萃取色谱树脂应用文献集（第一部分）

     ---核医学与放射性药物化学，99Tc，68Ga，44Sc,89Zr,64Cu,67Cu等元素的分离和纯化

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1.Svedjehed, J., Pärnaste M., Gagnon K. "Demystifying solid targets: Simple and rapid distribution-scale production of [68Ga]GaCl3 and [68Ga]Ga-PSMA-11".Nuclear Medicine and Biology, Volumes 104–105, 2022, Pages 1-10. https://doi.org/10.1016/j.nucmedbio.2021.10.002.

Abstract: 

Background

As the demand for 68Ga continues to grow, there is increasing interest in single-to-multi-Curie production quantities of both [68Ga]GaCl3 and tracers such as [68Ga]Ga-PSMA-11. While such quantities are possible with solid targets, this implementation is often challenging as it typically requires significant site expertise for solid target processing and careful operator-dependent synchronization of multiple independent time-sensitive chemistry steps. Herein we focus on a fully automated solid target production and purification process whereby we avoid the need for tongs/tele-pliers, and have simplified the chemistry by implementing a single sequence (i.e. “time-list”) to execute cassette-based dissolution, purification, and labeling.

MethodsElectroplated 68Zn was irradiated in a PETtrace prototype automated solid target system. Following irradiation, and using a single FASTlab time-list, the 68Zn was automatically dissolved with HCl/H2O2 and purified as [68Ga]GaCl3 using a combination of resins (ZR/TK400, A8, TK200: Triskem). For select experiments, [68Ga]Ga-PSMA-11 was also produced on the same cassette/single time-list (N = 4), or, by kit labeling (N = 1). Efforts focused towards on-cassette production of [68Ga]GaCl3 strived to maximize activity and quality, whereas efforts focused towards on-cassette production of [68Ga]Ga-PSMA-11 aimed at limiting the entire production cycle to 1 h including the irradiation time (i.e. start-of-bombardment ➔ end-of-synthesis [EOS]).

ResultsFor the high activity triplicate [68Ga]GaCl3 productions (i.e. 80 μA, 102 min, 216 ± 10 mg), [68Ga]GaCl3 was purified (end-of-bombardment ➔ end-of-purification [EOP]) in ~28 min with activity yields of 181 ± 8 GBq at EOP and average radiochemical yields of 66 ± 5%. Average AMAs of 2.26 ± 0.16 TBq/μmol using DOTA (N = 3) and 12.00 TBq/μmol using HBED (PSMA-11) (N = 1) at EOP were measured. For the single kit test, (80 μA, 120 min, 263 mg 68Zn) for which 18 mg ascorbic acid was added to the buffer, 199 GBq of [68Ga]Ga-PSMA-11 was successfully produced (thin layer chromatography-based radiochemical purity >99% at 6 h EOS). Finally, for efforts focused at expedient [68Ga]Ga-PSMA-11, up to 42 GBq [68Ga]Ga-PSMA-11 with a radiochemical yield of 51.2% was produced in 63 min, including beamtime, using 220 mg of 68Zn as target material.

ConclusionWith the goal of simplifying solid target production and purification efforts, automated methods using single-use, cassette-based approaches for rapid, large-scale, single time-list production of [68Ga]GaCl3 and [68Ga]Ga-PSMA-11 were developed. These methods were simple to execute and yielded high quality multi-Curie levels of both [68Ga]GaCl3 and [68Ga]Ga-PSMA-11.

