Qucosa – Hemholtz-Zentrum Dresden-Rossendorf
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Non-destructive evaluation of RbCl and Rb targets in Sr-82 production
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Sr-82 is produced for PET cardiac imaging at the Isotope Production Facility (IPF) with 100-MeV proton beams. During irradiation, the target material (RbCl, Rb) and Inconel capsule are ex-posed for extended periods to intense radiation, thermally and mechanically induced stresses, and chemicals. The structural integrity of the Inconel capsules is of crucial importance to containing the target starting materials and produced Sr-82. Unexpected failure capsules severely affects the reliability of the isotope supply chain and increases in radioactive emission and wastes, maintenance cost, and personnel radia-tion exposure. Knowledge of the structural integrity of a target before irradiation plays an important role in that defects may be identified and rejected prior to irradiation. In the cases of where a breach occurs, the location of the breach can be correlated with the inspected data.
Material and Methods
RbCl target failure: IPF has a successful irradiation history of RbCl targets at 230 A proton beam current since the facility commissioning in 2004. In 2013 run cycle, three targets irradiated in the medium energy B slot (35–65 MeV) [1] failed unexpectedly. The failure mode was the formation and propagation of cracks at the cor-ner radius along the edge of the target (FIGS. 1a-b). The common failure location was in the rear window relative to the beam direction and at the top of the target. These targets failed relatively early in the course of irradiation and typically after several cycles of beam loss and recovery.
Possible failure mechanisms: A calculated von-Mises stress analysis at room temperature of an Inconel capsule under a static pressure load at 4 MPa shows a stress concentration at the corner radius and deformation of the window (FIG. 2).
Additionally, a beam loss and recovery process causes the capsule windows to fatique especially at the corner due to a thermal and pressure cyclic loading. Furthermore, there is a thermal stress within the window due a temperature gradient resulting from nonuniform heating by the donut-shaped IPF beam [2]. Finally, Cl vapor in the void region or Rb liquid at the top of the target where the highest temperature of target material (RbCl or Rb) is expected may have contribution to a stress-corrosion cracking. An individual or a combination of these mechanisms aggrevate target failure if defects (voids, cracks, or thinning) exist. When the applied stress exceeds the ultimate tensile strength of Inconel, the target is likely to fail at these locations.
Non-destructive evaluation methods: Digital radiographic images were generated using a Philips 450 x-ray source set to 150–190 keV and a Varian panel detector. Ultrasonic (UT) amplitude and time-of-flight (TOF) images were generated with a spherically-focused transducer operated at 50 MHz.
Results
Inconel capsule halves: Radiographic images of the front and rear parts of 7 RbCl A targets (~65-95 MeV) and 7 RbCl B targets prior to target assembly (FIG. 3). For target A halves (left two columns), there is some variation in thickness between the front and rear parts. Other than thickness variation, no other defects (inclusions, voids, cracks) was detected. For target B halves (right two columns), all rear parts exhibit thinning around their edges, whereas the front parts appear more uniform.
UT TOF images were performed on 4 target A halves (155, 156, 157, and 159) and 7 target B halves (154-160). The rear window of 155A appears to thin out (~12.5%) near the rim on the right half. The front of 159A shows a similar thinning (~ 15%) near the rim on the left half. Although there is a thinning along the edges, all parts except 159A front have an average thickness within the stated specification (TABLE 1).
Similarly to radiographic data, UT TOF data con-firm a thinning towards the edges of the window on most of target B parts. Only images of 155B are illustrated in FIG. 4. Significant thinning (15%) is observed on 154B (front & rear), and the rear windows of 155B, 157B, 158B, and 159B. Although there is a thinning, all parts have an average thickness within the stated specification (0.0120” ± 0.0005”) except for the rear windows of 154B and 155B. No inclusions or voids are apparent in any of the parts.
RbCl filled targets: For comparison purpose, three B (130, 135, 147) and two A (137, 147) filled targets were evaluated. Radiographic data show no defects in the Inconel capsules while the RbCl pucks have numerous features (cracks, voids). The images of targets 130B and 135B illustrate the basic conditions of the RbCl pucks (FIG. 5).
UT TOF images of targets 130B and 135B rear and front windows are illustrated in FIG. 6. Average thicknesses of 0.011–0.014” for both rear and front windows of all 5 targets are within the stated specification. However, there is thinning around the edge of the target 135B front window.
Rb empty capsule: Radiograph of an unfilled Inconel capsule with and the fill tube is shown in FIG. 7. The predrilled 1-mm OD pinhole on the front window can be easily detected with the instrument’s detection limits of 30-μm pinhole and 5-μm crack. There is no other visible defect or thickness variation. This target was filled with Rb to characterize the reaction released Rb through the pinhole with water and its effects on equipment.
Rb metal filled targets: Radiographs of two Rb metal filled targets show the front and side views of Rb distribution and fill tube (FIG. 8). Voids are visible throughout the Rb and small amount of Rb remaining in the fill tube. TOF results indicate the average thicknesses of 0.0201–0.0214” for both rear and front windows of 2 targets. Except the 2B front window, all thicknesses are within stated specification (0.020” ± 0.0005).
