Dosimetric characterization of a novel UHDR megavoltage X-ray source for FLASH radiobiological experiments.

A first irradiation platform capable of delivering 10 MV X-ray beams at ultra-high dose rates (UHDR) has been developed and characterized for FLASH radiobiological research at TRIUMF. Delivery of both UHDR (FLASH mode) and low dose-rate conventional (CONV mode) irradiations was demonstrated using a common source and experimental setup. Dose rates were calculated using film dosimetry and a non-intercepting beam monitoring device; mean values for a 100 µA pulse (peak) current were nominally 82.6 and 4.40 × 10-2 Gy/s for UHDR and CONV modes, respectively. The field size for which > 40 Gy/s could be achieved exceeded 1 cm down to a depth of 4.1 cm, suitable for total lung irradiations in mouse models. The calculated delivery metrics were used to inform subsequent pre-clinical treatments. Four groups of 6 healthy male C57Bl/6J mice were treated using thoracic irradiations to target doses of either 15 or 30 Gy using both FLASH and CONV modes. Administration of UHDR X-ray irradiation to healthy mouse models was demonstrated for the first time at the clinically-relevant beam energy of 10 MV.

Proceedings of international symposium of trends in radiopharmaceuticals 2023 (ISTR-2023).

The International Atomic Energy Agency (IAEA) held the 3rd International Symposium on Trends in Radiopharmaceuticals, (ISTR-2023) at IAEA Headquarters in Vienna, Austria, during the week of 16-21 April 2023. This procedural paper summarizes highlights from symposium presentations, posters, panel discussions and satellite meetings, and provides additional resources that may be useful to researchers working with diagnostic and therapeutic radiopharmaceuticals in the academic, government and industry setting amongst IAEA Member States and beyond. More than 550 participants in person from 88 Member States attended the ISTR-2023. Over 360 abstracts were presented from all over the world by a diverse group of global scientists working with radiopharmaceuticals. Given this group of international radiochemists is unique to ISTR (IAEA funding enabled many to attend), there was an invaluable wealth of knowledge on the global state of the radiopharmaceutical sciences present at the meeting. The intent of this Proceedings paper is to share this snapshot from our international colleagues with the broader radiopharmaceutical sciences community by highlighting presentations from the conference on the following topics: Isotope Production and Radiochemistry, Industrial Insights, Regional Trends, Training and Education, Women in the Radiopharmaceutical Sciences, and Future Perspectives and New Initiatives. The authors of this paper are employees of IAEA, members of the ISTR-2023 Organizing Committee and/or members of the EJNMMI Radiopharmacy and Chemistry Editorial Board who attended ISTR-2023. Overall, ISTR-2023 fostered the successful exchange of scientific ideas around every aspect of the radiopharmaceutical sciences. It was well attended by a diverse mix of radiopharmaceutical scientists from all over the world, and the oral and poster presentations provided a valuable update on the current state-of-the-art of the field amongst IAEA Member States. Presentations as well as networking amongst the attendees resulted in extensive knowledge transfer amongst the various stakeholders representing 88 IAEA Member States. This was considered particularly valuable for attendees from Member States where nuclear medicine and the radiopharmaceutical sciences are still relatively new. Since the goal is for the symposium series to be held every four years; the next one is anticipated to take place in 2027.

Production and radiochemistry of antimony-120m: Efforts toward Auger electron therapy with 119Sb.

Targeted Meitner-Auger Therapy (TMAT) has potential for personalized treatment thanks to its subcellular dosimetric selectivity, which is distinct from the dosimetry of ß- and α particle emission based Targeted Radionuclide Therapy (TRT). To date, most clinical and preclinical TMAT studies have used commercially available radionuclides. These studies showed promising results despite using radionuclides with theoretically suboptimal photon to electron ratios, decay kinetics, and electron emission spectra. Studies using radionuclides whose decay characteristics are considered more optimal are therefore important for evaluation of the full potential of Meitner-Auger therapy; 119Sb is among the best such candidates. In the present work, we develop radiochemical purification of 120Sb from irradiated natural tin targets for TMAT studies with 119Sb.

Density reduction effects on the production of [11C]CO2 in Nb-body targets on a medical cyclotron.