ZR Resin, TK400 Resin, A8 Resin and TK200 Resin

2.Ni Yuan, Quan An, Shan Xing, Xiongxin Dai, Xiaolin Hou, Yonggang Yang, Yan Ma. "Rapid determination of 99Tc in water samples using Ti(OH)3-TcO2 co-precipitation and TK200 resin by liquid scintillation counting"

Journal of Environmental Radioactivity, Volumes 251–252, 2022 https://doi.org/10.1016/j.jenvrad.2022.106954

Abstract:

A novel method for the determination of 99Tc in water samples was developed using stable Re as a chemical yield tracer and TiCl3 as a reducing agent. The influences of several experimental parameters, including TiCl3 concentration, HCl concentration and reaction time, on the reduction of TcO4− and ReO4− as well as Ti(OH)3-TcO2-ReO2 co-precipitation were investigated. Tc(VII) and Re(VII) retained on TK200 resin were effectively eluted by 5 mL of 1 mol/L NH4SCN, which can be directly mixed with the scintillation cocktail for liquid scintillation counting. The results show that the chemical behaviors of Tc and Re are very consistent in the whole procedure. The decontamination factors of potential interferences from β-emitting nuclides mainly released from nuclear fuel reprocessing plants were also evaluated, and the minimum detectable activity concentration was calculated to be 0.08 Bq/L for 99Tc in water samples with a counting time of 2 h.

TK200 Resin

3.Kawabata, M., Motoishi, S., Ohta, A. et al.: "Large scale production of 64Cu and 67Cu via the 64Zn(n, p)64Cu and 68Zn(n, np/d)67Cu reactions using accelerator neutrons".

J Radioanal Nucl Chem 330, 913–922 (2021). https://doi.org/10.1007/s10967-021-07987-3

Abstract: Both 64Cu and 67Cu are promising radionuclides in nuclear medicine. Production yields of these radionuclides were quantified by irradiating 55.4 g of natural zinc with accelerator neutrons. Clinically suitable 64Cu and 67Cu yields were estimated by experimental based numerical simulations using 100 g of enriched 64Zn and 68Zn, respectively, and elevated neutron fluxes from 40 MeV, 2 mA deuterons. A combined thermal- and resin-separation method was developed to isolate 64Cu and 67Cu from zinc, resulting in 73% separation efficiency and 97% zinc recovery. Such methods can provide large scale production of 64Cu and 67Cu for clinical applications.

CU Resin and TK201 Resin

4.MCarmen Garcia Poyo et al.: "Laser ablation of microdroplets for copper isotopic analysis via MC-ICP-MS. Analysis of serum microsamples for the diagnosis and follow-up treatment of Wilson's disease."

J. Anal. At. Spectrom., 2021, Accepted Manuscript, https://doi.org/10.1039/D0JA00494D

Abstract:

Cu isotopic analysis -can provide valuable hindsight when investigating Wilson’s disease (WD), but one of the problems related with this type of study is that usually low sample volumes are available and/or low Cu concentrations are found in these samples. This paper presents a new approach for Cu isotope ratio determination that requires only 1 μL of pre-treated serum sample per replicate (after Cu separation and preconcentration to a Cu concentration range between 0.3 and 4 mg L-1). Cu determination was carried out by direct μ-injection of 1μL of pretreated serum samples into an ICP-MS, offering a LOD of 3 μg L-1. For Cu isotopic analysis, the method presented is based on micro-volume deposition on a pure silicon wafer and subsequent ablation analysis by fs-LA-MC-ICP-MS. Cu isotopic analysis of NIST 3114 at 1 mg L-1 Cu concentration with the self-bracketing method provided average δ65Cu values of -0.01 ± 0.19‰ (2SD) and for internal precision values of 517 ppm. This method was deployed for analysis of serum samples from WD patients under different treatments, as well as healthy newborns and patients with other liver disorders. The results seem to link decreased δ65Cu values to Cu release from the liver, further demonstrating the interest of this type of analysis in the biomedical context.

