Eq. (4).

Here, the elemental charge of a proton (\(q_{\mathrm{proton}}\)) is equal to \(1.6 \times 10^{-19}\) Coulombs (C), and 1 microampere (μA) is equivalent to 10−6 Cs−1. The proton production rate (\(R_{\mathrm{proton}}\)) for a beam current (\(I_{\mathrm{beam}}\)) can be calculated as:

$$\begin{aligned} R_{\mathrm{proton}} \biggl( \frac{\mathrm{proton}}{\mathrm{sec}} \biggr) = I_{\mathrm{beam}} (\mu A)* 10^{-6} \biggl( \frac{C}{\mathrm{sec}} \biggr) * \frac{1}{q} \biggl( \frac{\mathrm{proton}}{C} \biggr). \end{aligned}$$

Under standard operating beam currents, \(R_{\mathrm{proton}}\) values up to 1 × 1014 protonss−1 are achievable. However, because of scattering events and interactions with the target body, window, and other components, the proton beam is not fully converted into 18F. One indicator of approximating beam conversion efficiency in the target is the saturation activity (SA), which is a function of 18F activity per unit of beam current, i.e., mCiμA−1. Using SA of the target and \(I_{\mathrm{beam}}\) the number of 18F atoms produced per unit time can be determined, and thus the number of neutrons produced (Rneutron) can be inferred as:

$$\begin{aligned} R_{\mathrm{neutron}} \biggl( \frac{\mathrm{neutrons}}{\mathrm{sec}} \biggr) = I_{\mathrm{beam}} *SA \biggl( \frac{mCi}{\mu A} \biggr) * 3.7*10^{6} \biggl( \frac{s^{-1}}{mCi} \biggr). \end{aligned}$$

For determining the thermal neutron flux (\(\Phi _{\mathrm{neutron}}\), neutrons/cm2sec) from Rneutron as shown in Eq. (5), Patterson’s formula [11] shown in Eq. (6) can be applied, where K (=1.25) is a constant and I is the surface area exposed to the neutron field.

$$\begin{aligned} \Phi _{\mathrm{neutron}} \biggl( \frac{\mathrm{neutrons}}{\mathrm{sec}* \mathrm{cm}^{2}} \biggr) =K \frac{R}{ I}. \end{aligned}$$

Thus, the higher the saturation activity, the higher the efficiency of beam conversion is and production of neutrons from the target. Likewise, the total activity generated per batch of 18F is equivalent to the total number of neutrons manifested. However, Carroll observed computationally with ALICE9 that the correlation between neutron production and SA did not trend linearly when proton beam energies exceeded 12 MeV. This was attributed to other energetically accessible 18O(p, x) neutron-emitting channels that were not possible under 12 MeV [12]. Likewise, the neutrons resulting only from 18O transmutation do not completely account for the total production within the system. In fact, an array of (p, n) reactions occurs in the irradiation system, such as with nearby parts of the cyclotron or the 18O target including the Havar foil itself that interact with the stray proton beam. Accounting for the entirety of these possible interactions, the reported calculated flux produced from the production of 18F with a proton beam operating at 15 MeV and 75 μA approaches 1.3 × 1012 n/s [13].

