Imaging and dosimetric characteristics of 67 Cu.

In recent years the use of beta-emitting radiopharmaceuticals for cancer therapy has expanded rapidly following development of therapeutics for neuroendocrine tumors, prostate cancer, and other oncologic malignancies. One emerging beta-emitting radioisotope of interest for therapy is 67Cu (t1/2: 2.6 d) due to its chemical equivalency with the widely-established positron-emitting isotope 64Cu (t1/2: 12.7 h). In this work we evaluate both the imaging and dosimetric characteristics of 67Cu, as well as producing the first report of SPECT/CT imaging using 67Cu. To this end, 67Cu was produced by photon-induced reactions on isotopically-enriched 68Zn at the Low-Energy Accelerator Facility (LEAF) of Argonne National Laboratory, followed by bulk separation of metallic 68Zn by sublimation and radiochemical purification by column chromatography. Gamma spectrometry was performed by efficiency-calibrated high-purity germanium (HPGe) analysis to verify absolute activity calibration and establish radionuclidic purity. Absolute activity measurements corroborated manufacturer-recommended dose-calibrator settings and no radionuclidic impurities were observed. Using the Clinical Trials Network anthropomorphic chest phantom, SPECT/CT images were acquired. Medium energy (ME) SPECT collimation was found to provide the best image quality from the primary 185 keV gamma emission of 67Cu. Reconstructed images of 67Cu were similar in quality to images acquired using 177Lu. Recovery coefficients were calculated and compared against quantitative images of 99mTc, 177Lu, and 64Cu within the same anthropomorphic chest phantom. Production and clinical imaging of 67Cu appears feasible, and future studies investigating the therapeutic efficacy of 67Cu-based radiopharmaceuticals are warranted.

A simple and robust method for radiochemical separation of no-carrier-added 64Cu produced in a research reactor for radiopharmaceutical preparation.

Copper-64 is an excellent theranostic radiometal that is gaining renewed attention of the clinical community in the recent times. In order to meet the increasing demand of this radiometal, we have demonstrated the viability of its production via 64Zn (n,p) 64Cu reaction in a nuclear reactor. A semi-automated radiochemical separation module based on selective extraction of 64Cu as dithizonate complex was developed. The maximum available activity at the end of irradiation was ~ 700 MBq. The overall yield of 64Cu after the separation process was >85% and it could be obtained with ~12 GBq/µg specific activity, >99.9% radionuclidic purity and >98% radiochemical purity. The separated 64Cu could be utilized for preparation of a wide variety of radiopharmaceuticals.

Implementation of a new separation method to produce qualitatively improved 64 Cu.

BACKGROUND: 64 Cu (T1/2  = 12.7 h) is an important radionuclide for diagnostic purposes and used for positron emission tomography (PET). A previous method utilized at Paul Scherrer Institute (PSI) proved to be unreliable and, while a method using anion exchange chromatography is a popular choice worldwide, it was felt a different approach was required to obtain a robust chemical separation method. METHODS: Enriched 64 Ni targets were created by electroplating on gold foil. The targets were irradiated with protons degraded to approximately 11 MeV at PSI's Injector 2 72 MeV research cyclotron and subsequently dissolved in HCl. The resultant solution was loaded onto AG MP-50 cation exchange resin and the 64 Cu separated from its target material and radiocobalt impurities, produced as part of the irradiation process, using various specific mixtures of HCl/acetone solution. The eluted product was evaporated and picked up in dilute HCl (0.05 M). The chemical purity of 64 Cu was determined by radiolabeling experiments at the highest possible molar activities. RESULTS: Reproducible results were obtained, yielding 3.6 to 8.3 GBq 64 Cu of high radionuclidic and radiochemical purity. The product was labeled to NODAGA-RGD, achieved at up to 500 MBq/nmol, indicating the high chemical purity. In a proof-of-concept in vivo study, 64 Cu-NODAGA-RGD was used for PET imaging of a tumor-bearing mouse. CONCLUSION: The chemical separation devised to produce high-quality 64 Cu proved to be robust and reproducible. The concept can be used at medical cyclotrons utilizing a solid target station, such that 64 Cu can be used at hospitals for PET imaging.