CU Resin

5.Larenkov AA, Makichyan AG, Iatsenko VN: "Separation of 44Sc from 44Ti in the Context of A Generator System for Radiopharmaceutical Purposes with the Example of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T Synthesis"

Molecules 2021, 26(21), 6371; https://doi.org/10.3390/molecules26216371

Abstract:

Today, 44Sc is an attractive radionuclide for molecular imaging with PET. In this work, we evaluated a 44Ti/44Sc radionuclide generator based on TEVA resin as a source of 44Sc. The generator prototype (5 MBq) exhibits high 44Ti retention and stable yield of 44Sc (91 ± 6 %) in 1 mL of eluate (20 bed volumes, eluent—0.1 M oxalic acid/0.2 M HCl) during one year of monitoring (more than 120 elutions). The breakthrough of 44Ti did not exceed 1.5 × 10−5% (average value was 6.5 × 10−6%). Post-processing of the eluate for further use in radiopharmaceutical synthesis was proposed. The post-processing procedure using a combination of Presep® PolyChelate and TK221 resins made it possible to obtain 44Sc-radioconjugates with high labeling yield (≥95%) while using small precursor amounts (5 nmol). The proposed method takes no more than 15 min and provides ≥90% yield relative to the 44Sc activity eluted from the generator. The labeling efficiency was demonstrated on the example of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T synthesis. Some superiority of PSMA-I&T over PSMA-617 in terms of 44Sc labeling efficiency was demonstrated (likely due to presence of DOTAGA chelator in the precursor structure). It was also shown that microwave heating of the reaction mixture considerably shortened the reaction time and improved radiolabeling yield and reproducibility of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T synthesis.

TEVA Resin and TK221 Resin

6.Thisgaard, H., Kumlin, J., Langkjær, N. et al. Multi-curie production of gallium-68 on a biomedical cyclotron and automated radiolabelling of PSMA-11 and DOTATATE. EJNMMI radiopharm. chem. 6, 1 (2021). https://doi.org/10.1186/s41181-020-00114-9

Abstract

BackgroundWith increasing clinical demand for gallium-68, commercial germanium-68/gallium-68 ([68Ge]Ge/[68Ga]Ga) generators are incapable of supplying sufficient amounts of the short-lived daughter isotope. In this study, we demonstrate a high-yield, automated method for producing multi-Curie levels of [68Ga]GaCl3 from solid zinc-68 targets and subsequent labelling to produce clinical-grade [68Ga]Ga-PSMA-11 and [68Ga]Ga-DOTATATE.

ResultsEnriched zinc-68 targets were irradiated at up to 80 μA with 13 MeV protons for 120 min; repeatedly producing up to 194 GBq (5.24 Ci) of purified gallium-68 in the form of [68Ga]GaCl3 at the end of purification (EOP) from an expected > 370 GBq (> 10 Ci) at end of bombardment. A fully automated dissolution/separation process was completed in 35 min. Isolated product was analysed according to the Ph. Eur. monograph for accelerator produced [68Ga]GaCl3 and found to comply with all specifications. In every instance, the radiochemical purity exceeded 99.9% and importantly, the radionuclidic purity was sufficient to allow for a shelf-life of up to 7 h based on this metric alone. Fully automated production of up to 72.2 GBq [68Ga]Ga-PSMA-11 was performed, providing a product with high radiochemical purity (> 98.2%) and very high apparent molar activities of up to 722 MBq/nmol. Further, manual radiolabelling of up to 3.2 GBq DOTATATE was performed in high yields (> 95%) and with apparent molar activities (9–25 MBq/nmol) sufficient for clinical use.

ConclusionsWe have developed a high-yielding, automated method for the production of very high amounts of [68Ga]GaCl3, sufficient to supply proximal radiopharmacies. The reported method led to record-high purified gallium-68 activities (194 GBq at end of purification) and subsequent labelling of PSMA-11 and DOTATATE. The process was highly automated from irradiation through to formulation of the product, and as such comprised a high level of radiation protection. The quality control results obtained for both [68Ga]GaCl3 for radiolabelling and [68Ga]Ga-PSMA-11 are promising for clinical use.