More accurate determinations of neutron fluxes produced in PET cyclotrons during 18F production have been conducted through experimental flux wire, neutron detection, and dosimetry measurements coupled with multi-system computational modelling, such as Monte Carlo, MCNP, FLUKA, etc. For example, Jeffries et. al. have reported the neutron flux generated from a GE PETtrace-800 employing BTI Targetry high yield 18F targets TS-1700 (80 μA) and TS-1650P (72 μA) [14]. Measurements were performed using a variety of activation flux wires with different neutron threshold energies along with comparative modelling via STAYS PNNL, MCNP6, and 3-Group programs. Results determined that the fast neutron flux density adjacent to the target was 1.8 × 109 n/cm2s to 3.0 × 109 n/cm2s with 1 MeV equivalent flux density from 2.4 × 109 neutrons/cm2s to 4.9 × 109 n/cm2s. Castillo analysed modelled data from a compilation of past studies concerning the neutron production on a 16.5 MeV proton beam on an 18O[H2O] target normalised to a beam current of 75 μA [13]. A summary of the data shows that depending on the model employed and physical parameters integrated into the model, the \(R_{\mathrm{neutron}}\) rate varied from 1.20 × 1012 n/s to 1.73 × 1012 n/s with neutron fluxes ranging from 2.18 × 108 n/cm2s to 1.45 × 108 n/cm2s. The determined neutron energy distribution spanned a broad energy range with maxima occurring in the epithermal to fast neutron regime, i.e., 0.01 to 5 MeV, as well as in the thermal region, ≤ 0.025 eV. Bosko [15] also reported on modelled neutron production rates and neutron energy distributions from a GE PETtrace-800. The \(R_{\mathrm{neutron}}\) was determined for a 16.5 MeV proton beam on a thick 18O[H2O] target to be 3.21 × 1011 n/s assuming a 60 μA beam current. The neutron energy distribution ranged from 1 MeV with a relative flux of 1.1 × 1011 n/s and extended to over 10 MeV with a gradual drop in flux to 1.1 × 108 n/s; the majority of the flux focused in the neutron energy range from 1 MeV to 4 MeV. This \(R_{\mathrm{neutron}}\) value is similar to the one reported by Horitsugi et al. from the GE Healthcare ALARA reports as 7.13 × 1011 n/s at 80 μA during dual port irradiation [16, 17]. Figure 2 shows the correlation between proton beam current and the resulting neutron flux (n/s) for 16.5 and 18.5 MeV cyclotrons from reported values in the literature.

Figure 2
figure 2

Reported neutron fluxes arising from the \({}^{18} O(p,n)^{18}\)F transmutation reaction as a function of proton beam current for (A) 16.5 MeV and (B) 18.5 MeV energy cyclotrons [7, 12, 13, 1518]

Another factor that should be considered is the neutron direction or angular distribution from the target. This is particularly important when considering the placement of a source to be irradiated, where neutron energy distribution and flux can be determined by sample position relative to the neutron source, i.e., 18O[H2O] target. For example, in a nuclear reactor scenario neutrons are emitted isotropically, whereas for accelerators this is not necessarily the case and neutron angular distribution is anisotropic. For accelerators, some of the energy from the primary incoming beam will impart some of its energy on the secondary particle emitted, which can lead to scattering as well as backscattering of the secondary particles. Generally, the higher the energy of the incoming proton, the higher the energy of the neutrons produced.

For the transmutation of 18O to 18F with a high-energy proton beam, the majority of the generated neutrons are emitted in the same direction as the incoming proton beam. As mentioned previously, scattering is observed further out from the source origin in the 18O target, where the neutron field becomes more diffuse, although still mostly directionally forward. It is also noted that a lesser, yet significant amount of neutrons are emitted in the opposite direction, or essentially backwards from the target into the incoming proton beam. Specifically, the GE Site Planning Guide states that when compared to the total flux of neutrons in the forward direction, those perpendicular to the incoming particle beam will be 30% less of this value, and those in the backwards direction will be at least 10× lower in magnitude [18].

Irradiations were performed on several Mo metal samples (Table 1) with various physical characteristics, i.e., mass, thickness, surface area, and volume, using the complementary neutrons produced during the production of 18F with a low-energy cyclotron. As previously discussed, the proton-induced transmutation of 18O to 18F results in the liberation of a free neutron, which is directly correlated to the yield of 18F produced in the 18O target. Shown in Fig. 3 is an 18F production curve for a 20-minute irradiation at 75 μA yielding a total of 1.8 Ci of 18F at EOB. As every atom of 18F generated is equal to at least one neutron, then this would correspond to an average neutron flux of 5.2 × 1011 n/s with a total neutron output of \(2.3 \times 10^{13}\) in the measured time period. With routine production schedules consisting of 4 to 5 h of operational beam time, the total average neutron output on a system equivalent to the one tested would range between 7.5 × 1015 to 9.4 × 1015 neutrons in a working day based solely on 18F transmutation, not considering other avenues of neutron production, for example, (p, n) reactions with the Havar window. In comparison to literature-reported values for neutron fluxes in a 16.5 MeV cyclotron, the value inferred from the 18F activity, i.e., 5.2 × 1011 n/s, is comparable to the one of Castillo [13], i.e., 6.0 × 1011 n/s, at 75 μA, suggesting that the system is likely capable of outputting fluxes upwards of 1 × 1012 n/s with all other neutron producing reactions considered.

