Cyclotron Targets Research Articles

The strange case of the [13N]NH3: validation of the production process for human use.

PET radiopharmaceuticals are often injected in patients before all quality controls are performed and before sterility results are available. We propose a process validation to produce very safe and pure [N]NH3 for human use. [N]NH3 was produced in the cyclotron target. Online purification was performed by anionic exchange resin. All the production steps were subjected to a sterility test. Some additional controls were added to those required by the monograph. The radiochemical yield of the syntheses was 26.3 and 61.5% corrected for decay, with a radiochemical purity of 100%. In addition to quality controls requested by the European Pharmacopeia monograph, we carefully analyzed the product for the presence of possible contaminants. Some elements, mainly metals, were found in very low amounts at concentrations in the range of ppb. The radionuclidic purity was verified. The achievement of the parameters of osmolality, by addition of saline solution to the preparation, made the analysis of chemical purity difficult and worsened the measurement of radiochemical purity by high performance liquid chromatography. Only pH control is necessary before administration to patients and therefore a safe production process was set up to prevent microbiological contamination. All phases were carefully standardized, starting from in-target production of [N]NH3, to final splitting in the syringes. Sterility tests showed no bacterial growth, indicating the safety of the production process. All our syntheses followed the monograph indications and were optimal to obtain PET imaging of a patient's myocardium.

Experimental estimation of tungsten impurity sputtering due to Type I ELMs in JET-ITER-like wall using pedestal electron cyclotron emission and target Langmuir probe measurements

The ITER baseline scenario, with 500 MW of DT fusion power and Q = 10, will rely on a Type I ELMy H-mode and will be achieved with a tungsten (W) divertor. W atoms sputtered from divertor targets during mitigated ELMs are expected to be the dominant source in ITER. W impurity concentration in the plasma core can dramatically degrade its performance and lead to potentially damaging disruptions. Understanding the physics of the target W source due to sputtering during ELMs and inter-ELMs is important and can be helped by experimental measurements with improved precision. It has been established that the ELMy target ion impact energy has a simple linear dependence with the pedestal electron temperature measured by Electron Cyclotron Emission (ECE). It has also been shown that Langmuir Probes (LP) ion flux measurements are reliable during ELMs due to the surprisingly low electron temperature. Therefore, in this paper, LP and ECE measurements in JET-ITER-Like-Wall (ILW) unseeded Type I ELMy H-mode experiments have been used to estimate the W sputtering flux from divertor targets in ELM and inter-ELM conditions. Comparison with similar estimates using W I spectroscopy measurements shows a reasonable agreement for the ELM and inter-ELM W source. The main advantage of the method involving LP measurements is the very high time resolution of the diagnostic (∼10 μs) allowing very precise description of the W sputtering source during ELMs.

Optimization of sedimentation of tungsten on copper substrate for production of 186gRe via 186W(p,n) nuclear reaction: Feasibility of using high current, long irradiation

Tungsten is recognized as one of the important metals used in cyclotron targets for production of several vital radioisotopes. Adequate adhesion of the prepared targets to its substrate is a significant parameter that makes them optimized for high current beam collisions. The target morphology should be paid special attention as another important parameter. In this work, a rather thick layer of tungsten is deposited on a copper substrate by sedimentation technique to produce 186gRe radionuclide via 186W(p,n) reaction. Consecutive sedimentation experiments are carried out to determine the best suspension solution. The prepared targets are evaluated in morphology by scanning electron microscope. A mixture of 1g tungsten powder, 250mg ethyl cellulose and 5mL acetone is concluded for desirable target adhesion. Irradiation of the targets by 20μA proton current (15MeV energy) for 5h shows that they can withstand the proton beam.

Magnetic Droplet Microfluidics as a Platform for the Concentration of [18F]Fluoride and Radiosynthesis of Sulfonyl [18F]Fluoride.

The radioisotope 18F is often considered the best choice for positron emission tomography (PET) owing to its desirable chemical and radiochemical properties. However, nucleophilic 18F-fluorination of large, water-soluble biomolecules, based on C-F bond formation, has traditionally been difficult. Thus, several aqueous fluorination approaches that offer significant versatility in radiopharmaceutical synthesis with sensitive targeting vectors have been developed. Furthermore, because 18F decays rapidly, production of these 18F-labeled compounds requires an automated process to reduce production time, reduce radiation exposure, and minimize losses due to the transfer of reagents during tracer synthesis. Herein, we report the use of magnetic droplet microfluidics (MDM) as a means to concentrate [18F]fluoride from the cyclotron target solution, followed by the synthesis of an 18F-labeled compound on a microfluidic platform. Using this method, we have demonstrated 18F preconcentration in a small-volume droplet through the use of anion exchanging magnetic particles. By using MDM, the preconcentration step took approximately 5 min, and the [18F]fluoride solution was preconcentrated by 15-fold. After the preconcentration step, an 18F-labeling reaction was performed on the MDM platform using the S-F bond formation in aqueous conditions to produce an arylsulfonyl [18F]fluoride compound which can be used as a prosthetic group to label PET targeting ligands. The high radiochemical purity of 95±1% was comparable to the 96% previously reported using a conventional method. In addition, when MDM was used, the total synthesis time was improved to 15 min with lower reagent volumes (50-60 μL) used.