Keywords: Gallium-68, Cyclotron, Accelerator, DOTATATE, PSMA-11, Solid target, Targetry

ZR Resin, LN Resin and TK200 Resin

7.Rodnick, M.E., Sollert, C., Stark, D. et al. Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target. EJNMMI radiopharm. chem. 5, 25 (2020), https://doi.org/10.1186/s41181-020-00106-9

Abstract

Purpose:

To optimize the direct production of 68Ga on a cyclotron, via the 68Zn(p, n)68Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced 68Ga, extraction of [68Ga]GaCl3 and subsequent [68Ga]Ga-PSMA11 labeling using an automated synthesis module.

Methods:

Irradiations of a 1.0 M solution of [68Zn]Zn(NO3)2 in dilute (0.2–0.3 M) HNO3 were conducted using GE PETtrace cyclotrons and GE 68Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of 67 Ga through the 68Zn(p,2n)67Ga reaction without unduly compromising 68Ga yields. We also evaluated the effects of varying beam times (50–75 min) and beam currents (27–40 μA). Crude 68Ga production was measured. The extraction of [68Ga]GaCl3 was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted [68Ga]GaCl3 was used to label [68Ga]Ga-PSMA-11 that was intended for clinical use.

Results:

The decay corrected yield of 68Ga at EOB was typically > 3.7 GBq (100 mCi) for a 60 min beam, with irradiations of [68Zn]Zn(NO3)2 at 0.3 M HNO3. Target/chemistry performance was more consistent when compared with 0.2 M HNO3. Radionuclidic purity of 68Ga was typically > 99.8% at EOB and met the requirements specified in the European Pharmacopoeia (< 2% combined 66/67Ga) for a practical clinical product shelflife. The activity yield of [68Ga]GaCl3 was typically > 50% (~ 1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for [68Ga]Ga-PSMA-11 were near quantitative (~ 1.67 GBq, 45 mCi) at EOS. Cyclotron produced [68Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing, and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA).

Conclusion:

Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of [68Ga]Ga-PSMA-11 and is a viable alternative to traditional 68Ge/68Ga generators.

Keywords: Gallium-68, Cyclotron targetry, Positron emission tomography, PSMA

ZR Resin and TK200 Resin

8.Svedjehed, J., Kutyreff, C.J., Engle, J.W. et al. Automated, cassette-based isolation and formulation of high-purity [61Cu]CuCl2 from solid Ni targets.

EJNMMI radiopharm. chem. 5, 21 (2020), https://doi.org/10.1186/s41181-020-00108-7 

Abstract

Background:

A need for improved, cassette-based automation of 61Cu separation from irradiated Ni targets was identified given the growing interest in theranostics, and generally lengthy separation chemistries for 64Cu/64Ni, upon which 61Cu chemistry is often based.

Methods:

A method for separating 61Cu from irradiated natNi targets was therefore developed, with provision for target recycling. Following deuteron irradiation, electroplated natNi targets were remotely transferred from the cyclotron and dissolved in acid. The dissolved target solution was then transferred to an automated FASTlab chemistry module, where sequential TBP and TK201 (Triskem) resins isolated the [61Cu]CuCl2, removed Ni, Co, and Fe, and concentrated the product into a formulation suitable for anticipated radiolabelling reactions.

Results:

61Cu saturation yields of 190 ± 33 MBq/μA from energetically thick natNi targets were measured. The average, decay-corrected, activity-based dissolution efficiency was 97.5 ± 1.4% with an average radiochemical yield of 90.4 ± 3.2% (N = 5). The isolated activity was collected approximately 65 min post end of bombardment in ~ 2 mL of 0.06 M HCl (HCl concentration was verified by titration). Quality control of the isolated [61Cu]CuCl2 (N = 5) measured 58Co content of (8.3 ± 0.6) × 10− 5% vs. 61 Cu by activity, Ni separation factors ≥ (2.2 ± 1.8) × 106, EoB molar activities 85 ± 23 GBq/μmol and NOTA-based EoB apparent molar activities of 31 ± 8 MBq/nmol and 201 MBq/nmol for the 30 min and 3.3 h (N = 1) irradiations, respectively.