Figure 3
figure 3

Activity (mCi) of 18F generated as a function of time (s) in an enriched 18O target using the cyclotron and experimental setup described previously with an operating current of 75 μA

3.2 Hybridised production of 99mTc and 101Tc with complementary neutrons

Although Mo is characterised by seven naturally occurring isotopes, i.e., 92Mo (14.53%), 94Mo (9.16%), 95Mo (15.84%), 96Mo (16.67%), 97Mo (9.60%), 98Mo (24.39%), 100Mo (9.82%), only 98Mo and 100Mo provide direct routes to the appreciable formation of 99Mo when interacting with neutrons. For 98Mo, the fundamental interaction is via 98Mo(n, γ)99Mo. The neutron capture on 98Mo occurs across a wide range of neutron energies. The thermal neutron capture, i.e., 0.025 eV, on 98Mo has a cross-section (σthermal) of approximately 0.137 b. In comparison to the fission-based production of 99Mo with thermalised neutrons, this value is nearly \({\sim} 270{\times}\) less for the equivalent irradiation using 235U as the fuel source. Furthermore, neutron capture reactions with thermal neutrons generally yield specific activities of hundreds of mCi/g at most depending upon the neutron flux, the amount of self-shielding effects, and the level of enrichment of 98Mo in the target. It is noted that enrichment of 98Mo can increase production yields up to 4× more than natural isotopic samples.

For higher energy neutrons, particularly in the resonance, i.e., 10-300 eV, and intermediate regions, i.e., 300 eV-0.05 MeV, 98Mo exhibits multitudes of enhanced resonance capture maxima. The resulting averaged cross-section of this region (σresonance) approaches 7 b, which is more than 50× than that of σthermal for 98Mo, i.e., 0.130 b. Likewise, it has been established that the self-shielding of epithermal neutrons from other Mo isotopes is negligible comparative to interactions with 98Mo [19]. Because of the greater probability of interaction, it has been reported that specific activities up to 3.4 Ci/g and 15 Ci/g are achievable for natural and enriched targets, respectively, thus yielding significantly greater outputs in 99Mo [20]. The neutron capture behaviour of 98Mo is quite similar to 100Mo, where σthermal for 100Mo is 0.199 b and σresonance is 3.76 b.

The second accessible pathway for 99Mo production with neutrons via 100Mo(n,2n)99Mo only occurs for fast neutrons, (≥ 1 MeV) [21, 22]. The threshold reaction energy is approximately 8 MeV with a cross-section (σfast) maximum of roughly 1.5 b befalling between 13 and 16 MeV. Relative to σthermal of 98Mo, this value is nearly 11× larger, although, for the averaged σresonance of 98Mo, it is about 5× less. However, because of the lower isotopic concentrations of 100Mo in comparison to 98Mo in natural samples, enriched materials can provide up to 10× the production. Due to the higher reaction threshold energy, this pathway is generally associated with production means where adequate fast neutron fluxes are present [23].

In order to determine the production of 99Mo/99mTc via neutron activation in a Mo target, several Mo metal samples with varying geometries, i.e., cube versus sheet, were subjected to the neutron field within the cyclotron. Samples were placed in the vicinity of the highest neutron fluxes around the 18F target. Typically samples were arranged prior to 18F production for the given day and either measured at the end of the production day or after several days.

Shown in Fig. 4 is the γ-ray spectrum of a Mo cube measured 1.4 h post-EOB following irradiation after 4.5 h in an un-moderated zone directly behind the 18F target, aligned with the incoming proton beam. The γ-ray spectrum shows the characteristic peaks for 99Mo at 185 keV and 725 keV, 99mTc at 146 keV, and 101Tc at 311 keV and 531 keV. These are in good agreement with the reported gamma energies for 99Mo at 181.1 keV and 739.5 keV, 99mTc at 140.5 keV, and 101Tc at 306.8 keV and 531 keV. The presence of 99Mo is most likely attributed to the neutron activation of 98Mo in the target, whereas 99mTc present is a result of 99Mo decay.

