Production Of 89Zr Research Articles

Pressed Solid Target Production of 89Zr and its Application for Antibody Labelling.

Zirconium-89 ( 89Zr, t1/2=3.27d) is an important + emitting radionuclide used in Positron Emission Tomography (PET) immuno studies due to its unique characteristics and increased demand due to simple and cost-effective production capacity. Production of 89Zr is achieved primarily through solid natural yttrium targets via different target preparation methodologies, such as electrodeposition, pressed foils, and spark plasma sintering. In this study, we have investigated the pressed solid target methodology. The Yttrium Oxide (Y2O3) powder was pressed to pellet form and stacked over a different back support plate, such as platinum (Pt), niobium (Nb), and tantalum (Ta). The target was irradiated with approximately 12 MeV proton beam for 10-60 minutes at 20µA current. The irradiated target was purified through a solid phase extraction method via hydroxamate-based resin by manual or automatic approach. The purified 89Zr was analyzed using gamma scintigraphy, and specific activity was calculated through Deferoxamine (DFO) chelation. 89Zr radionuclide via pressed target was effectively produced with a production yield of 20-30 MBq/µA.h, and the purification was achieved in 35 minutes with (87.46)% average recovery and >98% purity while using automated purification, but manual purification took 2 hours with (91 ± 2)% recovery and >98% purity. The production yield was comparable to the reported pressed target approach. Deferoxamine (DFO) chelation with 89Zr-oxalate was performed with purity >98% and specific activity of 25-30 µCi/mmol. In this study, we explored the production of 89Zr by pressed targets and purification via manual or automated methods with good radionuclide purity. The chelation with DFO or its analog was performed with good labeling efficiency and stability</p>.

89Zr production with electron accelerators by irradiating molybdenum

89Zr is a promising radionuclide for high-resolution PET imaging with radiolabelled monoclonal antibodies. In the present study, the possibility of 89Zr production from molybdenum targets was investigated using electron accelerators. The 89Zr activity yields were determined experimentally for bremsstrahlung with endpoint energies of 20 and 55 MeV. The amount of radioactive impurities and stable zirconium isotopes associated with the 89Zr produced was estimated using experimental results and the TALYS 1.96 code. The conditions for achieving a minimum level of zirconium by-product isotopes to meet the expected clinical requirements are discussed in the article. The reaction 92Mo (γ, p2n)89Nb→89Zr was found to be the most promising for photonuclear production. It can provide the highest purity of zirconium radionuclide and the lowest amount of zirconium stable isotopes. A major advantage of the proposed method will be the ability to use natural molybdenum targets.

Design of proton-beam degrader for high-purity 89Zr production

This work investigated the most suitable type of degrader (Cu, Al or Nb) and its thickness, taking into consideration the salient aspects of concrete activation for high-purity 89Zr production by 89Y(p,n)89Zr nuclear reaction. The MCNP and FISPACT codes were used to determine the optimal degrader thickness and the radioactivity of shielding concrete by neutron activation, respectively. The results showed that the optimal thickness of the beam degraders was 1.16, 3.19, and 1.33 mm for Cu, Al, and Nb, respectively. The neutron production rate per proton and the energy and angular distributions of neutrons varied depending on the type of degrader. Considering the radioactivity of the target-room concrete and the amount of radioactive waste expected to be generated, the use of a 1.33-mm-thick Nb degrader for 89Zr production was determined to be the best choice.