Development of a remote purification apparatus with disposable evaporator for the routine production of high-quality 64Cu for clinical use.

We developed a new apparatus for the routine production of 64Cu in clinical use. The apparatus has many disposable parts that stabilize the product quality (such that there is a low deviation of the concentrations of impurity metals in the product) and reduce the work load of preparation for routine production. We also developed a new evaporator using near-infrared heaters for disposable use. We conducted a production test using the new apparatus and evaluated product quality. The product yield was 6.3 ±â€¯0.32 GBq (end of bombardment) (N = 4), the product quality in terms of the concentrations of impurity metals (Cu2+, Ni2+, Fe3+, Zn2+, Mn2+) was as good as that usually achieved, likely on the order of parts per billion, and the preparation time was reduced from 2 days to 1 day.

Early Evaluation of Copper Radioisotope Production at ISOLPHARM.

The ISOLPHARM (ISOL technique for radioPHARMaceuticals) project is dedicated to the development of high purity radiopharmaceuticals exploiting the radionuclides producible with the future Selective Production of Exotic Species (SPES) Isotope Separation On-Line (ISOL) facility at the Legnaro National Laboratories of the Italian National Institute for Nuclear Physics (INFN-LNL). At SPES, a proton beam (up to 70 MeV) extracted from a cyclotron will directly impinge a primary target, where the produced isotopes are released thanks to the high working temperatures (2000 °C), ionized, extracted and accelerated, and finally, after mass separation, only the desired nuclei are collected on a secondary target, free from isotopic contaminants that decrease their specific activity. A case study for such project is the evaluation of the feasibility of the ISOL production of 64Cu and 67Cu using a zirconium germanide target, currently under development. The producible activities of 64Cu and 67Cu were calculated by means of the Monte Carlo code FLUKA, whereas dedicated off-line tests with stable beams were performed at LNL to evaluate the capability to ionize and recover isotopically pure copper.

Establishing Reliable Cu-64 Production Process: From Target Plating to Molecular Specific Tumor Micro-PET Imaging.

Copper-64 is a useful radioisotope for positron emission tomography (PET). Due to the wide range of applications, the demand of 64Cu with low metallic impurities is increasing. Here we report a simple method for the efficient production of high specific activity 64Cu using a cyclotron for biomedical application. We designed new equipment based on the plating of enriched 64Ni as the target, and used automated ion exchange chromatography to purify copper-64 efficiently after irradiation and dissolution of the target in good radiochemical and chemical yield and purity. The 64Cu radionuclide produced using 99.32% enriched 64Ni with a density of 61.4 ± 5.0 mg/cm², reaching a total radioactivity greater than 200 mCi, with specific activity up to 5.6 GBq/µmoL. It was further incorporated into modified monoclonal antibody DOTA-rituximab to synthesize 64Cu-DOTA-rituximab, which was used successfully for micro-PET imaging.

Efficient preparation of high-quality 64Cu for routine use.

INTRODUCTION: Copper-64 is an attractive radionuclide for positron emission tomography and is emerging as a radiotherapeutic agent. The demand of 64Cu with low metallic impurities has increased because of its wide applications when incorporated with antibodies, peptides, and proteins. In this study, we propose a new separation method to produce high-quality 64Cu using a cation exchange column, as well as an automated separation system suitable for large-scale production. METHODS: 64Cu was produced from an electrodeposited 64Ni target via the 64Ni(p,n)-reaction with a 24MeV HH+ beam at 10eµA (electrical microampere) conducted for 1-3h. The irradiated target was transported to a hot cell and disassembled remotely. 64Cu was separated by a solvent mixture of HCl and acetone on a cation-exchange resin, AG50W-X8. The chemical purity of 64Cu final product was evaluated using ion-chromatography coupled with a UV detector and inductively coupled plasma mass spectroscopy for quality as well as metallic impurities. RESULTS: We obtained 64Cu in dried form at a yield of 5.2-13GBq at the end of separation, or 521±12MBq/eµAh as the final product within 2.5h of processing time. The metallic impurities were a satisfactory low level in the order of ppb. Major contaminants of Co and Ni were lower than those samples obtained by a widely accepted separation using an anion-exchange resin. CONCLUSION: Using a cation-exchange resin and a systematic operation, we successfully reduced the contamination level of the 64Cu product. As a straightforward separation method, which shortened the entire processing time, we obtained a satisfactory amount of high-quality 64Cu available for routine use.