Medical isotope production of 11C is commonly performed in gaseous targets. The power deposition of the proton beam during the irradiation decreases the target density due to thermodynamic mixing and can cause an increase of penetration depth and divergence of the proton beam. In order to investigate the difference how the target-body length influences the operation conditions and the production yield, a 12 cm and a 22 cm Nb-target body containing N2/O2 gas were irradiated using a 13 MeV proton cyclotron. It was found that the density reduction has a large influence on the pressure rise during irradiation and the achievable radioactive yield. The saturation activity of [11C]CO2 for the long target (0.083 Ci/µA) is about 10% higher than in the short target geometry (0.075 Ci/µA).

Membrane-based microfluidic solvent extraction of Ga-68 from aqueous Zn solutions: towards an automated cyclotron production loop.

BACKGROUND: The radionuclide Ga-68 is commonly used in nuclear medicine, specifically in positron emission tomography (PET). Recently, the interest in producing Ga-68 by cyclotron irradiation of [68Zn]Zn nitrate liquid targets is increasing. However, current purification methods of Ga-68 from the target solution consist of multi-step procedures, thus, leading to a significant loss of activity through natural decay. Additionally, several processing steps are needed to recycle the costly, enriched target material. RESULTS: To eventually allow switching from batch to continuous production, conventional batch extraction and membrane-based microfluidic extraction were compared. In both approaches, Ga-68 was extracted using N-benzoyl-N-phenylhydroxylamine in chloroform as the organic extracting phase. Extraction efficiencies of up to 99.5% ± 0.6% were achieved within 10 min, using the batch approach. Back-extraction of Ga-68 into 2 M HCl was accomplished within 1 min with efficiencies of up to 94.5% ± 0.6%. Membrane-based microfluidic extraction achieved 99.2% ± 0.3% extraction efficiency and 95.8% ± 0.8% back-extraction efficiency into 6 M HCl. When executed on a solution irradiated with a 13 MeV cyclotron at TRIUMF, Canada, comparable efficiencies of 97.0% ± 0.4% were achieved. Zn contamination in the back-extracted Ga-68 solution was found to be below 3 ppm. CONCLUSIONS: Microfluidic solvent extraction is a promising method in the production of Ga-68 achieving high efficiencies in a short amount of time, potentially allowing for direct target recycling.

Cyclotron production of 103Pd using a liquid target.

INTRODUCTION: In this work, we present the first feasibility study on the production of the medically important radionuclide 103Pd via the 103Rh(p,n)103Pd reaction by cyclotron irradiation of a liquid target. Using a liquid target removes the time consuming and complex dissolution process of rhodium post-irradiation due to its chemically inactive nature and thereby will improve the accessibility of this radioisotope. METHODS: Liquid targets made from Rh(NO3)3·×H2O salt dissolved in de-ionized water were irradiated using a 12 MeV beam at the TR13 cyclotron at TRIUMF, Vancouver. RESULTS: A maximum EOB activity of 1.03 ± 0.05 MBq was achieved with the tested conditions, sufficient for basic radiochemistry studies. An effective separation method using anion exchange chromatography is reported using 1 M HNO3 as an eluent for rhodium (90.1 ± 2.1 % recovery) and a 1:1 mixture of 0.5 M NH3 + NH4Cl palladium eluent (103.8 ± 2.3 % recovery). The solution showed good in-target pressure stability. However, the production efficiency decreased significantly with higher solution concentrations and irradiation lengths which puts into question the scaling potential of this method. CONCLUSION: This proof-of-concept study has demonstrated the potential for using liquid targets as complementary production method of 103Pd for research purposes. The liquid target route faces several scaling challenges but can nonetheless improve the availability of 103Pd and consequently aid in widening its utility for radiopharmaceuticals.

Determination of distribution coefficients of mercury and gold on selected extraction chromatographic resins - towards an improved separation method of mercury-197 from proton-irradiated gold targets.

Radioisotope mercury-197g (197gHg, half-life: 64.14 h) along with its metastable isomer (197mHg, half-life: 23.8 h) are potential candidates for targeted Meitner-Auger electron therapy due to their suitable decay properties. Their production can be achieved via proton irradiation of a natural gold target, but the number of studies surrounding their separation from an irradiated gold target is limited. This study focuses on the determination of distribution coefficients (Kd) of gold (III) and mercury (II) on seven extraction chromatographic resins. Mercury Kd were measured by means of radiotracers and Inductively Coupled Plasma Mass Spectrometry (ICP_MS); values obtained from the two methods were generally in good agreement. These results can provide insight on Hg and Au chemistry and aid in the design of improved separation system(s).