Target manufacturing by Spark Plasma Sintering for efficient 89Zr production

Zirconium-89 (89Zr) is an emerging radionuclide for positron emission tomography (PET), with nuclear properties suitable for imaging slow biological processes in cellular targets. The 89Y(p,n)89Zr nuclear reaction is commonly exploited as the main production route with medical cyclotrons accelerating low-energy (< 20 MeV) and low-current (< 100 μA) proton beams. Usually, natural yttrium solid targets manufactured by different methods, including yttrium electrodeposition, yttrium sputtering, compressed yttrium powders, and foils, were employed. In this study, the Spark Plasma Sintering (SPS) technique has been investigated, for the first time, to manufacture yttrium solid targets for an efficient 89Zr radionuclide yield. The natural yttrium disc was bonded to a niobium backing plate using a commercial SPS apparatus and a prototype machine assembled at the University of Pavia. The resulting targets were irradiated in a TR19 cyclotron with a 12 MeV proton beam at 50 μA. A dedicated dissolution module, obtained from a commercial system, was used to develop an automated process for the purification and recovery of the produced 89Zr radionuclide. The production yield and recovery efficiency were measured and compared to 89Zr produced by irradiating standard yttrium foils. SPS manufactured targets withstand an average heat power density of approximately 650 W∙cm−2 for continuous irradiation up to 5 h without visible damage. A saturation yield of 14.12 ± 0.38 MBq/μAh was measured. The results showed that the obtained 89Zr production yield and quality were comparable to similar data obtained using standard yttrium foil targets. In conclusion, the present work demonstrates that the SPS technique might be a suitable technical manufacturing solution aimed at high-yield 89Zr radioisotope production.

Medical radioisotope 89Zr production with RFT-30 cyclotron

Medical radioisotope 89Zr production with RFT-30 cyclotron

Evaluation of nuclear reaction cross sections for optimization of production of the important non-standard positron emitting radionuclide 89Zr using proton and deuteron induced reactions on 89Y target

89Zr (T1/2 = 3.27 d) is an important β+-emitting radionuclide of zirconium used in immuno PET. The excitation functions of the 89Y(d,2n)89Zr and 89Y(p,n)89Zr reactions were analyzed to deduce the optimum conditions for the high purity production of 89Zr. The nuclear model codes ALICE-IPPE, EMPIRE 3.2 and TALYS 1.9 were used to check the consistency and reliability of the experimental data. A polynomial fit to the chosen data for each reaction gave the excitation function, which was then used for the integral yield calculation of the product. The amount of the major radioactive impurity 88Zr was precisely analyzed for both the proton and the deuteron induced reactions on the 89Y target.

Cyclotron solid targets preparation for medical radionuclides production in the framework of LARAMED project

LARAMED project aims to set up an advanced science and technology facility to develop new and efficient methods to produce medical radioisotopes at Legnaro National laboratories of National Institute of Nuclear Physics. Waiting for the facility full operation, LARAMED group has already started working on the cyclotron production of several conventional and emerging radionuclides. Suitable target preparation is one of the most critical aspects in cyclotron production of radioisotopes. LARAMED group has investigated a set of non-classical techniques for metallic target preparation. Magnetron sputtering technique developed for ultra-thick film deposition was applied for the preparation of the Mo solid targets for 99mTc production, and Y ones for 89Zr production. Spark plasma sintering method provides efficient sintering of powders and good bonding of metallic pellet to a backing. Like magnetron sputtering, it was tested for natl00Mo and natY targets, as well as for natCr targets preparation aimed at 52Mn production. The High energy Vibration Powders Plating technique was instead applied for natural (Mo, Ti) and enriched 48Ti metallic powders with >95% deposition efficiency. All three techniques tested provided the cyclotron solid targets with high thermomechanical performance under the beam (IkW/cm2).

14 MeV high intensity cyclotrons: Two projects in progress

A 14 MeV high intensity compact cyclotron, CYCIAE-14, was built at China Institute of Atomic Energy (CIAE). In order to provide high quality proton beams for instant radiopharmaceutical distribution, and to produce a variety of radioactive ion beams taking use of the solid target, CYCIAE-14 adopts an injection system based on the external H- ion source, axial injection, and spiral inflector with a designed high beam intensity, while most PET cyclotrons adopt internal ion source. With the different using for the cyclotron, there are two projects. One project with 200μA/14 MeV can be used for isotope production of 11C, 15O, 13N and 18F. Another project with more than 400μA with 14 MeV can be used for more isotopes produced such as 64Cu, 124I and 99mTc. This paper will introduce the cyclotron of CYCIAE-14 with the two projects, and some experiments finished on the cyclotron will also be given in the paper, for example the 18F and 89Zr production, BNCT test.