Figure 4
figure 4

Gamma spectrum of Mo cube after 1.4 h post EOB showing characteristic peaks for 99Mo, \({}^{99 m}\)Tc, and 101Tc after being irradiated in a neutron field for 4.6 h

The radioisotope 101Tc is also a daughter product, however, from 101Mo, formed via (n, γ) on 100Mo; the absence of any characteristic γ-ray peaks (E\(\gamma = 229.1\) keV (2.20%), 257.1 keV (2.77%), 261.1 (20.6%), 359.1. keV (3.31%), 570.1 keV (6.62%)) from 101Mo is due to its shorter half-life (t\(_{1/2} = 14.16\) min.). Unlike 101Mo, which is formed directly during the neutron irradiation, 101Tc being the daughter product still persists and can be seen as one of the more prominent peaks in the spectrum. Likewise, because the irradiation period (4.6 h) is sufficiently long compared to the half-life of 101Mo to achieve saturation, the concentration of ingrown 101Tc should be equivalent to that of 101Mo at EOB in the Mo target. Therefore, the total amount of 101Tc generated after EOB should be equal to the amount present at EOB plus the amount generated from residual 101Mo decay. The decay-corrected activity for the 311 keV peak of 101Tc in the sample was calculated to be 74 μCi at EOB.

Presented in Fig. 5 is the γ-ray measurement of the same Mo cube after 26 h post-EOB. The identified species in the spectrum were 99Mo with peaks at 180 keV and 740 keV, and 99mTc with a peak at 150 keV. At this point, there was no remaining 101Tc. The peak-to-peak ratio of 99mTc to 99Mo was determined to be 22.7, which is 6.6× greater than after 1.4 hr post EOB; this time post-EOB correlates to the near-maximum ingrowth of 99mTc from 99Mo decay.

Figure 5
figure 5

(Left) Gamma spectrum of Mo cube after 26 h post EOB showing characteristic peaks for 99Mo and \({}^{99 m}\)Tc. (Right) Gamma spectrum (12 h count) of Mo foil acquired 24 h after EOB

In Fig. 5, the γ-ray spectrum acquired 24 h after EOB of an irradiated Mo foil is presented. The foil was positioned underneath the 18F target and behind several layers of Styrofoam and irradiated within the neutron field for a total duration of 4.6 h. The γ-ray spectrum shows identifiable peaks indicative of 99Mo at 180 keV and 740 keV, and 99mTc at 150 keV. As expected, no 101Mo and 101Tc were detectable at the time of/during measurement. The γ-ray spectrum here is also comparable with the one shown in Fig. 5 for the Mo cube.

The effect of various physical attributes, (i.e., volume, surface area) of the Mo targets and moderation / no moderation of the neutron field utilised in the production of 99Mo / 99mTc were of particular interest. Three different samples, i.e., two Mo cubes (Cube 1 and Cube 2) and one Mo foil (Foil 1), were compared (Table 2), where all samples were irradiated for similar times (4.3 to 4.6 h) over the course of two production runs, one in which the samples were attached to the 18F used for production (2.7 h) and a second run during which they were located adjacently to the 18F target being operated (1.6 to 1.9 h); between the two production runs was a pause of approximately 1.5 h, however, for simplicity, 99Mo production only accounted for total irradiation time during operation. The effect of moderation was determined, where Cube 1 was placed in an un-moderated zone behind the 18F target, and Cube 2 was positioned underneath the target behind both a Styrofoam moderator and Foil 1. Final production activities and rates determined using Eq. (1) and Eq. (2), respectively, for 99Mo were normalised for decay after EOB and mass of the targets.

Table 2 Comparison of activities and reaction rates of 99Mo in various Mo metal samples after one production day of 18F in a low-energy cyclotron with neutrons generated through the 18O(p, n)18F reaction

As shown in Table 2, the production and reaction rates of the two Mo cubes are presented. Both cubes exhibited identical volumes and surface areas, however, Cube 1 was subjected to no moderation of the incoming neutron field, whereas the neutron field was relatively moderated prior to interacting with Cube 2. The specific activities of 99Mo normalised to EOB and per gram of sample show that both samples yielded approximately 240 nCi/g to 340 nCi/g of 99Mo produced at EOB after one routine production day of 18F, or 12 nCi/gCi-18F to 18 nCi/gCi-18F. The reaction rates of formation of 99Mo in the samples were determined to be 5.0 μCi/g to 7.6 μCi/g, accounting for the irradiation time of each sample. From these values, it is seen that Cube 1 yielded slightly greater values of specific activity and reaction rates in comparison to Cube 2, although not significantly. When taking into consideration that the neutron flux generated perpendicular to the incoming proton beam is 70% of the beam generated in the same direction, the values of Cube 2 when adjusted for this are 343 nCi/g and 7.1 μCi/g for the specific activity and reaction rate, respectively, and are essentially identical for those of Cube 1. An explanation for this behaviour is as such: although Cube 2 experienced a lower neutron flux than that of Cube 1, the neutron energies due to moderation were more favourable for neutron capture reactions for Cube 2, thus allowing for equivalent production and reaction rates of 99Mo. As discussed previously, neutron capture on 98Mo is greatly favoured within neutron energies of 300 keV to 0.05 MeV, and it quickly diminishes with neutron energies outside of this region. Therefore, if the neutrons coming out of the target have energies greater than 0.05 MeV, which is likely the case, then there will be far fewer interaction probabilities for capture on 98Mo.