Harvesting (67)Cu from the Collection of a Secondary Beam Cocktail at the National Superconducting Cyclotron Laboratory.

Isotope harvesting is a promising new method to obtain isotopes for which there is no reliable continuous supply at present. To determine the possibility of obtaining radiochemically pure radioisotopes from an aqueous beam dump at a heavy-ion fragmentation facility, preliminary experiments were performed to chemically extract a copper isotope from a large mixture of projectile fragmentation products in an aqueous medium. In this work a 93 MeV/u secondary beam cocktail was collected in an aqueous beam stop at the National Superconducting Cyclotron Laboratory (NSCL) located on the Michigan State University (MSU) campus. The beam cocktail consisted of ∼2.9% (67)Cu in a large mixture of co-produced isotopes ranging in atomic number from ∼19 to 34. The chemical extraction of (67)Cu was achieved via a two-step process: primary extraction using a divalent metal chelation disk followed by anion-exchange chromatography. A significant fraction (74 ± 4%) of the (67)Cu collected in the aqueous beam stop was recovered with >99% radiochemical purity. To illustrate the utility of this product, the purified (67)Cu material was then used to radiolabel an anti-EGFR antibody, Panitumumab, and injected into mice bearing colon cancer xenografts. The tumor uptake at 5 days postinjection was found to be 12.5 ± 0.7% which was in very good agreement with previously reported studies with this radiolabeled antibody. The present results demonstrate that harvesting isotopes from a heavy-ion fragmentation facility could be a promising new method for obtaining high-quality isotopes that are not currently available by traditional methods.

Bifunctional cyclam-based ligands with phosphorus acid pendant moieties for radiocopper separation: thermodynamic and kinetic studies.

Two macrocyclic ligands based on cyclam with trans-disposed N-methyl and N-(4-aminobenzyl) substituents as well as two methylphosphinic (H2L1) or methylphosphonic (H4L2) acid pendant arms were synthesised and investigated in solution. The ligands form stable complexes with transition metal ions. Both ligands show high thermodynamic selectivity for divalent copper over nickel(II) and zinc(II)-K(CuL) is larger than K(Ni/ZnL) by about seven orders of magnitude. Complexation is significantly faster for the phosphonate ligand H4L2, probably due to the stronger coordination ability of the more basic phosphonate groups, which efficiently bind the metal ion in an "out-of-cage" complex and thus accelerate its "in-cage" binding. The rate of Cu(II) complexation by the phosphinate ligand H2L1 is comparable to that of cyclam itself and its derivatives with non-coordinating substituents. Acid-assisted decomplexation of the copper(II) complexes is relatively fast (τ1/2 = 44 and 42 s in 1 M aq. HClO4 at 25 °C for H2L1 and H4L2, respectively). This combination of properties is convenient for selective copper removal/purification. Thus, the title ligands were employed in the preparation of ion-selective resins for radiocopper(II) separation. Glycidyl methacrylate copolymer beads were modified with the ligands through a diazotisation reaction. The separation ability of the modified polymers was tested with cold copper(II) and non-carrier-added (64)Cu in the presence of a large excess of both nickel(II) and zinc(II). The experiments exhibited high overall separation efficiency leading to 60-70% recovery of radiocopper with high selectivity over the other metal ions, which were originally present in 900-fold molar excess. The results showed that chelating resins with properly tuned selectivity of their complexing moieties can be employed for radiocopper separation.