Conclusion:

High purity 61Cu was produced with the developed automated method using a single-use, cassette-based approach. It was also applicable for 64Cu, as demonstrated with a single proof-of-concept 64Ni target production run.

Keywords: 61Cu (radiocopper), Automation/automated, PET, Solid target, Dissolution, Recycling

TK201 Resin and TBP Resin

9.Tieu W. et al. "Rapid and automated production of Ga-68 chloride and Ga-68-DOTA-TATE on a medical cyclotron". 

Nuclear Medicine and Biology,  online 12 July 2019, In Press, https://doi.org/10.1016/j.nucmedbio.2019.07.005

Abstract:

IntroductionThe demand for Gallium-68 (68Ga) for labelling PET radiopharmaceuticals has increased over the past few years. 68Ga is obtained through the decayed parent radionuclide 68Ge using commercial 68Ge/68Ga generators. The principal limitation of commercial 68Ge/68Ga generators is that only a limited and finite quantity of 68Ga (

MethodsEnriched ZnCl2 was electrodeposited on a platinum backing using an NH4Cl (pH 2–4) buffer. The Zn target was irradiated with GE PETtrace 880 at 35 uA and 14.5 and 12.0 MeV beam energy. The irradiated Zn target was purified using octanol resin on an automated system.

ResultsFollowing the described procedure, 68Ga was obtained in 6.30 ± 0.42 GBq after 8.5 min bombardment and with low radionuclidic impurities (66Ga (<0.005%) and 67Ga (<0.09%)). Purification on a single octanol resin gave 82% recovery with resulting [68Ga]GaCl3 obtained in 3.5 mL of 0.2 M HCl. [68Ga]GaCl3 production from irradiation to final product was 70%.

ConclusionsA straightforward procedure for producing 68Ga on a low energy medical cyclotron was described. Current efforts are focus on high activity production and radiolabelling using solid target produced 68Ga.

KeywordsCyclotron, Ga-68, Solid targetry, PET, DOTA-TATE

TK400 Resin

10.Miller et al. "Antibiotic treatment affects the expression levels of copper transporters and the isotopic composition of copper in the colon of mice"

PNAS March 26, 2019 116 (13) 5955-5960, https://doi.org/10.1073/pnas.1814047116

Abstract:

Copper is a critical enzyme cofactor in the body but also a potent cellular toxin when intracellularly unbound. Thus, there is a delicate balance of intracellular copper, maintained by a series of complex interactions between the metal and specific copper transport and binding proteins.

The gastrointestinal (GI) tract is the primary site of copper entry into the body and there has been considerable progress in understanding the intricacies of copper metabolism in this region. The GI tract is also host to diverse bacterial populations, and their role in copper metabolism is not well understood.

In this study, we compared the isotopic fractionation of copper in the GI tract of mice with intestinal microbiota significantly depleted by antibiotic treatment to that in mice not receiving such treatment. We demonstrated variability in copper isotopic composition along the length of the gut. A significant difference, ∼1.0‰, in copper isotope abundances was measured in the proximal colon of antibiotic-treated mice. The changes in copper isotopic composition in the colon are accompanied by changes in copper transporters. Both CTR1, a copper importer, and ATP7A, a copper transporter across membranes, were significantly down-regulated in the colon of antibiotic-treated mice.

This study demonstrated that isotope abundance measurements of metals can be used as an indicator of changes in metabolic processes in vivo. These measurements revealed a host–microbial interaction in the GI tract involved in the regulation of copper transport.