UT TOF images for the rear and front of each target capsule are shown in FIG. 9. Moiré pat-terns are likely caused by a combination of stress arising in the manufacturing/filling process and some degree of measurement artifact. Target 1B windows exhibit uniform thickness across the bulk of the diameter, with the front window being slightly thinner overall than the rear. There is slight thinning observed near the edges on both windows. Thinning is more pronounced on the left side of the rear window than the right side of the front window. Target 2B shows a more pronounced distortion particularly on the rear window. The rear window appears to have a slightly thinner concentric region approximately one-quarter of diameter in. The front window displays good uniformity, with slight thinning along the inner edge of the left. Both targets 1B and 2B were successfully irradiated up to 230 A for 2 hours. Higher beam current and longer irradiation of Rb targets is underway.
Conclusion
Radiographic and ultrasonic methods were used in non-destructive evaluation of pre-assembly Inconel parts and fully assembled RbCl and Rb targets. These studies show the potential to identify defective parts and/or targets prior to irradiation, to provide useful information for improving target manufacturing process, and to enable better decision-making in managing risks of target failure. The results also have target quality assurance potential, enable comparison of target features and document data for future interpretation of target failure. The benefits of non-destructive evaluation include improved target reliability, reduced target failure rate, reduced revenue loss and increased productivity of Sr-82
Cyclotron Production and PET/MR Imaging of 52Mn
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The goal of this work is to advance the production and use of 52Mn (t½ = 5.6 d, β+: 242 keV, 29.6%) as a radioisotope for in vivo preclinical nuclear imaging. More specifically, the aims of this study were: (1) to measure the excitation function for the natCr(p,n)52Mn reaction at low energies to verify past results [1–4]; (2) to measure binding constants of Mn(II) to aid the design of a method for isolation of Mn from an irradiated Cr target via ion-exchange chromatography, building upon previously published methods [1,2,5–7]; and (3) to perform phantom imaging by positron emission tomography/magnetic resonance (PET/MR) imaging with 52Mn and non-radioactive Mn(II), since Mn has potential dual-modality benefits that are beginning to be investigated [8].
Material and Methods
Thin foils of Cr metal are not available commercially, so we fabricated these in a manner similar to that reported by Tanaka and Furukawa [9]. natCr was electroplated onto Cu discs in an industrial-scale electroplating bath, and then the Cu backing was digested by nitric acid (HNO3). The remaining thin Cr discs (~1 cm diameter) were weighed to determine their thickness (~ 75–85 μm) and arranged into stacked foil targets, along with ~25 μm thick Cu monitor foils. These targets were bombarded with ~15 MeV protons for 1–2 min at ~1–2 μA from a CS-15 cyclotron (The Cyclotron Corporation, Berkeley, CA, USA). The beamline was perpendicular to the foils, which were held in a machined 6061-T6 aluminum alloy target holder. The target holder was mounted in a solid target station with front cooling by a jet of He gas and rear cooling by circulating chilled water (T ≈ 2–5 °C). Following bombardment, these targets were disassembled and the radioisotope products in each foil were counted using a high-purity Ge (HPGe) detector. Cross-sections were calculated for the natCr(p,n)52Mn reaction.
Binding constants of Mn(II) were measured by incubating 54Mn(II) (t½ = 312 d) dichloride with anion- or cation-exchange resin (AG 1-X8 (Cl− form) or AG 50W-X8 (H+ form), respectively; both: 200–400 mesh; Bio-Rad, Hercules, CA) in hydrochloric acid (HCl) ranging from 10 mM-8 M (anion-exchange) and from 1 mM-1 M (cation-exchange) or in sulfuric acid (H2SO4) ranging from 10 mM-8 M on cation-exchange resin only. The amount of unbound 54Mn(II) was measured using a gamma counter, and binding constants (KD) were calculated for the various concentrations on both types of ion-exchange resin.
We have used the unseparated product for preliminary PET and PET/MR imaging. natCr metal was bombarded and then digested in HCl, resulting in a solution of Cr(III)Cl3 and 52Mn(II)Cl2. This solution was diluted and imaged in a glass scintillation vial using a microPET (Siemens, Munich, Germany) small animal PET scanner. The signal was corrected for abundant cascade gamma-radiation from 52Mn that could cause random false coincidence events to be detected, and then the image was reconstructed by filtered back-projection. Additionally, we have used the digested target to spike non-radioactive Mn(II)Cl2 solutions for simultaneous PET/MR phantom imaging using a Biograph mMR (Siemens) clinical scanner. The phantom consisted of a 4×4 matrix of 15 mL conical tubes containing 10 mL each of 0, 0.5, 1.0, and 2.0 mM concentrations of non-radioactive Mn(II)Cl2 with 0, 7, 14, and 27 μCi (at start of PET acquisition) of 52Mn(II)Cl2 from the digested target added. The concentrations were based on previous MR studies that measured spin-lattice relaxation time (T1) versus concentration of Mn(II), and the activities were based on calculations for predicted count rate in the scanner. The PET/MR imaging consisted of a series of two-dimensional inversion-recovery turbo spin echo (2D-IR-TSE) MR sequences (TE = 12 ms; TR = 3,000 ms) with a wide range of inversion times (TI) from 23–2,930 ms with real-component acquisition, as well as a 30 min. list-mode PET acquisition that was reconstructed as one static frame by 3-D ordered subset expectation maximization (3D-OSEM). Attenuation correction was performed based on a two-point Dixon (2PD) MR sequence. The DICOM image files were loaded, co-registered, and windowed using the Inveon Research Workplace software (Siemens)
Modeling a water target with proton range and target density coupling
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Combined thermal and fluid modeling is useful for design and optimization of cyclotron water targets. Previous heat transfer models assumed either a distribution of void under saturation conditions [1] or a static volumetric heat distribution [2]. This work explores the coupling of Monte Carlo radiation transport and Computation Fluid Dynamics (CFD) software in a computational model of the BTI Targetry visualization target [3].