Evaluation of excitation functions of the (68,67,66)Zn(p,xn)(68,67,66)Ga and 67Zn(p,α)64Cu reactions: validation of evaluated data through comparison with experimental excitation functions of the (nat)Zn(p,x)(66,67)Ga and (nat)Zn(p,x)64Cu processes.

Experimentally available cross section data for formation of the radionuclides (68)Ga, (67)Ga, (66)Ga and (64)Cu in proton induced reactions on enriched (68)Zn, (67)Zn and (66)Zn were evaluated by comparison with the excitation functions calculated by the nuclear model codes, EMPIRE and TALYS, followed by statistical fitting of the selected data. The recommended cross sections were used to obtain the integral yields. The validation of the recommended excitation functions was also attempted by normalization to (nat)Zn and comparison with the experimental data for the (nat)Zn(p,x)(67)Ga, (nat)Zn(p,x)(66)Ga and (nat)Zn(p,x)(64)Cu processes.

Target optimization for the photonuclear production of radioisotopes.

In this paper we discuss the optimum shape of a target for photonuclear production of radioisotopes using an electron linear accelerator. Different target geometries such as right cylinder, conical frustum, Gaussian volume of revolution and semi-ellipsoid have been considered for the production of (67)Cu via (68)Zn(γ,p)(67)Cu photonuclear reaction. The specific activity (SA) of (67)Cu was simulated for each target shape. Optimum ratio of radius to height for cylindrical targets was found to be between 0.2 and 0.25 for target masses ranging from 20 g to 100 g. It was shown that while some unconventional target shapes, such as semi-elliptical volume of revolution, result in slightly higher specific activities than cylindrical targets, the advantage is not significant and is outweighed by the complexity of the target production and handling. Power deposition into the target was modeled and the trade-off between the maximization of (67)Cu yield and the minimization of target heating has been discussed. The (67)Cu case can easily be extended for production of many other isotopes.

Nuclear model analysis of excitation functions of proton and deuteron induced reactions on (64)Zn and (3)He- and α-particle induced reactions on (59)Co leading to the formation of copper-61: Comparison of major production routes.

Cross section data for formation of the medically important radionuclide (61)Cu (T½=3.33h) in proton and deuteron induced reactions on enriched (64)Zn and in (3)He- and α-particle induced reactions on (59)Co were analyzed by using the nuclear model calculational codes, EMPIRE and TALYS. A well-defined statistical procedure was then employed to derive the recommended excitation functions, and therefrom to obtain integral yields. A comparison of major production routes of (61)Cu was done.

Triamidetriamine bearing macrobicyclic and macrotricyclic ligands: potential applications in the development of copper-64 radiopharmaceuticals.

A versatile and straightforward synthetic approach is described for the preparation of triamide bearing analogues of sarcophagine hexaazamacrobicyclic cage ligands without the need for a templating metal ion. Reaction of 1,1,1-tris(aminoethyl)ethane (tame) with 3 equiv of 2-chloroacetyl chloride, yields the tris(α-chloroamide) synthetic intermediate 6, which when treated with either 1,1,1-tris(aminoethyl)ethane or 1,4,7-triazacyclononane furnished two novel triamidetriamine cryptand ligands (7 and 8 respectively). The Co(III) and Cu(II) complexes of cryptand 7 were prepared; however, cryptand 8 could not be metalated. The cryptands and the Co(III) complex 9 have been characterized by elemental analysis, (1)H and (13)C NMR spectroscopy, and X-ray crystallography. These studies confirm that the Co(III) complex 9 adopts an octahedral geometry with three facial deprotonated amido-donors and three facial amine donor groups. The Cu(II) complex 10 was characterized by elemental analysis, single crystal X-ray crystallography, cyclic voltammetry, and UV-visible absorption spectroscopy. In contrast to the Co(III) complex (9), the Cu(II) center adopts a square planar coordination geometry, with two amine and two deprotonated amido donor groups. Compound 10 exhibited a quasi-reversible, one-electron oxidation, which is assigned to the Cu(2+/3+) redox couple. These cryptands represent interesting ligands for radiopharmaceutical applications, and 7 has been labeled with (64)Cu to give (64)Cu-10. This complex showed good stability when subjected to L-cysteine challenge whereas low levels of decomplexation were evident in the presence of L-histidine.