New excitation functions measurement of nuclear reactions induced by deuteron beams on yttrium with particular reference to the production of 89Zr

We investigated 89Zr production induced by deuteron beams on yttrium targets at energies up to Ed=32 MeV using the stacked-foil activation technique. Cross sections of the following nuclear reactions 89Y(d,2n)89Zr, 89Y(d,3n)88Zr and 89Y(d,x)88Y have also been measured. Based on the measured values, we determined the thick target yields for 89Zr and 88Zr which is the main contaminant associated to the production of 89Zr.

Radiolysis reduction in liquid solution targets for the production of 89Zr

Increased interest in radiometals for nuclear medicine and imaging can be hampered by radionuclide supply. 89Zr for example, is a PET imaging nuclide for which no radionuclide generator exists. One method to produce 89Zr involves irradiating aqueous solutions of yttrium nitrate salt on small medical cyclotrons. However, in irradiating these solutions the radiolysis of water can cause significant H2 and O2 gas buildup, which can eventually rupture a sealed target vessel.We examine the role of nitrate and nitrite in radiolysis. Here, we find that using copper-coated cadmium pellets to chemically reduce nitrate to nitrite in solution prior to irradiation can reduce in-target radiolysis by approximately 60% as compared to other published methods of radiolysis reduction, but only in acidic solutions. We hypothesize that during irradiation, nitrate is converted to nitrite, consuming free radicals which would otherwise be available to eliminate molecular gas species. Performing this conversion before irradiation may limit the consumption of these beneficial free radicals.

Development and Optimization of Zirconium-89 Production and Clinical TF-PET/CT Imaging Protocols for Breast Tumor Imaging and Immunotherapy Planning: A Review

Zirconium-89 (89Zr) has recently drawn significant interest to be a promising metallo-radionuclide for use in immuno-PET due to favorable decay characteristics. Despite all efforts that have been done over the last few years in the development of procedures for large-scale production and purification of 89Zr and its stable coupling to mAbs as well as successful preclinical and clinical 89Zr immuno-positron emission tomography (PET) studies, there is still gap for exploring new peptide-based pharmaceuticals radiolabeled with 89Zr and the development of 89Zr immuno-PET imaging protocols. The objectives of this study is intended to review the recent development and optimization of 89Zr production and to discuss the 89Zr immuno-PET clinical imaging applications for breast cancer. In addition, the 89Zr PET imaging safety and protocols as well as the potential use of 89Zr in 3-gamma PET Imaging are reviewed.

Comparative Study with 89Y-foil and 89Y-pressed Targets for the Production of 89Zr †

Zirconium-89 (89Zr, t1/2 = 3.27 days) owns great potential in nuclear medicine, being extensively used in the labelling of antibodies and nanoparticules. 89Zr can be produced by cyclotron via an 89Y(p,n)89Zr reaction while using an 89Y-foil target. In this study, we investigated for the first time the use of 89Y-pressed target for the preparation of 89Zr-oxalate via a (p,n) reaction. We performed comparative studies with an 89Y-foil target mounted on custom-made target supports. A new automated cassette-based purification module was used to facilitate the purification and the fractionation of 89Zr-oxalate. The effective molar activity (EMA) was calculated for both approaches via titration with deferoxamine (DFO). The radionuclidic purity was determined by gamma-ray spectroscopy and the metal impurities were quantified by ICP-MS on the resulting 89Zr-oxalate solution. The cassette-based purification process leading to fractionation is simple, efficient, and provides very high EMA of 89Zr-oxalate. The total recovered activity was 81 ± 4% for both approaches. The highest EMA was found at 13.3 MeV and 25 μA for 0.25-mm thick 89Y-foil. Similar and optimal production yields were obtained at 15 MeV and 40 μA while using 0.50-mm thick 89Y-foil and pressed targets. Metallic impurities concentration was below the general limit of 10 ppm for heavy metals in the US and Ph.Eur for both 89Y-foil and pressed targets. Overall, these results show that the irradiation of 89Y-pressed targets is a very effective process, offering an alternative method for 89Zr production.