In a batch water target, as the target medium is heated by energy deposition from the proton beam, a non-uniform density distribution develops. Production target operation is ultimately limited by the range thickness of the target un-der conditions of reduced water density. Since proton range is a function of target density, the system model must include the corresponding change in the volumetric heat distribution. As an initial attempt to couple the radiation transport and fluid dynamics calculations, the scope of this work was limited to subcooled target conditions. With the increasing availability of multi-phase CFD capabilities, this work provides the basis for extending these calculations to boiling targets where the coupling of the radiation transport and fluid dynamics is expected to be much stronger.
Material and Methods
The Monte Carlo radiation transport code MCNPX was used to create energy deposition data tallies from proton interaction with the target water and beam window. The beam was modeled as a Gaussian distribution with 50% transmission through a 10 mm diameter collimator. The energy deposition tally was translated into a 3-dimensional, point-wise heat generation table and supplied as an input to the CFD code ANSYS CFX.
An iterative method was developed to couple the volumetric heat distribution from MCNPX to the fluid density distribution computed within ANSYS CFX. A 3-dimensional table of water density was exported from ANSYS CFX and imported into MCNPX. MCNPX was then used to calculate the heat generation rate (due to proton interactions) based on the assumed density profile. Applying the new heat generation profile to the ANSYS CFX model resulted in changes to the beam shape and penetration depth. The iterative scheme continued until converged values for density and heat generation rate were achieved.
Monte Carlo methods are computationally ex-pensive due to the large number of particle histories needed to generate accurate results. CFD simulations are also computationally expensive due to the large number of mesh elements needed. Optimization methods were used for both MCNPX and ANSYS CFX to result in achievable solution times and memory requirements. Local mesh refinement in the beam strike area was necessary for convergence. This was achieved by extending the boundary layer of the mesh within the target water domain deeper into the fluid. This allowed for better resolution within the beam strike area without significantly increasing the expense in the remainder of the fluid domain.
Additionally, direct simulation of the cooling water domain was decoupled from the computational model during the iterative process. Heat transfer coefficients from the first iteration were applied as a boundary condition for subsequent iterations. Once the beam and density distributions reached convergence, the beam data was applied to a high fidelity “full” model, which included the cooling water domain as well as increased particle histories in MCNPX.
Results and Conclusions
The target was initially modeled assuming a 10 μA beam of 18 MeV protons into uniform density target water with operating pressure of 400 psi. These conditions resulted in predicted maximum temperatures below the saturation temperature.
The final converged beam data was compared to the original (uniform density) beam data. As expected, the density-dependent beam penetrates farther into the target water than when a uniform density is assumed. The density-dependent beam has a broader Bragg peak region with a lower maximum heat generation rate than the original beam. A line plot of the volumetric heat generation rate through the center of the beam is shown in FIG. 2.
Even though the maximum volumetric heat generation rate was lower, the density-dependent beam resulted in a higher maximum fluid temperature.
Experiments were performed with the visualization target on an IBA 18/9 cyclotron, and video was recorded for a range of target operating conditions. Analysis of the video recordings from the experiment gives a peak fluid velocity in the target chamber of roughly 5–10 centimeters per second with a 10 A beam current. The velocities predicted by the CFD model are within the same range. There is also good agreement be-tween proton beam range between the experiment and model. The effective proton range can be seen in FIGURES 3 and 4.
Future work will include applying the coupling technique for two-phase boiling conditions and to gas targets. If successful, this method should be a powerful tool for design and optimization of liquid and gas targets
Pursuit of purity: Measurement of chelation binding affinities for NOTA, DOTA, and desferal with applications to effective specific activity
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The effective specific activity of a radioisotope is an indirect and highly useful way to describe a radioactive sample’s purity. A high effective specific activity combines the concept of an isotopically pure product with suitability via selectivity of a particular chelating body. The primary goals of this work are twofold: 1) To determine which metallic impurities have the largest impact on the effective specific activity for a given chelator, and 2) to form a model based on the binding affinities of each metal for to calculate a ‘theoretical effective specific activ-ity’ from broad band trace metal analysis. If successful, this information can be used to guide the production of high specific activity products through the systematic elimination of high-impact metallic impurities.
