[89Zr]ZrCl4 for direct radiolabeling of DOTA-based precursors.

INTRODUCTION: Zirconium-89 (89Zr) is a positron emitter with several advantages over other shorter-lived positron emission tomography (PET) compatible radiometals such as gallium-68 or copper-64. These include practically unlimited availability, extremely low cost, greatly facilitated distribution logistics, positron energy fit for medical PET imaging, and sufficiently long physical half-life to enable PET imaging at later time points for patient-specific dosimetry estimations. Despite these apparent benefits, the reception of 89Zr in the nuclear medicine community has been tepid. The driving factor for the absence of broader adaptation is mostly routed in its final formulation - [89Zr]zirconium oxalate. While serving as a suitable precursor solution for the gold standard chelator deferoxamine (DFO), [89Zr]Zr-oxalate is inaccessible for the most commonly used chelators, such as the macrocyclic DOTA, due to its pre-chelated state. Consequently, pioneering work has been conducted by multiple research groups to create oxalate-free forms of [89Zr]Zr4+, either via chemical conversion of oxalate into other counterion forms or via direct radiochemical isolation of [89Zr]ZrCl4, showing that [89Zr]Zr-DOTA complexes are possible and stable. However, this success was accompanied by challenges, including complex and labor-intensive radiochemical processing and radiolabeling procedures as well as the relatively minuscule conversion rates. Here, we report on the direct production of [89Zr]ZrCl4 avoiding oxalate and metal contaminants to enable efficient radiolabeling of DOTA constructs. METHODS: We based our direct production of [89Zr]ZrCl4 on previously reported methods and further optimized its quality by including an additional iron-removing step using the TK400 Resin. Here, we avoided using oxalic acid and effectively minimized the content of trace metal contaminants. Our two-step purification procedure was automated, and we confirmed excellent radionuclide purity, minimal trace metals content, great reactivity over time, and high specific molar activity. In addition, DOTA-based PSMA-617 and DOTAGA-based PSMA-I&T were radiolabeled to demonstrate the feasibility of direct radiolabeling and to estimate the maximum apparent specific activities. Lastly, the biodistribution of [89Zr]Zr-PSMA-617 was assessed in mice bearing PC3-PIP xenografts, and the results were compared to the previously published data. RESULTS: A total of 18 batches, ranging from 6.9 to 20 GBq (186 to 541 mCi), were produced. The specific molar activity for [89Zr]ZrCl4 exceeded 0.96 GBq (26 mCi) per nanomole of zirconium. The radionuclidic purity was >99 %, and the trace metals content was in the <1 ppm range. The [89Zr]ZrCl4 remained in its reactive chemical form for at least five days when stored in cyclic olefin polymer (COP) vials. Batches of 11.1 GBq (300 mCi) of [89Zr]Zr-PSMA-617 and 14.4 GBq (390 mCi) of [89Zr]Zr-PSMA-I&T, corresponding to specific activities of 11.1 MBq/µg (0.3 mCi/µg), and 14.4 MBq/µg (0.39 mCi/µg), respectively, were produced. [89Zr]Zr-PSMA-617 animal PET imaging results were in agreement with the previously published data. CONCLUSION: In this work, we report on a suitable application of TK400 Resin to remove iron during [89Zr]ZrCl4 radiochemical isolation. The breakthrough allows for direct radiolabeling of DOTA-based constructs with [89Zr]ZrCl4, leading to high apparent molar activities and excellent conversion rates.

Quantification of [99Tc]TcO4- in urine by means of anion-exchange chromatography-aerosol desolvation nebulization-inductively coupled plasma-mass spectrometry.

To sensitively determine 99Tc, a new method for internal quantification of its most common and stable species, [99Tc]Tc O 4 - , was developed. Anion-exchange chromatography (IC) was coupled to inductively coupled plasma-mass spectrometry (ICP-MS) and equipped with an aerosol desolvation system to provide enhanced detection power. Due to a lack of commercial Tc standards, an isotope dilution-like approach using a Ru spike and called isobaric dilution analysis (IBDA) was used for internal quantification of 99Tc. This approach required knowledge of the sensitivities of 99Ru and 99Tc in ICP-MS. The latter was determined using an in-house prepared standard manufactured from decayed medical 99mTc-generator eluates. This standard was cleaned and preconcentrated using extraction chromatography with TEVA resin and quantified via total reflection X-ray fluorescence (TXRF) analysis. IC coupled to ICP-MS enabled to separate, detect and quantify [99Tc]Tc O 4 - as most stable Tc species in complex environments, which was demonstrated in a proof of concept. We quantified this species in untreated and undiluted raw urine collected from a patient, who previously underwent scintigraphy with a 99mTc-tracer, and determined a concentration of 19.6 ± 0.5 ng L-1. The developed method has a high utility to characterize a range of Tc-based radiopharmaceuticals, to determine concentrations, purity, and degradation products in complex samples without the need to assess activity parameters of 99(m)Tc.