Co-sputtered amorphous Nb–Ta, Nb–Zr and Ta–Zr coatings for corrosion protection of cyclotron targets for [18F] production

Protective corrosion resistant coatings serve for decreasing the amount of ionic contaminants from Havar® entrance foils of the targets for [18F] production. The corrosion damage of coated entrance foils is caused mainly by the diffusion of highly reactive products of water radiolysis through the protective film toward Havar® substrate. Since amorphous metal alloys (metallic glasses) are well-known to perform a high corrosion resistance, the glass forming ability, microstructure and diffusion barrier efficiency of binary alloys containing chemically inert Nb, Ta, Zr were investigated. Nb–Ta, Nb–Zr and Ta–Zr films of different alloy composition and ∼1.5μm thickness were co-deposited by magnetron sputtering. Diffusion barrier efficiency tests used reactive aluminum underlayer and protons of acid solution and gallium atoms at elevated temperature as diffusing particles. Though co-sputtered Nb–Ta and Nb–Zr alloy films of different contents were crystalline, Ta–Zr alloy was found to form dense amorphous microstructures in a range of composition with 30–73% atomic Ta. The diffusion barrier efficiency of Nb–Zr and Nb–Ta alloy coatings decreased with increase of Nb content. The diffusion barrier efficiency of sputtered Ta–Zr alloy coatings increased with the transition from nanocrystalline columnar microstructure to amorphous for coatings with 30–73at.% Ta.

The design and performance of a portable handheld 11CO2 delivery system

We constructed a hand-held device to efficiently trap [11C]CO2 from the cyclotron target, safely transport up to 3.7GBq (100mCi) doses to remote sites and release it without the need for a liquid cryogen. The system consists of a 180W furnace and a miniature molecular sieve trap (80–100mg; 80–100mesh 13×) placed inside a lead pig weighing 11.1kg. The overall [11C]CO2 delivery efficiency of the device is ~82% (> 99% trapping efficiency). Radiation dose rates measured at 30cm from the surface of the pig are <43.5µSv/h (5mR/h) up to 2.59GBq (70mCi).

Batch-reactor microfluidic device: first human use of a microfluidically produced PET radiotracer.

The very first microfluidic device used for the production of (18)F-labeled tracers for clinical research is reported along with the first human Positron Emission Tomography scan obtained with a microfluidically produced radiotracer. The system integrates all operations necessary for the transformation of [(18)F]fluoride in irradiated cyclotron target water to a dose of radiopharmaceutical suitable for use in clinical research. The key microfluidic technologies developed for the device are a fluoride concentration system and a microfluidic batch reactor assembly. Concentration of fluoride was achieved by means of absorption of the fluoride anion on a micro ion-exchange column (5 μL of resin) followed by release of the radioactivity with 45 μL of the release solution (95 ± 3% overall efficiency). The reactor assembly includes an injection-molded reactor chip and a transparent machined lid press-fitted together. The resulting 50 μL cavity has a unique shape designed to minimize losses of liquid during reactor filling and liquid evaporation. The cavity has 8 ports for gases and liquids, each equipped with a 2-way on-chip mechanical valve rated for pressure up to 20.68 bar (300 psi). The temperature is controlled by a thermoelectric heater capable of heating the reactor up to 180 °C from RT in 150 s. A camera captures live video of the processes in the reactor. HPLC-based purification and reformulation units are also integrated in the device. The system is based on "split-box architecture", with reagents loaded from outside of the radiation shielding. It can be installed either in a standard hot cell, or as a self-shielded unit. Along with a high level of integration and automation, split-box architecture allowed for multiple production runs without the user being exposed to radiation fields. The system was used to support clinical trials of [(18)F]fallypride, a neuroimaging radiopharmaceutical under IND Application #109,880.

A simplified synthesis of the hypoxia imaging agent 2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-[(18)F]pentafluoropropyl)-acetamide ([18F]EF5).