Production of Zr-89 using sputtered yttrium coin targets

An increasing interest in zirconium-89 (89Zr) can be attributed to the isotope's half-life which is compatible with antibody imaging using positron emission tomography (PET). The goal of this work was to develop an efficient means of production for 89Zr that provides this isotope with high radionuclidic purity and specific activity. We investigated the irradiation of yttrium sputtered niobium coins and compared the yields and separation efficiency to solid yttrium coins. The sputtered coins were irradiated with an incident beam energy of 17.5MeV or 17.8MeV providing a degraded transmitted energy through an aluminum degrader of 12.5MeV or 12.8MeV, respectively, with various currents to determine optimal cyclotron conditions for 89Zr production. Dissolution of the solid yttrium coin took 2h with 50mL of 2M HCl and dissolution of the sputtered coin took 15–30min with 4mL of 2M HCl. During the separation of 89Zr from the solid yttrium coins, 77.9 ± 11.2% of the activity was eluted off in an average of 7.3mL of 1M oxalic acid whereas for the sputtered coins, 91 ± 6% was eluted off in an average of 1.2mL of 1M oxalic acid with 100% radionuclidic purity. The effective specific activity determined via DFO-SCN titration from the sputtered coins was 108±7mCi/μmol as compared to 20.3mCi/μmol for the solid yttrium coin production. ICP-MS analysis of the yttrium coin and the sputtered coins showed 99.99% yttrium removed with 178μg of yttrium in the final solution and 99.93–100% of yttrium removed with remaining range of 0–42μg of yttrium in the final solution, respectively. The specific activity calculated for the solid coin and 3 different sputtered coins using the concentration of Zr found via ICP-MS was 140±2mCi/μmol, 300±30mCi/μmol, 410±60mCi/μmol and 1719±5mCi/μmol, respectively. Labeling yields of the 89Zr produced via sputtered targets for 89Zr- DFO-trastuzumab were >98%. Overall, these results show the irradiation of yttrium sputtered niobium coins is a highly effective means for the production of 89Zr.

A simple and convenient method for production of 89Zr with high purity

A simple and convenient method for radiochemical separation 89Zr with no harmful substance was explored. The separated 89Zr was found to be [89Zr]Zr-chloride, and the recovery of the radioactivity was 85%±3% with high radionuclidic purity (99.99%). The yields of 89Zr via the reaction of (p, n) or (d, 2n) on Y target were also evaluated on CS-30 cyclotron, indicating the latter was more favorable for the production of 89Zr with a yield of 58±4 MBq/μA·h.

Improved production and processing of 89Zr using a solution target

ObjectiveThe objectives of the present work were to improve the cyclotron production yield of 89Zr using a solution target, develop a practical synthesis of the hydroxamate resin used to process the target, and develop a biocompatible medium for 89Zr elution from the hydroxamate resin. MethodsA new solution target (BMLT-2) with enhanced heat dissipation capabilities was designed by using helium-cooled dual foils (0.2mm Al and 25μ Havar) and an enhanced water-cooled, elongated solution cavity in the target insert. Irradiations were performed with 14MeV protons on a 2M solution of yttrium nitrate in 1.25M nitric acid at 40-μA beam current for 2h in a closed system. Zirconium-89 was separated from Y by use of a hydroxamate resin. A one-pot synthesis of hydroxamate resin was accomplished by activating the carboxylate groups on a carboxymethyl cation exchange resin using methyl chloroformate followed by reaction with hydroxylamine hydrochloride. After trapping of 89Zr on hydroxamate resin and rinsing the resin with HCl and water to release Y, 89Zr was eluted with 1.2M K2HPO4/KH2PO4 buffer (pH3.5). ICP-MS was used to measure metal contaminants in the final 89Zr solution. ResultsThe BMLT-2 target produced 349±49MBq (9.4±1.2mCi) of 89Zr at the end of irradiation with a specific activity of 1.18±0.79GBq/μg. The hydroxamate resin prepared using the new synthesis method showed a trapping efficiency of 93% with a 75mg resin bed and 96–97% with a 100–120mg resin bed. The elution efficiency of 89Zr with 1.2M K2HPO4/KH2PO4 solution was found to be 91.7±3.7%, compared to >95% for 1M oxalic acid. Elution with phosphate buffer gave very small levels of metal contaminants: Al=0.40–0.86μg (n=2), Fe=1.22±0.71μg (n=3), Y=0.29μg (n=1). ConclusionsThe BMLT-2 target allowed doubling of the beam current for production of 89Zr, resulting in a greater than 2-fold increase in production yield in comparison with a conventional liquid target. The new one-pot synthesis of hydroxamate resin provides a simpler synthesis method for the 89Zr trapping resin. Finally, phosphate buffer elutes the 89Zrfrom the hydroxamate resin in high efficiency while at the same time providing a more biocompatible medium for subsequent use of 89Zr.