Production of 61Cu using natural cobalt target and its separation using ascorbic acid and common anion exchange resin.

(61)Cu was produced by (nat)Co(α, xn)(61)Cu reaction. (61)Cu production yield was 89.5 MBq/µAh (2.42 mCi/µAh) at the end of irradiation (EOI). A simple radiochemical separation method using anion exchange resin and ascorbic acid has been employed to separate the product radionuclide from inactive target material and co-produced non-isotopic impurities. The radiochemical separation yield was about 90%. Radiochemical purity of (61)Cu was >99% 1 h after EOI. Final product was suitable for making complex with N(2)S(2) type of ligands.

Effective separation method of (64)Cu from (67)Ga waste product with a solvent extraction and chromatography.

A simple chemical process with a solvent extraction was investigated as an effective separation method for (64)Cu radionuclide from waste production, which is collected as solution after extracting (67)Ga and recovering (68)Zn target materials. For the production of radionuclide (67)Ga, the enriched (68)Zn material electroplated on Cu backing plate is usually exposed to energetic protons. The protons produce (67)Ga including other radionuclides, such as (57)Ni, (57,55)Co, (64,67)Cu by several nuclear reactions. After extracting (67)Ga and recovering (68)Zn through several steps of chemical processes, the residual solution is usually discarded even though it contains other species of radioisotopes. In this study, a simple chemical process having a high separation efficiency of (64)Cu from the waste solution was investigated. With this method, a promising radiotracer as a diagnostic in PET and a therapeutic in radio-immunotherapy, (64)Cu was estimated to be produced as high as 1,200mCi at EOB within 3h chemical processing after extraction of (67)Ga and (68)Zn.

Chelating ion-exchange methods for the preparation of no-carrier-added 64Cu.

INTRODUCTION: We have developed a method for producing no-carrier-added (64)Cu by using chelating resin bearing iminodiacetic acid groups. METHODS: We optimized the conditions for the selective separation of radioactive Cu from Ni and Co using the chelating resin and produced no-carrier-added (64)Cu under the optimized conditions. We analyzed the amounts of the metal ions present in (64)Cu by inductively coupled-plasma mass spectroscopy (ICP-MS) and optical emission spectroscopy (ICP-OES), and performed radiolabeling of monoclonal antibodies in order to investigate the quality of the (64)Cu produced in this study. RESULTS: Radioactive Cu was separated from Ni and Co with 0.1 and 2 M HCl solutions. The yield of (64)Cu isolated from the (64)NiO target was almost 87%. The radiochemical purity of (64)Cu obtained from different amounts of (64)NiO targets was >99% in all cases. We found that the (64)Cu solution presented extremely low amounts of the metal ions and showed high specific activity (average: 595 GBq/mumol). Moreover, the antibodies were labeled with (64)Cu with a high average efficiency (average: 88%). CONCLUSIONS: We could efficiently separate (64)Cu by using short ion-exchange columns. The chelating ion-exchange method provides a high quality of (64)Cu that is sufficient for the synthesis of (64)Cu-labeled antibodies and medical applications.

A simple Cu-64 production and its application of Cu-64 ATSM.

One of the positron emission radionuclides, (64)Cu, has been reported to be a particularly effective radioisotope in PET imaging study. This utility of (64)Cu depends on the chemical stability in water with proper energy and half-life as gamma-emitters. Hence, we tried to develop a simple method for producing this isotope using an old cyclotron model in our site (50MeV, Scantronics co.). In particular, we designed the equipments of enrich (64)Ni plating system and radioactive (64)Cu separation using plastic cartridge column; (64)Ni plating system on gold foil which located in the 13 degrees angle target toward beam irradiation. For the nuclear reaction of (64)Cu, it was applied to (64)Ni(p, n) (64)Cu at low energy under the degrader composed of Al and Ta foils. After beam irradiation, (64)Cu was identified by multichannel analyzer installed for a HPGe detector and its utility was certified by the microPET images of (64)Cu-ATSM (CT-26 tumor bearing mouse as reported previously). The image quality of (64)Cu was also very similar to that of (18)F radioisotope in microPET scanner. In conclusion, a method of (64)Cu production and its application was successfully established in old cyclotron having high energy.