Material and Methods
Phosphor plate thin layer chromatography (TLC) was used to measure the effective specific activ-ity of 64Cu by NOTA and DOTA, and 89Zr by des-feral (DF). Typical measured effective specific activities are 2–5 Ci/μmol for 64Cu and 1–2 Ci/μmol for 89Zr.
Samples were created containing increasing cod competitive burdens (X) of CuCl2, ZnCl2, FeCl2, NiCl2, CrCl3, CoCl2, MnCl2, and YCl3. Standard concentrations were measured by microwave plasma atomic emission spectrometry. 50 pmol of NOTA, DOTA, or DF were added following the activity aliquots of 64Cu or 89Zr. Labeling efficien-cies (64Cu-NOTA, 64Cu-DOTA, 89Zr-DF) were measured using TLC’s, and were fit by linear regression to the form f(X) = b/(1 − AX), where A is the chelation affinity (inverse of dissociation constant) and X is the molar ratio of the metallic impurity to the amount of chelator.
Results and Conclusion
Affinity of Zr for DF was assumed to be unity, while the affinities of Cu for NOTA and DOTA were explicitly measured and were found to be 0.93 ± 0.13 and 5.2 ± 3.2 respectively.
It was found that Cu had the highest affinity for NOTA by a factor of 266, and that Zr had the highest affinity for DF by a factor of 40.
• In order of decreasing affinity to NOTA: Cu, Zn, Fe, Co, Cr, Y, and Ni
• In order of decreasing affinity to DOTA: Cu, Y, Zn, Co, Ni, Cr, and Fe
• In order of decreasing affinity to DF: Zr, Y, Cu, Zn, Ni, Fe, Co, Cr
These results suggest that aside from the carrier element it is most important to remove zinc from 64Cu products prior to chelation with NOTA and yttrium from 64Cu and 89Zr products prior to chelation with DOTA and DF, respectively. Therefore, it is logical to believe that 89Zr effective specific activities could be greatly improved by secondary separations with the goal of re-moving additional yttrium target material.
Chelation affinities of NOTA, DOTA, and DF for several common metals have successfully been investigated. These values will guide our future attempts to provide high effective specific activity 64¬Cu and 89Zr. Furthermore, a preliminary model has been formed to calculate effective specific activity from the quantitative broad band analysis of trace metals. Future work will include chelator affinity measurements for other likely contaminants, such as scandium, titanium, zirconium, molybdenum, niobium, gold, gallium, and germanium. Details will be presented
Leitwertkontrolle einzelner elektrisch kontaktierter Moleküle
Get PDFDie molekulare Elektronik setzt sich zum Ziel, passive und aktive Bausteine in integrierten Schaltkreisen auf molekularer Ebene zu realisieren. Dabei ist entscheidend, dass sich der elektrische Leitwert der molekularen Bauelemente hinreichend regulieren lässt. Um zu belegen, dass dies möglich ist, wird in dieser Dissertation die gezielte Leitwertkontrolle einzelner über Nanoelektroden kontaktierter Moleküle nachgewiesen. Die erzielten Ergebnisse ergänzen dabei nahtlos aktuellste Studien.
Zum einen werden kontaktierte molekulare Schalter durch Bestrahlung mit Licht einer bestimmten Wellenlänge in-situ von einem nicht-leitenden in einen leitenden Zustand geschaltet, wobei der Einfluss unterschiedlicher Seitengruppen für eine zusätzliche Modifikation des Leitwerts sorgt. Ausschlaggebend ist hierbei die elektronische Anbindung des Moleküls an die Elektroden. Zum anderen werden Molekül-Metall-Komplexe durch die Einbindung eines Übergangsmetallions von einem isolierenden in einen leitenden Zustand versetzt. In diesem Fall lässt sich der leitende Zustand durch die Wahl des Ions innerhalb einer Größenordnung variieren, was eine völlig neue Möglichkeit der Leitwertkontrolle in molekularen Bausteinen darstellt. Das Ion bestimmt dabei sowohl die mechanische Stabilität als auch die elektronische Struktur des Moleküls.
Für die Kontaktierung einzelner Moleküle kommt die Technik des mechanisch kontrollierten Bruchkontakts zum Einsatz. So lassen sich feine Goldnanoelektroden herstellen, an die Moleküle anbinden. Um eine präzise Analyse durchzuführen, werden über zwei unabhängige Messstrategien Informationen über das elektrische Transportverhalten sowie über die elektronische Struktur der Moleküle erworben.
In dieser Arbeit sind echte Neuentwicklungen auf dem Gebiet der molekularen Elektronik gelungen, die einen wesentlichen Beitrag für die Umsetzung integrierter molekularer Schaltkreise leisten
Production of radiometals in a liquid target
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Access to radiometals suitable for labeling novel molecular imaging agents requires that they be routinely available and inexpensive to obtain. Proximity to a cyclotron center outfitted with solid target hardware, or to an isotope generator for a radiometal of interest is necessary, both of which can be significant hurdles in availability of less common isotopes. Herein, we describe the production of 44Sc, 68Ga, 89Zr, 86Y and 94mTc in a solution target which allows for the production of various radiometallic isotopes, enabling rapid isotope-biomolecule pairing optimization for tracer development. Work on solution targets has also been performed by other groups [e.g. 1, 2].