Chromatographic separation of silver-111 from neutron-irradiated palladium target: toward direct labeling of radiotracers.

BACKGROUND: Silver-111 is a promising ß--emitting radioisotope with ideal characteristics for targeted radionuclide therapy and associated single photon emission tomography imaging. Its decay properties closely resemble the clinically established lutetium-177, making it an attractive candidate for therapeutic applications. In addition, the clinical value of silver-111 is further enhanced by the existence of the positron-emitting counterpart silver-103, thus imparting a truly theranostic potential to this element. A so-fitting matching pair could potentially overcome the current limitations associated with the forced use of chemically different isotopes as imaging surrogates of lutetium-177, leading to more accurate and efficient diagnosis and treatment. However, the use of silver-111-based radiopharmaceuticals in vivo has faced obstacles due to the challenges related to its production and radiochemical separation from the target material. To address these issues, this study aims to implement a chromatographic separation methodology for the purification of reactor-produced silver-111. The ultimate goal is to achieve a ready-to-use formulation for the direct radiolabeling of tumour-seeking biomolecules. RESULTS: A two-step sequence chromatographic process was validated for cold Ag-Pd separation and then translated to the radioactive counterpart. Silver-111 was produced via the 110Pd(n,γ)111Pd nuclear reaction on a natural palladium target and the subsequent ß--decay of palladium-111. Silver-111 was chemically separated from the metallic target via the implemented chromatographic process by using commercially available LN and TK200 resins. The effectiveness of the separations was assessed by inductively coupled plasma optical emission spectroscopy and γ-spectrometry, respectively, and the Ag+ retrieval was afforded in pure water. Recovery of silver-111 was > 90% with a radionuclidic purity > 99% and a separation factor of around 4.21·10-4. CONCLUSIONS: The developed separation method was suitable to obtain silver-111 with high molar activity in a ready-to-use water-based formulation that can be directly employed for the labeling of radiotracers. By successfully establishing a robust and efficient production and purification method for silver-111, this research paves the way for its wider application in targeted radionuclide therapy and precision imaging.

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).

Selective Diffusive Gradients in Thin Films (DGT) for the Simultaneous Assessment of Labile Sr and Pb Concentrations and Isotope Ratios in Soils.

A method using diffusive gradients in thin films (DGT) for the accurate quantification of trace-level (µg L-1) Sr and Pb concentrations and isotope ratios [δSRM 987(87Sr/86Sr) and δSRM 981(207Pb/206Pb)] in labile, bioavailable element fractions in soils is reported. The method is based on a novel poly(tetrafluoroethylene) (PTFE) membrane binding layer with combined di(2-ethyl-hexyl)phosphoric acid (HDEHP) and 4,4'(5')-bis-t-butylcyclohexano-18-crown-6 (crown-ether) functionality with high selectivity for Sr and Pb (TK100 membrane). Laboratory evaluation of the TK100 DGT showed linear uptake of Sr over time (2-24 h) up to very high Sr mass loadings on TK100 membranes (288 µg cm-2) and effective performance in the range of pH (3.9-8.2), ionic strength (0.001-0.1 mol L-1), and cation competition (50-160 mg L-1 Ca in a synthetic soil solution matrix) of environmental interest. Selective three-step elution of TK100 membranes using hydrochloric acid allowed us to obtain purified Sr and Pb fractions with adequate (≥75%) recovery and quantitative (≥96%) matrix reduction. Neither DGT-based sampling itself nor selective elution or mass loading effects caused significant isotopic fractionation. Application of TK100 DGT in natural soils and comparison with conventional approaches of bioavailability assessment demonstrated the method's unique capability to obtain information on Sr and Pb resupply dynamics and isotopic variations with low combined uncertainty within a single sampling step.

Dissolved iodide in marine waters determined with Diffusive Gradients in Thin-films technique.

For the first time, Diffusive Gradient in Thin-films (DGT) focuses on the inorganic iodine species iodate (IO3-) and iodide (I-). A silver-doped Cl resin (AgdCl), which is known to selectively accumulate I-, was used to make a binding gel. Laboratory investigations were designed to verify the suitability of the AgdCl-DGT method to measure the total I- concentration in environmental waters. Total recovery of I- was obtained using an elution solution containing 100 mmol L-1 KCN. DGT validation experiments in 10 mmol L-1 NaCl showed linear accumulation of I- over time, contrary to IO3-, thus confirming the selectivity of AgdCl-binding gel. The AgdCl-DGT measurement of total I- concentration was independent of pH (4.5-8.8) and was not impacted by the presence of bicarbonate (1-5 mmol L-1). Finally, the performance of AgdCl-DGT samplers were tested in two continental waters and a synthetic seawater. The AgdCl-DGT samplers measured 27-33% of the total I- concentration in the two continental waters up to 24 h of deployment time, whereas the AgdCl-DGT response retrieved the total I- concentration in seawater up to 72 h (106 ± 7%). The difference in DGT response was attributed to the low ionic strength of the two continental waters, limiting the application of AgdCl-DGT method to media with higher ionic strength.

