Introduction 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.

Introduction 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).

Introduction To explore new questions and techniques in nuclear medicine, new isotopes with novel chemical and nuclear properties must be developed. We are interested in the small cyclotron production of new radiometals for the development of new radiopharmaceuticals (RX). In an example of RX multifunctionality, Luminescence Cell Imaging (LCI) has been combined with radio-isotopes to allow compounds that can be imaged with both optical microscopy and nuclear techniques [1]. Within this field, iridium cy-clometalates have good potential with excellent photophysical properties [2]. As well, low specific activity iridium-192 has found use in brachy-therapy as a high-intensity beta emitter [3]. Despite this, iridium radioisotopes have yet to be applied to cyclometalation chemistry, or a radiochemical isolation method developed for carrier free production on a medical cyclotron. Our goal is to demonstrate the feasibility of the production and isolation of radio-iridium, and its application to cyclometalate chemistry as a potentially interesting tool for nuclear medicine research. Materials and Methods Following literature precedent [4], natural osmium was electroplated onto a silver disc from basic media containing osmium tetroxide and sulphamic acid. The thin deposits obtained (15–20 mg cm−2) were weighed and characterized with scanning electron microscopy. Targets were irradiated using the TRIUMF TR13 cyclotron, delivering 12.5 MeV protons to the target disc. Initial bombardments were per-formed at 5 μA; gamma spectra of the targets were collected 24 hours after end of bombardment. The irradiated material was oxidized, dissolved from the target backing, and separated via anion exchange. In parallel to the isotope production work, non-radioactive iridium was used to define a chemical procedure suitable for the synthesis of model iridium cyclometalate compounds given low concentrations of radioiridium. These experiments will be performed with radioactive iridium in the next step of the research project. Results and Conclusion Proton bombardment of natural osmium yielded a range of iridium isotopes, with characteristic spectral lines corresponding to 186-190Ir, and 192Ir; no other characteristic radiation was observed. The EOB activity of each isotope was then used in thin target calculations to approximate their (p,n) cross section. Preliminary cross section measurements of the 192Os(p,n)192Ir reaction (53 ± 13 mb @ 12.5 MeV) confirm published data (52.3 ± 5.7 mb @ 12.2 MeV) [6], and provide as-yet unpublished data on the lower mass number isotopes. The progress of radioactive iridium through the radiochemical separation was tracked with a dose calibrator; the osmium complex formed was brightly coloured and could be seen retained on the column. The overall efficiency of the process is estimated at 80 %. Radioactive cyclometallation chemistry is currently under-way. The production and isolation of a range of iridium isotopes in a chemically useful form was demonstrated, and is ready to be applied to a cyclometalate model compound. Future work will investigate the production of 192Ir from enriched 192Os.

Introduction High starting radioactivity is usually advantageous for producing radiopharmaceuticals with high specific radioactivity. However, the [11C]CH4 yields from N2-H2 gas target fall short from theoretical amounts, as calculated from the cross section for the well-known 14N(p,α)11C nuclear reaction1. The beneficial effect of increased target chamber temperature on [11C]CH4 yields has recently been brought forward by us2 and others3. In addition to the temperature effect, our attention has also been on the hydrogen content factor. This study intends to examine the N2-H2 target performance in a substantially larger target chamber and at higher temperatures than our setup before and compare the results to the existing data. Materials and Methods Aluminium bodied custom design target chamber is used in fixed 17 MeV proton beam irradiations. Target chamber is equipped with heating elements and cooling circuit for temperature control. In addition to the target chamber body temperature, the target gas loading pressure and irradiation current can be varied. The irradiation product is collected into an ad-sorbent trap that was immersed in a liquid argon cooling bath within a dose calibrator. Results and Conclusion Pursued data will show [11C]CH4 saturation yields (Ysat [GBq/µA]) at different irradiation and target parameters.

Introduction Gold nanoparticles (AuNPs) have demonstrated their incredible versatility in applications such as in vitro and in vivo imaging, cancer therapy, and drug delivery.[1-3] These AuNPs come in many shapes including nanospheres, nanorods, nanoshells, and nanocages. Their versatility stems from the ability to construct or label a single AuNP with many functions. Many types of AuNPs are inherently flourescent, allowing for ex vivo utilization as well as small animal fluorescence imaging.[4] High atomic number and physical density allow for the possibility of using AuNPs as computed tomography (CT) contrast agents, especially in dual energy applications.[5] Some attempts have been made to bring AuNPs into the realm of nuclear medicine, mostly involving the extrinsic labeling of chelated radio-metals. Although these strategies have brought some success, an intrinsic labeling strategy could reduce concerns of in vivo instability, and changes in pharmacokinetic behavior.[6] Intrinsic radiolabeling strategies involve synthesizing the nanoparticles in the presence of a gold radioisotope, which is thereby structurally incorporated. The isotope of choice for this technique has typically been 198Au (t½ = 2.7 d, Eγ = 411.8 keV) as it is reactor produced and commercially available. However with such a high energy gamma ray, SPECT aquisition is far from optimal. Motivated by the shortcomings of previous intrinsic labeling techniques, we have sought to develop 194Au (t½ = 1.48 d, β+ = 1.73 %) as a potential PET isotope for labeling AuNPs. Although this nuclide has a weak positron branching ratio, it also has prominent gamma ray energies of 328 and 294 keV which are closer to the optimal SPECT energy window, allowing for the ability to image with both PET and SPECT. Material and Methods 194Au was produced by natPt(p,x) using 16 MeV protons. Target construction consisted of a water jet cooled platinum disc. Following irradiation, targets were etched by fresh concentrated aqua regia at 80 °C for four hours. The resulting solution was diluted by a factor of four and loaded onto a 50 mg UTEVA (Eichrom extraction resin) column equilibrated by 1 M HNO3. The column was rinsed with 10 mL 1 M HNO3, and the product was eluted using concentrated HNO3 in less than 1 mL. Results and Conclusion End of bombardment (EOB) yield for 194Au was measured to be 0.134 mCi/μAh by high purity germanium analysis. The half life was measured to be 38.5 ± 2.8 hours, which agrees well with the true half life of 37.92 hours. In addition to the production of 194Au, the production of 190–193Au and 196Au was observed. Most notably, the EOB yield for 193Au (t½ = 17.7 h) was 0.189 mCi/μAh. Target dissolution was slow and incomplete after four hours of etching. Alternative dissolution strategies i.e. electrolytic dissolution may be needed moving forward. The separation of 194Au from bulk Pt via the UTEVA extraction resin was robust and efficient, with an average separation efficiency of 96 %. An extensive literature review revealed no other Au/Pt separation from solutions containing aqua regia. Future goals include synthesis of ultrasmall 194Au incorporated AuNPs using a facile thermal reduction method.PET, CT and fluorescence imaging will also be carried out in vivo to establish the multimodal capabilities of the intrinsically radio-labeled nanoplatforms. To conclude, a novel separation technique has been developed to separate 194Au from Pt for use in intrinsically radiolabeled multi-modal AuNPs.

Zugl.: Dresden, Techn. Univ., Diss., 2005

Zugl.: Aachen, Techn. Hochsch., Diss., 2005

Zugl.: Stuttgart, Univ., Diss., 2006

Techn. Hochsch., Diss.--Aachen, 2008.

Zugl.: Bayreuth, Universiẗat, Diss., 2008.