Material and Methods
Solutions containing a high concentration of natural-abundance zinc nitrate, yttrium nitrate, calcium nitrate [3], strontium nitrate or ammonium heptamolybdate [4] were irradiated on a 13 MeV cyclotron using a standard liquid target. Some of the solutions contained additional hydrogen peroxide or nitric acid to improve solubility and reduce pressure rise in the target during irradiation. Yields calculated using theoretical cross sections (EMPIRE [5]) were compared to the measured yields. In addition, we tested a thermo-syphon target design for the production of 44Sc. Chemical separation of the product from the target material was carried out on a remote apparatus modeled after that of Siikanen [6].
Results and Conclusion
The proposed approach enabled the production of quantities sufficient for chemical or biological studies for all metals discussed. In the case of 68Ga, activity up to 480 ± 22 MBq was obtained from a one hour run with a beam current of 7 µA, potentially enabling larger scale clinical production. Considering all reactions, the ratio of theoretical saturation yields to experimental yields ranges from 0.8 for 94mTc to 4.4 for 44Sc. The thermo-syphon target exhibited an increase of current on the target by a factor of 2.5 and an increase in yield by a factor of five for the production of 44Sc. Separation methods were developed for all isotopes and separation efficiency ranges from 71 ± 1 % for 94mTc to 99 ± 4 % for 86Y. 44Sc, 68Ga, and 86Y were successfully used in labeling studies with a model 1,4,7,10-tetrazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelate, while 89Zr coordination behavior was tested using desferrioxamine-alkyne (DFO-alkyne). In summary, we present a promising new method to produce a suite of radiometals in a liquid target. Future work will continue to expand the list of radiometals and to apply this approach to the development of various peptide, protein and antibody radiotracers
Experience with top-of-foil loading [18O]water targets on an IBA 18 MeV cyclotron
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Liquid targets using top-of-foil loading concept have been succesfully employed for routine high current production of 18F and 13N at Cyclotope (Houston,TX), over the past ten years1,2. These targets are typically filled with 3.5 ml of water, then pressurized with helium gas at 22 bar and bombarded with 18MeV protons (70–100 µA). Average calculated saturation yield for produc-tion of 18F is ~7.8 GBq/µA (210 mCi/µA) using in-house recycled [18O]-water at approximately 93% enrichment.
Reduction of beam power per unit of area is one of the advantages of a tilted entrance-foil geo-metry. Implementation of this target geometry on the ACSI TR19 cyclotron 25degrees upwards irradiation port results in an almost horizontal target entrance foil. A 6ml total cavity volume target allows variable liquid fill volumes of 1.2–4.5 ml for beam current operation from 30–120 µA, resulting in a very efficient use of the costly 18O-water. In a near horizontal installation as in the mayority of cyclotrons, the fill volume flexibility is drastically reduced, having a minimum fill volume of 3.3 ml.
At the requirement of Laboratorios Bacon, Cyc-lotope modified the target design with a front mounted collimator compatible with the IBA Cyclone 18/9 cyclotron. A second requirement was to reduce the minimum fill volume for horizontally mounted targets to 2.5 ml or less, while maintaining saturation yield performance. To preserve compatibility with existing IBA targets, the target hardware was modified to operate in self-pressurization mode.
This paper presents the results obtained with high and low volume Niobium target inserts (6ml and 4 ml) mounted near horizontally on the IBA Cyclone 18/9 cyclotron and operated in self-pressurization mode.
We present pressure/current characteristics, target performance (saturation yield, produced activities, maintenance frequency, FDG yields, etc.).
Material and Methods
The following targets manufactured by Cyclotope were tested and routinely used for production at Laboratorios Bacon:
1-High Volume Target CY2 model (“American Standard”), 6ml Niobium cavity.
2-Low Volume Target, CY3a model (“Traful”), 4ml Niobium cavity.
3- Low volume Target, CY3b model (“Ferrum”), 4.1ml Niobium cavity.
Results and Conclusion
The advantages of self-pressurization mode (Laboratorios Bacon setup) are:
- Using the vapor pressure as a performance parameter
- heat removal by boiling/condensation cycle starts at lower temperature (beam cur-rent) .
While, the advantages of the pre-pressurized targets (Cyclotope setup) are:
- reduced pressure fluctuations
- performance is basically unaffected by plumbing dead volume
- flexibility to locate instrumentation farther away from radiation fields
- less dependence on fill volume
- potential target leaks can be detected before starting an irradiation
No significant differences were found in target performance when operated in either pressu-rization mode. The self-pressurizing setup seems to require a sligthly lower fill volume (approxi-mately 5%).
The maximum beam current was limited by the foil rupture pressure (~ 40 bar). Safe maximum operating pressure was determined as 30 bar. No foil rupture was experienced during nine months of daily irradiation of these targets in self-pressurizing mode at Laboratorios Bacon.