Design optimization of an electron-to-photon conversion target for ultra-high dose rate x-ray (FLASH) experiments at TRIUMF.

OBJECTIVE: To develop a bremsstrahlung target and megavoltage (MV) x-ray irradiation platform for ultrahigh dose-rate (UHDR) irradiation of small-animals on the Advanced Rare Isotope Laboratory (ARIEL) electron linac (e-linac) at TRIUMF. APPROACH: An electron-to-photon converter design for UHDR radiotherapy (RT) was centered around optimization of a tantalum-aluminum (Ta-Al) explosion-bonded target. Energy deposition within a homogeneous water-phantom and the target itself were evaluated using EGSnrc and FLUKA MC codes, respectively, for various target thicknesses (0.5-1.5 mm), beam energies (Ee-= 8, 10 MeV) and electron (Gaussian) beam sizes (2σ= 2-10 mm). Depth dose-rates in a 3D-printed mouse phantom were also calculated to infer the compatibility of the 10 MV dose distributions for FLASH-RT in small-animal models. Coupled thermo-mechanical FEA simulations in ANSYS were subsequently used to inform the stress-strain conditions and fatigue life of the target assembly. MAIN RESULTS: Dose-rates of up to 128 Gy s-1at the phantom surface, or 85 Gy s-1at 1 cm depth, were obtained for a 1 × 1 cm2field size, 1 mm thick Ta target and 7.5 cm source-to-surface distance using the FLASH-mode beam (Ee-= 10 MeV, 2σ= 5 mm,P = 1 kW); furthermore, removal of the collimation assembly and using a shorter (3.5 cm) SSD afforded dose-rates >600 Gy s-1, albeit at the expense of field conformality. Target temperatures were maintained below the tantalum, aluminum and cooling-water thresholds of 2000 °C, 300 °C and 100 °C, respectively, while the aluminum strain behavior remained everywhere elastic and helped ensure   the converter survives its prescribed 5 yr operational lifetime. SIGNIFICANCE: Effective design iteration, target cooling and failure mitigation have culminated in a robust target compatible with intensive transient (FLASH) and steady-state (diagnostic) applications. The ARIEL UHDR photon source will facilitate FLASH-RT experiments concerned with sub-second, pulsed or continuous beam irradiations at dose rates in excess of 40 Gy s-1.

Dosimetric Application of Phosphorus Doped Fibre for X-ray and Proton Therapy.

Phosphorous-doped silica optical fibres with a core diameter of 4 µm were tested in X-ray and proton fields for application in cancer therapy dosimetry. Specifically, the radiation-induced attenuation was investigated in terms of linearity in deposited dose in 15 MV and 6 MV photons and 74 MeV protons, as well as Bragg-peak detection along the proton track. Fibres were found to demonstrate linear relative dose response in both radiation modalities, but possible saturation did occur at the high linear energy transfer of the Bragg peak. This demonstrates the possibility to use these fibres as a relative dosimeter for radiation therapy applications.

Production and Supply of α-Particle-Emitting Radionuclides for Targeted α-Therapy.

Encouraging results from targeted α-therapy have received significant attention from academia and industry. However, the limited availability of suitable radionuclides has hampered widespread translation and application. In the present review, we discuss the most promising candidates for clinical application and the state of the art of their production and supply. In this review, along with 2 forthcoming reviews on chelation and clinical application of α-emitting radionuclides, The Journal of Nuclear Medicine will provide a comprehensive assessment of the field.

Improved Sc-44 production in a siphon-style liquid target on a medical cyclotron.