CU Resin

11.Larenko et al. "Preparation of Zirconium-89 Solutions for Radiopharmaceutical Purposes: Interrelation Between Formulation, Radiochemical Purity, Stability and Biodistribution"

Molecules 2019, 24(8), 1534, https://doi.org/10.3390/molecules24081534

Abstract:

Zirconium-89 is a promising radionuclide for nuclear medicine. The aim of the present work was to find a suitable method for obtaining zirconium-89 solutions for radiopharmaceutical purposes.For this purpose, the ion exchange behavior of zirconium-89 solutions was studied. Radio-TLC (thin layer chromatography) and biodistribution studies were carried out to understand speciation of zirconium-89 complexes and their role in the development of new radiopharmaceuticals. Three methods of zirconium-89 isolation were studied using ZR (hydroxamate) and Chelex-100 resins. It was found that ZR-resin alone is not enough to obtain stable zirconium-89 formulations. An easy and effective method of reconstitution of [89Zr]Zr-oxalate to [89Zr]Zr-citrate using Chelex-100 resin was developed.

Developed procedures allow obtaining [89Zr]Zr-oxalate (in 0.1 M sodium oxalate solution) and [89Zr]Zr-citrate (in 0.1–1.0 M sodium citrate solution). These solutions are perfectly suitable and convenient for radiopharmaceutical purposes. Our results prove [89Zr]Zr-citrate to be advantageous over [89Zr]Zr-oxalate. During evaluation of speciation of zirconium-89 complexes, a new TLC method was developed, since it was proved that there is no comprehensive methodfor analysis or zirconium-89 preparations. The new method provides valuable insights about the content of “active” ionic form of zirconium-89. The interrelation of the chromatographic behavior of zirconium-89 preparations and their biodistribution was studied.

ZR Resin

12.Riga et al. "Production of Ga-68 with a General Electric PETtrace cyclotron by liquid target"

Physica Medica Available online 25 October 2018 In Press, Corrected Proof, 

https://doi.org/10.1016/j.ejmp.2018.10.018

Abstract:

PurposeIn recent years the use of 68Ga (t1/2 = 67.84 min, β+: 88.88%) for the labelling of different PET radiopharmaceuticals has significantly increased. This work aims to evaluate the feasibility of the production of 68Ga via the 68Zn(p,n)68Ga reaction by proton irradiation of an enriched zinc solution, using a biomedical cyclotron, in order to satisfy its increasing demand.

MethodsIrradiations of 1.7 M solution of 68Zn(NO3)2 in 0.2 N HNO3 were conducted with a GE PETtrace cyclotron using a slightly modified version of the liquid target used for the production of fluorine-18. The proton beam energy was degraded to 12 MeV, in order to minimize the production of 67Ga through the 68Zn(p,2n)67Ga reaction. The product’s activity was measured using a calibrated activity meter and a High Purity Germanium gamma-ray detector.

ResultsThe saturation yield of 68Ga amounts to (330 ± 20) MBq/μA, corresponding to a produced activity of 68Ga at the EOB of (4.3 ± 0.3) GBq in a typical production run at 46 μA for 32 min. The radionuclidic purity of the 68Ga in the final product, after the separation, is within the limits of the European Pharmacopoeia (>99.9%) up to 3 h after the EOB. Radiochemical separation up to a yield not lower than 75% was obtained using an automated purification module. The enriched material recovery efficiency resulted higher than 80–90%.

ConclusionsIn summary, this approach provides clinically relevant amounts of 68Ga by cyclotron irradiation of a liquid target, as a competitive alternative to the current production through the 68Ge/68Ga generators.

ZR Resin and TK200 Resin

13.Yu Tang et al.: "A Radiopharmaceutical [89Zr]Zr-DFO-nimotuzumab for ImmunoPET with Epidermal Growth Factor Receptor Expression In Vivo", Nuclear Medicine and Biology, Available online 8 February 2019, In Press, Accepted Manuscript, 

https://doi.org/10.1016/j.nucmedbio.2019.01.007 

Abstract:

Introduction: The potential of the positron-emitting zirconium-89 (89Zr) (t1/2=78.4 h) has been recently reported for immune positron emission tomography (immunoPET) radioimmunoconjugates design. In our work, we explored the optimized preparation of [89Zr]Zr-DFO-nimotuzumab, and evaluated 89Zr-labeled monoclonal antibody (mAb) construct for targeted imaging of epidermal growth factor receptor (EGFR) overexpressed in glioma. Methods: To optimize the radiolabeling efficiency of 89Zr with DFO-nimotuzumab, multiple immunoconjugates and radiolabeling were performed. Radiolabeling yield, radiochemical purity, stability, and activity assay were investigated to characterize [89Zr]Zr-DFO-nimotuzumab for chemical and biological integrity. The in vivo behavior of this tracer was studied in mice bearing subcutaneous U87MG (EGFR-positive) tumors received a 3.5±0.2 MBq/dose using PET/CT imaging. One group mice bearing subcutaneous U87MG (EGFR-positive) tumors received [89Zr]Zr-DFO-nimotuzumab (3.5±0.2 MBq, ~3 μg) (nonblocking) for immunoPET; the other group had 30 μg predose (blocking) of cold nimotuzumab 24 h prior to [89Zr]Zr-DFO-nimotuzumab. Results: [89Zr]Zr-DFO-nimotuzumab was prepared with high radiochemical yield (>90%), radiochemical purity (>99%), and specific activity (115±0.8 MBq/mg). In vitro validation showed that [89Zr]Zr-DFO-nimotuzumab had an initial immunoreactive fraction of 0.99±0.05 and remained active for up to 5 days. A biodistribution study revealed excellent stability of [89Zr]Zr-DFO-nimotuzumab in vivo compared with 89Zr as a bone seeker. High uptake in the liver and heart and modest penetration in the brain were observed, with no significant accumulation of activity in other organs. ImmunoPET studies also indicated prominent image contrast that remarkably high uptake up to ~20 %ID/g for nonblocking and ~2 %ID/g for blocking in tumor between 12-120 h after administration.Conclusion: These studies developed a radiopharmaceutical [89Zr]Zr-DFO-nimotuzumab with optimized synthesis. The potential utility of [89Zr]Zr-DFO-nimotuzumab in assessing EGFR status in glioma was demonstrated inthis study.

ZR Resin

14.Malinconico, M., Asp, J., Lang, C., Boschi, F., Tieu, W., Kuan, K., Guidi, G., Takhar, P.:"68Ga and 45Ti production on a GE PETtrace cyclotron using the ALCEO solid target" 

J Nucl Med May 1, 2018 vol. 59 no. supplement 1 664 , presentation available online.

Abstract:

Objectives: The ALCEO solid target system has been developed by Comecer for cyclotron production of 64Cu 89Zr, 123I and 124I. ALCEO Solid Target is composed by one irradiation unit (PTS), one dissolution/transfer unit (EDS/FDS) and one purification module (TADDEO PRF); all the units work automatically, avoiding any radiation exposures to operators. Many sites are already producing these radioisotopes with yields respectively of >2mCi/μAh (64Cu), >0.4mCi/μAh (89Zr and 123I), >0.1mCi/μAh (124I). The aim of this work was to expand the use of the ALCEO system to also produce 68Ga and 45Ti. Production and labelling results will be presented as well. Methods 68Zn was electroplated onto a target shuttle and irradiated (with a typical current from 10μA to 30μA) with 12.1 MeV protons to produce 68Ga. Irradiated target was dissolved in 10M HCl. The 68Ga was separated from the irradiated 68Zn using LN resin (TRISKEM), then labelled to PSMA and DOTATATE using an Eckert and Ziegler Modular-Lab eazy synthesis module. Natural scandium was irradiated with 12.1 MeV protons, with a typical current of 10μA to produce 45Ti. Irradiated target was dissolved by drop-by-drop 6M HCl. The 45Ti was separated from the irradiated scandium using ZR resin (TRISKEM), then labelled manually to DFO mesylate salt . Results 68Ga is produced with a saturation yield of 1330±590 MBq/μA (N=2), and was successfully labelled to PSMA and DOTATATE with 79.2% and 76.0% synthesis yields and 99.0% and 91.3% radiochemical purity respectively. 45Ti is produced with a saturation yield of 312 MBq/μA (N=1). It was not successfully labelled to PSMA and DOTATATE, however the labelling efficiency for DFO mesylate salt was 41%. Conclusions The Comecer ALCEO solid target system has been used successfully to produce 64Cu, 89Zr, 68Ga and 45Ti. The produced PET-isotopes have a very high radio-purity and chemical-purity and they can be used for radio-labeling processes. Future work includes optimisation of separation processes, and production of 203Pb and 44Sc.