The irradiation parameters and target performance for the different targets are shown in Tables 1 and 2 below. The low volume Traful and Ferrum targets have the best saturation activity vs. fill volume, A(sat)/V, relation. Both targets produce 310 ± 31GBq (8.4 ± 0.8 Ci) of high quali-ty fluoride (F-18) in two hours of irradiation at 70 µA. The low volume targets have a low operation pressure (20bar @ 70µA) when compared to the IBA (NIRTA XL) targets. The typical saturation activity for the low volume targets was 592 ± 59 GBq (16 ± 1.6 Ci) of F-18 at 70 µA, 8.5 GBq/µA (228 mCi/µA) using 2.7ml enriched O-18 water (98 % +). The maintenance interval (> 10 mA.h) is very conveniente to reduce personnel radiation dose. No reduction in FDG yields was observed during that operation interval. In contrast, operation of the high volume targets in pre-presurization mode at the Cyclotope facility results in a higher maximum beam current limit (135 µA) for the same operating pressure (25 bar). Nevertheless, more O-18 water will be required to irradiate at this high current (4.5 ml vs. 3.0 ml). In self-pressurizing mode, a higher filling volume will reduce the expansion volume and, in consequence, the maximum beam current
Fully automated production of Zr-89 using IBA Nirta and Pinctada Systems
Get PDFFew PET isotopes are suitable for antibody labelling since immunoPET requires that the PET isotope can be attached to the mAb with high in-vivo stability and the decay half-life of the isotope should match the pharmacokinetics of the mAb (Phelps 2004). Both 124I (t½ = 4.2 d) and 89Zr (t½ = 3.3 d) have a near ideal half-life for anti-body-based imaging, but there are several ad-vantages of using 89Zr over 124I. For 124I, the high energy of its positrons (2.13 MeV), results in a relatively low PET image resolution and the possible dehalogenation in vivo can lead to significant radioactivity uptake in non-targeted organs. In comparison, for 89Zr the low energy of its positron (395.5 keV), results in a PET images with a higher spatial resolution and furthermore, 89Zr is a residualizing isotope, which is trapped inside the target cell after internalization of the mAb. One disadvantage of 89Zr is its abundant high energy gamma-ray (909 keV), which may limit the radioactive dose that can be administered to the patients.
The most popular reaction to produce 89Zr is the 89Y(p,n)89Zr nuclear reaction (Sahar et al., 1966; Link et al., 1986). A proton beam with 14-16MeV energy is used to bombard inexpensive high-purity 89Y metal target (99.9%), avoiding cumbersome recycling of the target material. The yttrium targets could be either a foil (Dejesus and Nickels, 1990), sputtered onto a copper support (Meijs et al., 1994) or Y2O3 pellets (S. A. Kandil, B. Scholten, 2007).
Although 89Zr is currently commercially available, its price is prohibitive for routine clinical applications of 89Zr immuno-PET. The motivation of the present work was the fully automated production of small quantities of 89Zr using commercially available automated systems. We also describe a newly designed and tested platinum cradle, capable of holding a metallic foil and being directly transferable/compatible between the IBA NIRTA target and IBA Pinctada Metal dissolution/purification module.
Material and Methods
The solid target infrastructure used for 89Zr production was identical to the implementation reported earlier for production of 64Cu and 124I (S. Poniger et al. 2012). The commercially avail-able Nirta Solid Target from IBA was coupled to our 18/9 IBA cyclotron using a 2-meter external beam line. A fully automated pneumatic solid target transfer system (STTS) designed by TEMA Sinergie was used to deliver the irradiated tar-gets to a dedicated hotcell. The newly designed platinum cradle holding the yttrium foil (0.127 mm thick, 8 mm d) is shown in FIG. 1.
Typical irradiation parameters were 14.9 MeV at 20 μA for 1.5 hours (90o angle of incidence). The irradiated cradle, containing the 89Zr target is then loaded directly into the IBA Pinctada Metal module (see FIG. 2) for dissolution/purification without disassembly. We used the dissolution/purification method described by Holland et al. 2009, without modification (Purification of 89Zr from 89Y, 88Y and other radionuclidic impurities using a hydroxamate column, with 89Zr eluted with 1.0M Oxalic acid). Radionuclidic purities were evaluated by gamma spectroscopy and traces of metallic impurities were determined by ICP-MS.
Results and Conclusion
FIGURE 3 shows the gamma spectrum of the purified 89Zr solution. Since yttrium has one stable isotope only, relatively pure 89Zr is produced at low energy (14.9 MeV). In these preliminary non-optimized cyclotron productions, average purified 89Zr yield of 0.34 mCi/μAh was achieved, in comparison to values of 1.5 mCi/μAh found in the literature (10° angle of incidence). In these preliminary experiments, no deformation of the foil was observed at 20 μA beam current and higher currents are under investigation
Improvements in the production of a low cost targetry for direct cyclotron production of 99mTc
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The established methods for the production of 99Mo, based on fission in nuclear reactors, continue to present problems as a result of the plant’s aging and the significant investments needed for maintenance or for their renewal. Much research work is thus in progress on the study of alternative methods for the production of 99mTc in quantities and with the degree of purity required for the clinical use. Between them, the cyclotron production of 99mTc via the 100Mo(p,2n)99mTc reaction has turned out as the most attractive alternative. One critical aspect regarding the production of 99mTc with cyclotron is the need for a robust and reliable target production process. Several techniques have been indicated as extremely promising such has plasma spray and laser cladding; however these methods require specialized instrumentation and complex operations to be performed handling activated materials in order to recover irradiated Mo.