In order to use new and promising radiometals for molecular imaging, it is important that they can be obtained as inexpensively and easily as possible. This often requires a cyclotron with solid target hardware or a radionuclide generator, which are not widely available for rarely used radionuclides. Here, we investigate the improved production of 44Sc with a siphon-style liquid target system and compare to our previous work with a simple liquid target. A metal salt solution with a high concentration of natural abundance Ca(NO3)2 (0.14 g/cm3) was irradiated with a medical cyclotron (12 MeV protons; 20 µA). 44Sc was produced via the natCa(p,x)44Sc reaction. As the pressure increase during irradiation was reduced in the siphon-style target, it was possible to irradiate with a higher proton beam current (20 µA) than with the simple liquid target system (7.9 µA). In addition, the saturation yield per µA of 44Sc was increased by a factor of 3.18 ± 0.05 (6.2 ± 0.1 MBq/µA with the siphon target versus 1.94 ± 0.08 MBq/µA with the simple target). This results in an overall increase in 44Sc activity by a factor of 11.

Production, purification, and radiolabeling of the 203Pb/212Pb theranostic pair.

BACKGROUND: Lead-212 (212Pb, t1/2 = 10.6 h) and lead-203 (203Pb, t1/2 = 51.9 h) are an element-equivalent, or a matched theranostic radioisotope pair that show great potential for application in targeted radionuclide therapy (TRT) and single-photon emission computed tomography (SPECT), respectively. At TRIUMF we have produced both 203Pb and 212Pb using TRIUMF's TR13 (13 MeV) and 500 MeV cyclotrons, and subsequently purified and evaluated both radioisotopes using a series of pyridine-modified DOTA analogues in comparison to the commercially available chelates DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and TCMC (1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane). RESULTS: Proton irradiation (12.8 MeV) of natural and enriched thallium-203 (203Tl) targets gave 203Pb saturation yields of 134 ± 25 and 483 ± 3 MBq/µA, respectively. Thorium-228 (228Th, t1/2 = 1.9 y), a by-product of 232Th proton spallation on TRIUMF's main 500 MeV beamline (beamline 1A, BL1A), was recovered to build a 228Th/212Pb generator with the ability to deliver up to 9-10 MBq of 212Pb daily. Both lead isotopes were purified via solid phase extraction chromatography (Pb resin), and isolated in an acetate form ([203/212Pb]Pb(OAc)2) suitable for direct radiolabeling of chelators and bioconjugates. A series of cyclen-based chelators (herein referred to as DOTA-1Py, -2Py, and -3Py) along with established chelates DOTA and TCMC were evaluated for their ability to complex both 203Pb and 212Pb. All chelates incorporated 212Pb/203Pb efficiently, with higher radiolabeling yields observed for the 212Pb-complexes. CONCLUSION: The production of 203Pb and 212Pb was established using TRIUMF 13 MeV and 500 MeV cyclotrons, respectively. Both production methods provided radiometals suitable for subsequent radiolabeling reactions using known and novel chelates. Furthermore, the novel chelate DOTA-3Py may be a good candidate for biomolecule conjugation and further theranostic 212Pb/203Pb studies.

Meitner-Auger Electron Emitters for Targeted Radionuclide Therapy: Mercury-197m/g and Antimony-119

Targeted Radionuclide Therapies (TRTs) based on Auger emitting radionuclides have the potential to deliver extremely selective therapeutic payloads on the cellular level. However, to fully exploit this potential, suitable radionuclides need to be applied in combination with appropriate delivery systems. In this review, we summarize the state-of-the-art production, purification, chelation and applications of two promising candidates for Targeted Auger Therapy, namely antimony- 119 (119Sb) and mercury-197 (197Hg). Both radionuclides have great potential to become efficient tools for TRT. We also highlight our current progress on the production of both radionuclides at TRIUMF and the University of Wisconsin.

Atmospheric Neutron Monitoring through Optical Fiber-Based Sensing.

The potential of fiber-based sensors to monitor the fluence of atmospheric neutrons is evaluated through accelerated tests at the TRIUMF Neutron Facility (TNF) (BC, Canada), offering a flux approximatively 109 higher than the reference spectrum observed under standard conditions in New York City, USA. The radiation-induced attenuation (RIA) at 1625 nm of a phosphorus-doped radiation sensitive optical fiber is shown to linearly increase with neutron fluence, allowing an in situ and easy monitoring of the neutron flux and fluence at this facility. Furthermore, our experiments show that the fiber response remains sensitive to the ionization processes, at least up to a fluence of 7.1 × 1011 n cm-², as its radiation sensitivity coefficient (~3.36 dB km-1 Gy-1) under neutron exposure remains very similar to the one measured under X-rays (~3.8 dB km-1 Gy-1) at the same wavelength. The presented results open the way to the development of a point-like or even a distributed dosimeter for natural or man-made neutron-rich environments. The feasibility to measure the dose caused by the neutron exposure during stratospheric balloon experiments, or during outer space missions, is presented as a case study of a potential future application.