Optimization of Cyclotron Production for Radiometal of Zirconium 89

Zirconium 89 (89Zr) is a promising radionuclide for development of new PET agents due to its convenient half life of 78.4 h, β+ emission rate of 23%, low maximum energy of 0.9 MeV resulting in good spatial resolution, a stable daughter isotope of yttrium-89 (89Y) and favorable imaging characteristics, with only one significant γ-line of 909 keV emitted during decay alongside the 511 keV positron photons. Our aim was to share over 2 years of experience of producing isotopically pure 89Zr via the 89Y(p,n)89Zr nuclear reaction with a COSTIS Solid Target System (STS) and CYCLONE 18/9 cyclotron. We optimized the yields without producing either of the long-lived impurities 88Zr or 88Y. The degradation of the beam energy with 400 and 500 μm thick niobium foils was tested without overheating problems within 2-6 h of irradiation. From repeated measurements of activity, it was clear that there is a bi-exponential decay of radioactivity due to the short lived 89mZr and 89Zr. The measured half life of the longer lived radionuclide was consistent with value for 89Zr. The energy spectrum from 89Zr had energy peaks at 511 keV and 909 keV and was consistent with 89Zr. Production of 89Zr with 400 (Ep = 9.8 MeV) and 500 μ m (Ep = 11.6 MeV) thick niobium beam degrader was achieved, without producing either 88Zr or 88Y. It was necessary to wait at least 4 hours before measuring the activity and decay correct in order to calculate the 89Zr activity at the end of cyclotron production. Degrading the proton beam to 10 MeV produces radionuclidically pure 89Zr with yields from 8 to 9 MBq/μAh. Whilst this is enough for pre-clinical use, the yield is not enough for either clinical use or commercial supply. Use of thinner beam degraders (400 μm) increases the proton beam energy and increases the radionuclidic yield to 15.5 MBq/μAh whilst maintaining radionuclidic purity.

Production of 89Zr via the 89Y(p,n)89Zr reaction in aqueous solution: Effect of solution composition on in-target chemistry

The existing solid target production method of radiometals requires high capital and operational expenditures, which limit the production of radiometals to the small fraction of cyclotron facilities that are equipped with solid target systems. Our objective is to develop a robust solution target method, which can be applicable to a wide array of radiometals and would be simply and easily adopted by existing cyclotron facility for the routine production of radiometals. We have developed a simplified, solution target approach for production of (89)Zr using a niobium target by 14 MeV energy proton bombardment of aqueous solutions of yttrium salts via the (89)Y(p,n)(89)Zr nuclear reaction. The production conditions were optimized, following a detailed mechanistic study of the gas evolution. Although the solution target approach avoided the expense and complication of solid target processing, rapid radiolytic formation of gases in the target represents a major impediment in the success of solution target. To address this challenge we performed a systematic mechanistic study of gas evolution. Gas evolution was found to be predominantly due to decomposition of water to molecular hydrogen and oxygen. The rate of gas evolutions varied >40-fold depending on solution composition even under the same irradiation condition. With chloride salts, the rate of gas evolution increased in the order rank Na<Ca<Y. However, the trend was reversed with the corresponding nitrate salts, and further addition of nitric acid to the irradiating solution minimized gas evolution. At optimized condition, (89)Zr was produced in moderate yield (4.36 ± 0.48 MBq/μA • h) and high effective specific activity (464 ± 215 MBq/μg) using the solution target approach (2.75 M yttrium nitrate, 1.5 N HNO3, 2h irradiation at 20 μA). The novel findings on substrate dependent, radiation-induced water decomposition provide fundamental data for the development and optimization of conditions for solution targets. The developed methodology of irradiation of nitrate salts in dilute nitric acid solutions can be translated to the production of a wide array of radiometals like (64)Cu, (68)Ga and (86)Y, and is well suited for short-lived isotopes.