After establishing the approximate yield of 99Mo that could be generated in a single 18F production day, it was of interest to investigate and track production over the course of a several-day period. However, it is noted that because 18F production days were not all homogenous, where some days accounted for a single run and others multiple runs, attempting to extract any definitive behaviour of 99Mo / 99mTc production was beyond the limit of the study and only broad trends in the data were to be considered. Figure 6 shows the relative activity of 99Mo produced over the course of several 18F production days. The starting day corresponds to a Friday, after which no irradiations were performed for the following two days over the weekend. Generally, the trend of the curve shows the relative build-in of 99Mo as a function of successive irradiations. Furthermore, a similar trend was also observed when tracking the ingrowth of 99mTc in the samples, as shown in Fig. 6.

Figure 6
figure 6

(Left) Production of 99Mo in a Mo foil tracked over several days of irradiation. Days 2 and 3 correspond to a weekend and no irradiations were performed. (Right) Presence of \({}^{99 m}\)Tc (raw counts per second) in Mo foils 1–4 over the duration of the irradiation experiment

4 Conclusion

The purpose of the study was to determine whether it was feasible to co-produce 99mTc and 101Tc in parallel with 18F using a hybridised system based upon liberated neutrons from the 18O(p, n)18F and other potential associated (p, n) reactions generated with a low-energy biomedical cyclotron. From the data, it was demonstrated that the co-production of both isotopes under the tested conditions was feasible. It is noted that Mo sample design and placement were extremely rudimentary—if much higher quantities of 99Mo / 99mTc or 101Mo / 101Tc were to be produced, possibilities for increasing yields, considering target mass/volume, irradiation time, and neutron flux could be applied for scaling. Linking a system like this with the appropriate separation platform for isolating Tc isotopes from irradiated low-specific activity (LSA) Mo targets, may become a distributed source of these and other medically relevant radioisotopes [3, 24]. Additionally, the possibility of leveraging at least some of the currently existing cyclotron infrastructures already in place could be seen as a huge advantage compared to building new reactors or facilities for radioisotope production.

Availability of data and materials

Data will be available from the authors upon reasonable request.


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The authors would like to extend sincere thanks to Mr. Jim Davis and Shertech Nuclear Laboratories for the use of the cyclotron and facilities. N. Mayordomo acknowledges the funding from the German Federal Ministry of Education and Research (BMBF) for the young investigator group NukSiFutur TecRad funding (02NUK072).


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Authors and Affiliations



Conceptualization, EJM and EVJ; methodology, EJM, EVJ; validation, EJM, EVJ; formal analysis, EJM, and EVJ; investigation, EJM and EVJ; writing—original draft preparation, EJM, EVJ, and NM; writing—review and editing, EJM, EVJ, and NM; project administration, EJM, EVJ. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Natalia Mayordomo.

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Competing interests

E.J.M. and E.V.J. are developing patent-pending technology related to production and isolation of Tc isotopes entitled: (US/International Patent) Direct, Continuous Transmutation of Molybdenum (Mo) for the Production and Recovery of Technetium (Tc) and Ruthenium (Ru) using a Neutron Source, submitted 2018. IFS, LLC consults on topics related to radioisotope production, use, and disposal. N.M. declares no competing interests.

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Johnstone, E.V., Mayordomo, N. & Mausolf, E.J. Hybridised production of technetium-99m and technetium-101 with fluorine-18 on a low-energy biomedical cyclotron. EPJ Techn Instrum 10, 1 (2023).

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  • F-18
  • Tc-99m
  • Tc-101
  • Radiopharmaceuticals
  • Radiopharmacy