Pressure rise in medical cyclotron liquid targets: Transient analysis.

Transient behavior of proton-beam bombarded liquid-targets are studied at various initial conditions at the TR13 cyclotron at TRIUMF. Depending on the initial condition, experiments show a range of different responses from steady-state to self-sustained oscillations. To address this, a system of equations based on the conservation of mass and energy is proposed. Coupling between the beam and fluid-density and chemical reactions driven by the beam (radiolysis) are identified as the main reasons to describe this behavior. Excellent qualitative agreements are achieved.

89Zr for antibody labeling and in vivo studies - A comparison between liquid and solid target production.

INTRODUCTION: Zirconium-89 (89Zr, t1/2=78.4h) liquid target (LT) production offers an approach to introduce this positron-emitting isotope to cyclotron centres without the need for a separate solid target (ST) production set up. We compared the production, purification, and antibody radiolabeling yields of 89Zr-(LT) and 89Zr-(ST), and assessed the feasibility of 89Zr-(LT) for preclinical PET/CT. METHODS: 89Zr-(ST) production was performed with an 89Y foil on a TR 19 cyclotron at 13.8MeV. For LT production; an aqueous solution of yttrium nitrate (Y(NO3)3·6H2O) was irradiated on a TR 13 cyclotron at 12MeV. 89Zr was purified from the ST or LT material with hydroxamate resin, and used to radiolabel p-SCN-Bn-Deferoxamine (DFO)-conjugated Trastuzumab. MicroPET-CT imaging was performed at 1, 3 and 5days post-injection of 89Zr-DFO-Trastuzumab from ST or LT with biodistribution analysis on day 5. RESULTS: Irradiation of the ST yielded 2.88±1.07GBq/µA with a beam current of 14.0±3.8µA and irradiation time of 137±48min at end of bombardment while LT yielded 0.27±0.05GBq/µA with a beam current of 9.9±2.2µA and irradiation time of 221±29min. Radiolabeling of DFO-Trastuzumab with 89Zr-(ST) or 89Zr-(LT) was successful with purity>97% and specific activity>0.12MBq/µg (of antibody). MicroPET-CT imaging and biodistribution profiles showed similar uptake of 89Zr-(ST)-DFO-Trastuzumab and 89Zr-(LT)-DFO-Trastuzumab in tumor and all organs of interest. CONCLUSION: 89Zr-(LT) was effectively used to prepare antibody bioconjugates with specific activities suitable for small animal imaging. PET imaging and biodistribution revealed similar behaviours between bioconjugates labeled with 89Zr produced from the two target systems. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: These results have important implications for the production of PET isotopes such as 89Zr to cyclotron facilities with only LT capabilities - such as most clinical centres - expanding the availability of 89Zr-immunoPET.

Manganese concentration mapping in the rat brain with MRI, PET, and autoradiography.