Zirconium-89 labeled antibodies: a new tool for molecular imaging in cancer patients.

Antibody based positron emission tomography (immuno-PET) imaging is of increasing importance to visualize and characterize tumor lesions. Additionally, it can be used to identify patients who may benefit from a particular therapy and monitor the therapy outcome. In recent years the field is focused on 89Zr, a radiometal with near ideal physical and chemical properties for immuno-PET. In this review we will discuss the production of 89Zr, the bioconjugation strategies, and applications in (pre-)clinical studies of 89Zr-based immuno-PET in oncology. To date, 89Zr-based PET imaging has been investigated in a wide variety of cancer-related targets. Moreover, clinical studies have shown the feasibility for 89Zr-based immuno-PET to predict and monitor treatment, which could be used to tailor treatment for the individual patient. Further research should be directed towards the development of standardized and robust conjugation methods and improved chelators to minimize the amount of released Zr4+ from the antibodies. Additionally, further validation of the imaging method is required. The ongoing development of new 89Zr-labeled antibodies directed against novel tumor targets is expected to expand applications of 89Zr-labeled immuno-PET to a valuable method in the medical imaging.

Effective dose to immuno-PET patients due to metastable impurities in cyclotron produced zirconium-89

Immuno-PET is a nuclear medicine technique that combines positron emission tommography (PET) with radio-labeled monoclonal antibodies (mAbs) for tumor characterization and therapy. Zirconium-89 (89Zr) is an emerging radionuclide for immuno-PET imaging. Its long half-life (78.4h) gives ample time for the production, the administering and the patient uptake of the tagged radiopharmaceutical. Furthermore, the nuclides will remain in the tumor cells after the mAbs are catabolized so that time series studies are possible without incurring further administration of radiopharmarceuticals. 89Zr can be produced in medical cyclotrons by bombarding an yttrium-89 (89Y) target with a proton beam through the 89Y(p,n)89Zr reaction. In this study, we estimated the effective dose to the head and neck cancer patients undergoing 89Zr-based immune-PET procedures. The production of 89Zr and the impurities from proton irradiation of the 89Y target in a cyclotron was calculated with the Monte Carlo code MCNPX and the nuclear reaction code TALYS. The cumulated activities of the Zr isotopes were derived from real patient data in literature and the effective doses were estimated using the MIRD specific absorbed fraction formalism. The estimated effective dose from 89Zr is 0.5±0.2mSv/MBq. The highest organ dose is 1.8±0.2mSv/MBq in the liver. These values are in agreement with those reported in literature. The effective dose from 89mZr is about 0.2−0.3% of the 89Zr dose in the worst case. Since the ratio of 89mZr to 89Zr depends on the cooling time as well as the irradiation details, contaminant dose estimation is an important aspect in optimizing the cyclotron irradiation geometry, energy and time.

Routine Production of 89Zr Using an Automated Module

89Zr has emerged as a useful radioisotope for targeted molecular imaging via positron emission tomography (PET) in both animal models and humans. This isotope is particularly attractive for cancer research because its half-life (t1/2 = 3.27 days) is well-suited for in vivo targeting of macromolecules and nanoparticles to cell surface antigens expressed by cancer cells. Furthermore, 89Zr emits a low-energy positron (Eβ+,mean = 0.40 MeV), which is favorable for high spatial resolution in PET, with an adequate branching ratio for positron emission (BR = 23%). The demand for 89Zr for research purposes is increasing; however, 89Zr also emits significant gamma radiation (Γ15 keV = 6.6 R×cm2/mCi×h), which makes producing large amounts of this isotope by hand unrealistic from a radiation safety standpoint. Fortunately, a straightforward method exists for production of 89Zr by bombarding a natural Y target in a biomedical cyclotron and then separation of 89Zr from the target material by column chromatography. The chemical separation in this method lends itself to remote processing using an automated module placed inside a hot cell. In this work, we have designed, built and commissioned a module that has performed the chemical separation of 89Zr safely and routinely, at activities in excess of 50 mCi, with radionuclidic purity &gt; 99.9% and satisfactory effective specific activity (ESA).