[(18)F]EF5 is a validated marker for PET imaging of tumor hypoxia. It is prepared by reacting a trifluoroallyl precursor with carrier-added [(18)F]F(2) gas in trifluoroacetic acid (TFA) solvent. We report here an improved radiosynthesis and purification of [(18)F]EF5 by utilizing an electroformed nickel (Ni) target for [(18)F]F(2) production, and Oasis® HLB cartridges for on-line solid phase extraction of [(18)F]EF5 prior to HPLC purification. [(18)F]F(2) was produced by deuteron bombardment of neon plus F(2) in an Ni target, and bubbled through the radiolabelling precursor solution. Purification was achieved by extracting the contents of the crude reaction mixture onto Oasis HLB cartridges, and subsequently eluted onto a semi-preparative HPLC column for further separation. Purified [(18)F]EF5 was evaluated in small animal PET studies using HCT116 tumor xenografts in nude mice. The electroformed Ni target enabled recovery of >75% of the radioactivity from the cyclotron target, resulting in 16.2 ± 2.2 GBq (438 ± 58 mCi) of [(18)F]F(2) available for the synthesis. Use of Oasis cartridges yielded a less complex mixture for purification. On average, 1140 ± 200 MBq (30.8 ± 5.4 mCi) of [(18)F]EF5 were collected at EOS. Small animal PET imaging studies showed specific retention of [(18)F]EF5 in tumors, with tumor-to-muscle ratios of 2.7 ± 0.3 at about 160 min after injection. A simple procedure has been developed for the routine synthesis of [(18)F]EF5 in amounts and purity required for clinical studies. This new method avoids the need for TFA evaporation and also enables facile automation of the synthesis using commercially available radiosynthesis modules.

Cyclotron production of 101Pd/101mRh radionuclide generator for radioimmunotherapy

Abstract 101mRh is one of such radionuclides that has been considered as a potential candidate for targeted radiotherapeutic use, due to its nuclear decay and chemical properties. Electrodeposition of rhodium metal on a copper backing was performed in acidic sulphate. The target was bombarded with a current intensity of 120 μA (Ep = 29 → 25 MeV) for 30 min (60 μAh). Radiochemical methods were investigated to optimize the production of no-carrier-added 101Pd/101mRh. The use of a cyclotron target with radiochemical processes (i.e. electrodeposition, electrodissolution and ion-exchange column chromatography) were carried out to produce this radionuclide in high-specific activity and radiochemical form suitable for radiopharmaceutical syntheses.

Optimal shielding design for bunkers of compact cyclotrons used in the production of medical radionuclides

There are several options to consider in the design of a vault that will house a cyclotron for radioisotopes production with regards to the door entrance. Alternatives are a direct-shielded door, a simple maze, or a double-legged maze. In this work, the impact of the neutron and photon doses at the vault entrance was evaluated for these options. Monte Carlo simulations were carried out in order to assess photon and neutron ambient dose equivalents. Simulations results were compared to experimental measurements taken inside a vault with a direct-shielded door. The double-legged maze is the configuration that provides the higher degree of radiological protection at the vault entrance. In addition, the fact of the location of the cyclotron target plays an important role in the ambient dose equivalents. The comparison performed between measurements and results of MCNP simulations confirmed a favorable agreement; maze legs reduce the neutron energies at the entrances of the vault. However, a degree of dose reduction similar to the one obtained for a two-legged maze can be achieved with the addition of shielding against neutrons in the inner maze entrance to act as a second door. A choice of a vault design is more evident by comparing the results of this study.

Production of 34mCl and 38Cl via the (d,α) reaction on 36Ar and natAr gas at 8.4MeV

Production of (38)Cl and (34m)Cl via the (d, α) reaction on natural argon and (36)Ar reveal medical cyclotrons' ability to supply these isotopes in small quantities. (38)Cl provides an inexpensive developmental tool, while (34m)Cl is a positron emitter of interest in PET imaging. Production yields, cyclotron target development, cryo-recovery of enriched gases, and nucleophilic chemistry of a model compound are described.

PC-controlled radiochemistry system for preparation of no-carrier-added 64Cu

A homemade modular PC-controlled radiochemistry system, used to separate the no-carrier-added 64Cu from irradiated electroplated solid cyclotron target 64Ni layers was developed. Upon irradiation the target layer is dissolved in diluted nitric acid, followed by selective liquid–liquid extraction of the 64Cu. The final purification step is achieved making use of an anion exchange column. All the separation procedures can be carried out remote-controlled with a minimized risk of operator errors within less than 2 h, with excellent processing yield (>95%).

Novel cyclotron targets for 67Ga production

A new type of cyclotron targets was suggested for 67Ga production. The use of high-melting metallic Ta as the target support excludes physicochemical interaction of the target components (material being activated, Zn; desired product, 67Ga; support, Ta) in the course of both irradiation and the subsequent heat treatment and allows implementation of a very simple and labor-saving procedure for the 67Ga isolation.