ZR Resin and LN Resin

15.Pupillo G. et al. :"New production cross sections for the theranostic radionuclide 67Cu" 

Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 415, 2018, 41-47, https://doi.org/10.1016/j.nimb.2017.10.022

Abstract:

The cross sections of the 68Zn(p,2p)67Cu, 68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga reactions were measured at the ARRONAX facility by using the 70 MeV cyclotron, with particular attention to the production of the theranostic radionuclide 67Cu. Enriched 68Zn material was electroplated on silver backing and exposed to a low-intensity proton beam by using the stacked-foils target method. Since 67Cu and 67Ga radionuclides have similar half-lives and same γ-lines (they both decay to 67Zn), a radiochemical process aimed at Cu/Ga separation was mandatory to avoid interferences in γ-spectrometry measurements. A simple chemical procedure having a high separation efficiency (>99%) was developed and monitored during each foil processing, thanks to the tracer isotopes 61Cu and 66Ga. Nuclear cross sections were measured in the energy range 35–70 MeV by using reference reactions recommended by the International Atomic Energy Agency (IAEA) to monitor beam flux. In comparison with literature data a general good agreement on the trend of the nuclear reactions was noted, especially with latest measurements, but slightly lower values were obtained in case of 67Cu. Experimental results of the 68Zn(p,2p)67Cu, 68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga reactions were also compared with the theoretical values estimated by using the software TALYS. The production yield of the theranostic radionuclide 67Cu was estimated considering the results obtained in this work.

CU Resin

16.Graves, S.A.: "Evaluation of a chloride-based 89Zr isolation strategy using a tributyl phosphate (TBP)-functionalized extraction resin" 

Nuclear Medicine and Biology, Volumes 64–65, September–October 2018, Pages 1-7, https://doi.org/10.1016/j.nucmedbio.2018.06.003

Abstract:

IntroductionThe 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.

Methods89Zr, 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

ResultsEquilibrium 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

ConclusionTBP-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.

TBP Resin

17.Pupillo, G. et al. "New production cross sections for the theranostic radionuclide 67Cu" 

Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 15, 2018, 41-47, https://doi.org/10.1016/j.nimb.2017.10.022

Abstract:

The cross sections of the 68Zn(p,2p)67Cu, 68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga reactions were measured at the ARRONAX facility by using the 70 MeV cyclotron, with particular attention to the production of the theranostic radionuclide 67Cu. Enriched 68Zn material was electroplated on silver backing and exposed to a low-intensity proton beam by using the stacked-foils target method. Since 67Cu and 67Ga radionuclides have similar half-lives and same γ-lines (they both decay to 67Zn), a radiochemical process aimed at Cu/Ga separation was mandatory to avoid interferences in γ-spectrometry measurements. A simple chemical procedure having a high separation efficiency (>99%) was developed and monitored during each foil processing, thanks to the tracer isotopes 61Cu and 66Ga. Nuclear cross sections were measured in the energy range 35–70 MeV by using reference reactions recommended by the International Atomic Energy Agency (IAEA) to monitor beam flux. In comparison with literature data a general good agreement on the trend of the nuclear reactions was noted, especially with latest measurements, but slightly lower values were obtained in case of 67Cu. Experimental results of the 68Zn(p,2p)67Cu, 68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga reactions were also compared with the theoretical values estimated by using the software TALYS. The production yield of the theranostic radionuclide 67Cu was estimated considering the results obtained in this work.

CU Resin

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