In this work we report the development of the work done at the University of Bologna, as a part of a wider INFN project, as regards the methods of preparation of solid targets suitable for the production of 99mTc irradiating a target of 100Mo, employing a cyclotron for biomedical use, normally operated for the production of PET radionuclides.
Material and Methods
Irradiations were performed with a 16.5 MeV GE PETtrace cyclotron equipped with a solid target station previously developed by our group (1). In initial tests, a stack of 1–3 metallic foils, 100 μm thick, of natMo were irradiated with protons in the 15.9→9.8 MeV energy range. Foils were then dissolved in a HNO3-HCl solution and samples were analyzed with high resolution gamma-ray spectrometry (Canberra, including a HPGe detector with a 30% relative efficiency and a resolution of 1.8 keV at 1332 keV) using Genie2000 software; the measurement campaign lasted several weeks to take into account the different half-lives of the produced radionuclides. Results were extrapolated to a highly enriched 100Mo target and compared to Monte Carlo simulations previously performed with FLUKA and TALYS codes (2).
In order to investigate a method of preparation of the target that would make easier the recovery of the enriched material and recycling for the preparation of a new target, it was subsequently studied the preparation of pellets of Molybdenum trioxide. MoO3 powder (Sigma Aldrich, 99.9% trace metals basis, particle size < 150 μm) was used to prepare pellets using a 10 ton press. Pellets obtained in this way were then sintered on a Platinum support using a CARBOLITE furnace under a controlled atmosphere; the temperature was ramped according to a controlled and reproducible temperature cycle.
Sintered pellets were subjected to visual inspection, mechanical tests of resistance to loading and downloading in the cyclotron target station, thermal tests and then irradiated at increasing current. The irradiated targets were again visually inspected then weighed, dissolved and subjected to gamma-ray spectrometry analysis.
Results and Conclusion
The experimental saturation yield for 99mTc calculated on the basis of the gamma-ray analysis of irradiated metal foils, gave an extrapolated yield of 1.115 ± 0.015 GBq/μA for a 100 μm thick 100Mo enriched target, in accordance with the value of 1.107 ± 0.002 GBq/μA obtained in Monte Carlo simulations. On these bases, an irradiation of 3 h at 50 μA is expected to produce 16.3 ± 0.2 GBq of 99mTc; considering the use of an efficient purification system, a radionuclidic purity > 99.9 % 2 h after the EndOfBombardment and a specific activity comparable with the actual standards are expected as achievable.
Experiments on sintering pellets are still on going at the time of writing this report; initial results showed that addition of proper aggregating materials allows for suitable pellets preparation. The sintering process allows to obtain pellets having sufficient mechanical strength to withstand loading and downloading operations.
Initial irradiation tests with beam current up to 25 μA were performed successfully with no changes in mass and mechanical properties of the pellet.
These encouraging results suggest that sintered pellets may be a relatively inexpensive and easy solution to prepare 100Mo targets for the cyclotron production of 99mTc.
Further experimental tests at higher beam current will be performed in order to assess the maximum current achievable with no damage of the target.
At the same time, a prototype automated module based on standard industrial components is in testing phase as regards performance in the separation and purification processes
Titanium-45 as a candidate for PET imaging: production, processing & applications
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The 80kD glycoprotein transferrin (TF) and its related receptor (TFR1) play a major role in the recruitment by cancer cells of factors for their multiplication, adhesion, invasion and metastatic potential. Though primarily designed to bind iron and then be internalised into cells with its receptor, TF can also bind most transition metals such as Co, Cr, Mn, Zr, Ni, Cu, V, In & Ga. Under certain conditions TF binds Ti (IV) even more tightly than it does Fe and that this occurs at the N-lobe (as distinct from C) of apoTF. Further, under physiological conditions the species Fe(C)Ti(N)-TF may provide the route for Ti entry into cells via TFR1 (1). Thus, the radiometal PET reporter isotope 45Ti with an ‘intermediate’ (~hrs) half-life suited to tracking cell-focused biological mechanisms is an attractive option for elucidating cellular mechanisms involving TF binding and internalisation, at least in (preclinical) animal models.
45Ti (T½ = 3.08 hr; + branching ratio = 85 %; mean β+ energy = 439keV, no significant dose-conferring non-511keV γ-emissions) was produced using the reaction 45Sc(p,n)45Ti by irradiating (monoisotopic) scandium discs with an energy-degraded proton beam produced by an 18MeV isochronous medical cyclotron. Separation and purification was achieved with an hydroxylamine hydrochloride functionalised resin. Comparative microPET imaging was performed in an immunodeficient mouse model, measuring biodistributions of the radiolabels 45Ti-oxalate and 45Ti-human-TF (45Ti-h-TF), out to 6hr post-injection.