Experimental study of excitation functions for the deuteron induced reactions 64Zn(d,2p)64Cu and 64Zn(d,alphan)61Cu using the stacked-foil technique.

There is considerable, and growing, interest in the 64Cu radioisotope for application in Nuclear Medicine for PET imaging and targeted radiotherapy of tumours. We are investigating the cyclotron production of this isotope by way of deuteron bombardment of enriched 64Zn target material. In this study, experimental excitation functions for both the 64Zn(d,2p)64Cu and 64Zn(d,alphan)61Cu reactions up to 18.2 MeV deuteron energy have been measured using the stacked-foil technique. The deuteron energies in the various foils were calculated with the SRIM 2003 code and gamma-ray spectrometry was used to measure the activities of the various radioisotopes produced. Monitor foils were used to determine the deuteron beam current on the target stack. Theoretical excitation functions, calculated both with the Empire II code and with an updated version of the Alice code, were compared with the experimental results and a reasonable agreement was found. The experimental work was performed at the MC40 Cyclotron at the European Commission's Joint Research Centre at Ispra, Italy.

Simultaneous production of high specific activity 64Cu and 61Co with 11.4 MeV protons on enriched 64Ni nuclei.

The (64)Cu and (61)Co radionuclides were produced simultaneously by irradiation of enriched (64)Ni on a low energy proton-only cyclotron. Nickel targets were prepared by electrodeposition of enriched (64)Ni (>95%) on Au backing at thicknesses of 25-225 mg/cm(2) with efficiencies >99%. Irradiations up to 30 microA for 8h were performed with 11.4 MeV protons using a water-cooled target mounting. Radiochemical separation of (64)Cu and (61)Co from (64)Ni was performed by chromatography of the chlorocomplexes in a single step using an anion exchange resin column with a yield >95%. Using this method, the Ni target material was recovered and re-plated for subsequent production runs with an overall efficiency >96%. The excitation function for the (64)Ni(p,n)(64)Cu reaction was measured and compared with published values. Experimental thick target saturation yields of 159 mCi/microA for (64)Cu and 715 microCi/microA for (61)Co were achieved. Typical specific activities of (64)Cu were found to be 18.8+/-3.3 Ci/micromol.

A simple and selective method for the separation of Cu radioisotopes from nickel.

Separation of copper radioisotopes from a nickel target is normally performed using solvent extraction or anion exchange rather than using cationic exchange. A commonly held opinion is that cationic exchangers have very similar thermodynamic complexation constants for metallic ions with identical charges, therefore making the separation very difficult or impossible. The results presented in this article indicate that the selectivity of Chelex-100 (a cationic ion exchanger) for Cu radioisotope and Ni ions not only depends on the thermodynamic complexation constant in the resin but also markedly varies with the concentration of mobile H+. In our developed method, separation of copper radioisotopes from a nickel target was fulfilled in a column filled with Chelex-100 via controlling the HNO3 concentration of the eluent, and the separation is much more effective, simple and economical in comparison with the common method of anion exchange. For an irradiated nickel target with 650 mg Ni, after separation, the loss of Cu radioisotopes in the nickel portion was reduced from 30% to 0.33% of the total initial radioactivity and the nickel mixed into the radioactive products was reduced from 9.5 to 0.5 mg. This significant improvement will make subsequent labeling much easier and reduce consumption of chelating agents and other chemicals during labeling. If the labeled agent is used in human medical applications, the developed method will significantly decrease the uptake of Ni and chelating agents by patients, therefore reducing both the stress on human body associated with clearing the chemicals from blood and tissue and the risk of various types of acute and chronic disorder due to exposure to Ni.