Characterization of actinide resin for separation of 51,52gMn from bulk target material.

We report an extraction chromatography-based method via Actinide Resin for the isolation of radio-manganese from both natural chromium and isotopically enriched iron targets for cyclotron production of 52gMn and 51Mn. For the separation of 52gMn from natCr, a decay-corrected radiochemical yield of 83.7 ± 8.4% was achieved. For 51Mn from 54Fe, a decay-corrected radiochemical yield of 78 ± 11% was achieved. This automatable method efficiently isolates both radionuclides from accelerator target material.

Evaluation of a chloride-based 89Zr isolation strategy using a tributyl phosphate (TBP)-functionalized extraction resin.

INTRODUCTION: The remarkable stability of the 89Zr-DOTA complex has been shown in recent literature. The formation of this complex appears to require 89Zr-chloride as the complexation precursor rather than the more conventional 89Zr-oxalate. In this work we present a method for the direct isolation of 89Zr-chloride from irradiated natY foils. METHODS: 89Zr, 88Zr, and 88Y were prepared by 16 MeV proton irradiation of natY foils and used for batch-extraction based equilibrium coefficient measurements for TBP and UTEVA resin. Radionuclidically pure 89Zr was prepared by 14 MeV proton-irradiation of natY foils. These foils were dissolved in concentrated HCl, trapped on columns of TBP or UTEVA resin, and 89Zr-chloride was eluted in <1 mL of 0.1 M HCl. For purposes of comparison, conventionally-isolated 89Zr-oxalate was converted to 89Zr-chloride by trapping, rinsing, and elution from a QMA cartridge into 1 M HCl. Trace metal analysis was performed on the resulting 89Zr products. RESULTS: Equilibrium coefficients for Y and Zr were similar between UTEVA and TBP resins across all HCl concentrations. Kd values of <10-1 mL/g were observed for Y across all HCl concentrations. Kd values of >103 mL/g were observed at HCl concentrations >9 M for Zr, falling to Kd values of <100 mL/g at low HCl concentrations. 89Zr-chloride was recovered from small columns of TBP in <1 mL of 0.1 M HCl with an overall recovery efficiency of 89 ±â€¯3% (n = 3). An average Y/Zr separation factor of 1.5 × 105 (n = 3) was obtained. Trace metal impurities, notably Fe, were higher in TBP-isolated 89Zr-chloride compared with 89Zr-chloride prepared using the conventional two-step procedure. CONCLUSION: TBP-functionalized resin appears promising for the direct isolation of 89Zr-chloride from irradiated natY targets. Excellent 89Zr recovery efficiencies were obtained, and chemical purity was sufficient for proof-of-concept chelation studies.

Sequential analyses of actinides in large-size soil and sediment samples with total sample dissolution.

There is a growing demand for the determination of actinides in soil and sediment samples for environmental monitoring and tracing, radiological protection, and nuclear forensic reasons. A total sample dissolution method based on lithium metaborate fusion, followed by sequential column chromatography separation, was developed for simultaneous determination of Pu, Am and Cm isotopes in large-size environmental samples by alpha spectrometry and mass spectrometric techniques. The overall recoveries of both Pu and Am for the entire procedure were higher than 70% for large-size soil samples. The method was validated using 20 g of soil samples spiked with known amounts of 239Pu and 241Am as well as the certified reference materials IAEA-384 (Fangataufa Lagoon sediment) and IAEA-385 (Irish Sea sediment). All the measured results agreed very well with the expected values.

Improved Separation of Pa from Th and U in Marine Sediments with TK400 Resin.

Protactinium-231 is a radionuclide of broad interest in paleoceanography and paleoclimatology. This study describes an improved method for the purification and separation of Pa from marine sediment samples using the new TK400 resin by TrisKem International. The focus lies on the improvement of the separation of the abundant 232Th from the Pa fraction of the sample, which would reduce the peak tailing from 232Th on masses 231 and 233 during ICP-MS measurement. Furthermore, the reusability of TK400 has been tested. For this purpose, the conventional method using Dowex AG1X8 for the separation and purification of Pa has been compared to methods using the TK400 resin. A combination of a Dowex AG1X8 prior to a TK400 column has shown most convincing results. Based on our results we suggest a new efficient procedural method of analyzing 231Pa from marine sediment samples using TK400. Chemical Pa yields for a Dowex-TK400 combination are highest compared to the Dowex only method. Furthermore, the 232Th/231Pa ratio of the Pa-fractions has been reduced by 1 order of magnitude compared to conventional methods with Dowex AG1X8. Additionally, the reusability of TK400 resin up to nine times has been proven. The usage of TK400 is only limited in the presence of samples with a high matrix load (e.g., Fe). Therefore, matrix from sediment samples needs to be removed (here using Dowex resin) before samples are loaded onto TK400. We also report a series of concentration measurements from standard reference materials (UREM-11, NIST 2702), which have been used for 233Pa calibration.