Materials and Methods
High purity 15mm diameter scandium disc foils (99.5%, Goodfellow, UK) each thickness 0.100 ± 0.005 mm (55 mg) were loaded into an in-house constructed solid-targetry system mounted on a 300mm external beam line utilising helium-gas and chilled water to cool the target body (2). The proton beam was degraded to 11.7 MeV using a graphite disc integrated into the graphite collimator. This energy abolishes the competing ‘contaminant’ reactions 45Sc(p,n+p)44Sc and 45Sc(p,2n)44Ti. Beam current was measured using the well documented 65Cu(p,n)65Zn reaction. Calculations showed that the chosen energy is close to the optimal primary energy (~12 MeV) for maximising the (thin-target) yield from a 0.100 mm thick target.
For separation of Ti from the Sc target two methods were examined; (i) ion exchange column separation using 2000 mg AG 50W-X8 resin conditioned with 10mL 9M HCl. Disc is dissolved in 1 mL of 9M HCl, which at completion of reaction is pipetted into column. Successive 1 mL volumes of 9M HCl are added, and subsequent elutions collected. (ii) Following Gagnon et al., (3) a method employing hydroxylamine hydro-chloride functionalised resin (’hydroxamate method’) was applied, similar to its use in our hands for purification and separation of 89Zr (2) following its original description for 89Zr by Holland et al., (4). Disc dissolved in 2mL 6M HCl, then diluted to 2M. Elute through column to waste fraction 1 (w1 – see FIG. 1). Then elute 6 mL of 2M HCl through column to w2, followed by 6 mL of traceSELECT H2O to w3. Finally, elute Ti into successive 1 mL product fractions (p1, 2 etc.) using 5 mL of 1M oxalic acid. This procedure takes approximate 1 hr. 45Ti in elution vials was measured using γ-spectroscopy. Sc in the same vials was determined later using ICP-MS.
Results
A typical production run using a beam current of 40 μA for 60min on a 0.100mm-thick disc produced an activity of 1.83 GBq. Radionuclidic analysis of an irradiated disc using calibrated cryo-HPGe γ-spectroscopy revealed T½ = 2.97–3.19 hr (95% CI) for 45Ti, and with contaminant 44Sc < 0.19 %, with no other isotopes detected.
Despite systematic adjustments to column conditions satisfactory chemical separation was not achieved using the ion exchange column method (i), despite previous reports of its success (5). Typical results of separation using the successful hydroxamate method (ii) are shown on the FIGURE 1.
It is seen that significant portion of 45Ti is lost in the initial washing steps leading to waste collection. N = 4 replicate experiments showed a variation (SD) of 10 % of the mean in each elu-tion fraction. Subsequent ICP-MS of the same elutions for (cold) Sc showed approximately 80 % by mass appeared in w1 and 20 % in w2, with negligible total mass (total fraction ~1/6000) of Sc in product (p1–4) vials. However, the FIG. 1 shows that a total of only 30% of the original activity of 45Ti (corrected to EOB) is available in the product vials, with the vial of highest specific activity (p1) containing 14 %. However, using a stack of 2×0.100mm thick Sc discs as a target yields isotope of adequate specific activity with-out need for concentration, for subsequent labelling and small-animal imaging purposes.
In a ‘proof-of-principle’ experiment, two groups of healthy Balb/c-nu/nu female adult mice were administered with 45Ti radiotracers. The first group (N = 3) received approximately 20 MBq IP of 45Ti-oxalate buffered to pH = 7.0, and under-went microPET/CT imaging (Super Argus PET, Sedecal, Spain) out to 6hr post-injection, plus biodistribution analysis of radioactivity by dis-section at sacrifice (6hr). The second group (N = 3) received approximately 20 MBq IP of 45Ti-h-TF and were also studied to 6hr post-injection, followed by radioactive analysis after dissection at sacrifice. Organ and tissue biodistributions of the two groups at 6hr were similar but with 45Ti-oxalate showing slightly greater affinity for bone. Biodistribution by dissection results broadly confirmed the findings from PET images. However, TLC results suggested that similarity of radiolabel biodistributions of the two groups may be due to contamination of the TF radiolabel with non-conjugated Ti at time of injection. An alternative explanation is dechelation in vivo of 45Ti from 45Ti-h-TF.
Conclusion
Despite significant loss of 45Ti to the waste fractions of the separation process (total 53 %, corrected to EOB), 45Ti of acceptable specific activity and high radionuclidic purity has been produced from the reaction 45Sc(p,n)45Ti, with separation and purification of the product by hydroxamate column chemistry, confirming an earlier report. Though microPET in vivo imaging using 45Ti-based radiolabels was shown to be feasible, the similarity in the results for the label 45Ti-h-TF compared with ‘raw’ 45Ti-oxalate suggests further investigations. These may include a direct comparison of in vivo 45Ti-h-TF small-animal imaging plus post-dissection biodistribution with the same procedures using 89Zr labelled h-apotransferrin (6)