PURPOSE: Mn2+ is used as a contrast agent and marker for neuronal activity with magnetic resonance imaging (MRI) in rats and mice, but its accumulation is generally not assessed quantitatively. In this work, nonradioactive Mn and 52 Mn are injected simultaneously in rats, and imaged with MRI, positron emission tomography (PET) and autoradiography (AR). Mn distributions are compared between modalities, to assess the potential and limitations on quantification of Mn with MRI, and to investigate the potential of multimodal measurement of Mn accumulation. METHODS: MRI (in vivo), PET (in vivo and post mortem), and AR (ex vivo) were acquired of rat brains, for which animals received simultaneous intraperitoneal (IP) or intracerebrovertricular (ICV)-targeted injections containing the positron-emitting radionuclide 52 Mn and additional nonradioactive MnCl2 , which acts as an MRI contrast agent. Pre and postinjection MR images were fit for the longitudinal relaxation rate (R1), coregistered, and subtracted to generate R1 difference maps, which are expected to be proportional to change in Mn concentration in tissue. AR and PET images were coregistered to smoothed R1 difference maps. RESULTS: Similar spatial distributions were seen across modalities, with Mn accumulation in the colliculus, near the injection site, and in the 4th ventricle. There was no 52 Mn accumulation measurable with PET in the brain after IP injection. In areas of very highly localized and concentrated 52 Mn accumulation in PET or AR, consistent increases of R1 were not seen with MRI. Scatter plots of corresponding voxel R1 difference and PET or AR signal intensity were generated and fit with least squares linear models within anatomical regions. Linear correlations were observed, particularly in regions away from very highly localized and concentrated Mn accumulation at the injection site and the 4th ventricle. Accounting for radioactive decay of 52 Mn, the MnCl2 longitudinal relaxivity was between 4.0 and 5.1 s-1 /mM, which is within 22% of the in vitro relaxivity. CONCLUSIONS: This proof-of-concept study demonstrates that MR has strong potential for quantitative assessment of Mn accumulation in the brain, although local discrepancies from linear correlation suggest limitations to this use of MR in areas of inflammation or very high concentrations of Mn. These discrepancies also suggest that a combination of modalities may have additional utility for discriminating between different pools of Mn accumulation in tissue.

Modeling the pressure rise of a liquid target on a medical cyclotron: Steady-state analysis.

The steady-state behaviour of a liquid target used to produce medical isotopes by low-energy cyclotrons is studied. A model based on the conservation of mass and energy is proposed to describe the pressure rise of the target assuming equilibrium between liquid and vapour phases during irradiation. The effects of water radiolysis are taken into account. Excellent agreement is achieved between the model, and both constant-temperature bath tests and experiments conducted on a 13MeV cyclotron at TRIUMF.

Practice Patterns Analysis of Ocular Proton Therapy Centers: The International OPTIC Survey.

PURPOSE: To assess the planning, treatment, and follow-up strategies worldwide in dedicated proton therapy ocular programs. METHODS AND MATERIALS: Ten centers from 7 countries completed a questionnaire survey with 109 queries on the eye treatment planning system (TPS), hardware/software equipment, image acquisition/registration, patient positioning, eye surveillance, beam delivery, quality assurance (QA), clinical management, and workflow. RESULTS: Worldwide, 28,891 eye patients were treated with protons at the 10 centers as of the end of 2014. Most centers treated a vast number of ocular patients (1729 to 6369). Three centers treated fewer than 200 ocular patients. Most commonly, the centers treated uveal melanoma (UM) and other primary ocular malignancies, benign ocular tumors, conjunctival lesions, choroidal metastases, and retinoblastomas. The UM dose fractionation was generally within a standard range, whereas dosing for other ocular conditions was not standardized. The majority (80%) of centers used in common a specific ocular TPS. Variability existed in imaging registration, with magnetic resonance imaging (MRI) rarely being used in routine planning (20%). Increased patient to full-time equivalent ratios were observed by higher accruing centers (P=.0161). Generally, ophthalmologists followed up the post-radiation therapy patients, though in 40% of centers radiation oncologists also followed up the patients. Seven centers had a prospective outcomes database. All centers used a cyclotron to accelerate protons with dedicated horizontal beam lines only. QA checks (range, modulation) varied substantially across centers. CONCLUSIONS: The first worldwide multi-institutional ophthalmic proton therapy survey of the clinical and technical approach shows areas of substantial overlap and areas of progress needed to achieve sustainable and systematic management. Future international efforts include research and development for imaging and planning software upgrades, increased use of MRI, development of clinical protocols, systematic patient-centered data acquisition, and publishing guidelines on QA, staffing, treatment, and follow-up parameters by dedicated ocular programs to ensure the highest level of care for ocular patients.

An analytical approach of thermodynamic behavior in a gas target system on a medical cyclotron.

An analytical model has been developed to study the thermo-mechanical behavior of gas targets used to produce medical isotopes, assuming that the system reaches steady-state. It is based on an integral analysis of the mass and energy balance of the gas-target system, the ideal gas law, and the deformation of the foil. The heat transfer coefficients for different target bodies and gases have been calculated. Excellent agreement is observed between experiments performed at TRIUMF's 13 MeV cyclotron and the model.