Production of radionuclides for nuclear therapy and environmental studies

This work is devoted to the production of the radionuclides used in nuclear medicine and as radiotracers for environmental research. Production methods for high LET radionuclides (67Ga, 77Br, 111In, 211At) that are promising for radioimmunotherapy are proposed. Production techniques for short-lived analogues of highly radiotoxic long-lived fission products (Tc, Se, Sr) are developed. The techniques are based on extraction and chromatographic separation from a cyclotron target irradiated by α-particles and deuteron beams.

On-line monitoring of cyclotron target-gas output by means of tunable lead salt diode laser absorption spectroscopy

We demonstrate what is, to our knowledge, the first use of mid-infrared laser absorption spectroscopy for trace-gas measurements of cyclotron target outputs used for the generation of radioactive carbon-11 in positron emission tomography (PET). The spectrometer was based upon a liquid-nitrogen-cooled lead salt diode laser generating single-mode radiation in the wavenumber range of 2230–2240 cm−1. The sample flowed to a multiple-pass optical cell with a total path length of 15.23 m and the laser radiation was detected by two liquid-nitrogen-cooled InSb photodetectors. We present the results of CO, N2O and CO2 measurements on PET trace cyclotron output and discuss future work on 11CO and 11CO2 detection.

Removal of Organic Impurities in an Aqueous Solution Using UV Irradiation Produced from High and Low Pressure Hg Lamps

Organic impurities such as ethanol, methanol, acetonitrile, and acetone contained in a used cyclotron target water should be removed so it can be used as a target again. In this investigation, removal efficiency of the organic impurities contained in an aqueous solution using UV irradiation induced oxidation was evaluated under various experimental situations. A low pressure Hg lamp (L-lamp) with the UV emission of 185 and 254 nm and a high pressure Hg lamp (H-lamp) with the UV emission of 254 nm were used to irradiate the water mixed with the organic substances. A quartz UV absorption flow cell was situated closely to the UV lamp in the reactor maximizing the UV absorption dose in the medium. For most cases, the decomposition of acetone was the fastest while acetonitrile was decomposed the slowest. To determine the effects of the wavelength, the UV absorption dose, and the catalytic reaction on decomposition of the organics, generation of the intermediate species and the degrees of organic decompositions were observed by various spectroscopic means including gas chromatography (GC), Fourier transform infrared (FTIR), and UV−vis spectrometers depending on the experimental schemes. With the aid of the catalytic reaction of dissolved oxygen (DO) in the medium, the organics and the other intermediate byproducts such as acids, acetone, and acetaldehyde, etc. produced from the L-lamp UV irradiation were removed faster by about 3-fold when compared to the irradiation without the catalytic reaction of DO. For H-lamp irradiation, however, organic removal was very slow and intermediate acids were not removed efficiently even with DO. Overall decomposition efficiency of the UV irradiated organics under L-lamp UV irradiation with the aid of DO, as a result, was much higher than that with H-lamp UV irradiation.

Separating long-lived metal ions from 18F during H218O recovery

Cyclotron targets for the production of [18F]-fluoride usually use a thin metal window to contain the 18O-enriched water during irradiation. This window is activated by the proton beam, and undesired radioisotopes can enter the target water. A pre-packaged strong anion exchange resin is commonly used for [18O]-water recovery. A two-column method has been developed which delivers >95% of the [18F]-fluoride for radiosynthesis while rejecting >99.9% of the contaminants.

Cyclotron production and radiochemical isolation of the therapeutical radionuclide 186Re

The reaction cross sections and the energy dependences of the yields of 186Re in the reactions natW(d, 2n) and 186W(d, 2n) in the range of low deuteron energies (<14 MeV) were determined. The specific features of the physicochemical behavior of impurity 186Re atoms in irradiated tungsten cyclotron targets were studied in relation to the gas medium composition. The yield of the desired product increases with an increase in the oxygen content in the course of heat treatment of the targets. A simple “dry” procedure was developed for isolation of 186Re with a yield no less than 85% and radiochemical purity no worse than 99.99%. A proto-type of a cyclotron target for commercial production of the therapeutical radionuclide 186Re was suggested.

Development of Diffusion-Thermal Methods for Preparing 67Cu and 124I for Radionuclide Therapy and Positron Emission Tomography

Diffusion-thermal procedures for preparing 67Cu and 124I for radionuclide therapy and positron emission tomography are suggested. For these procedures, new cyclotron targets of metallic tantalum were developed, which, when exposed to high irradiation doses, ensure the absence of physicochemical interaction (diffusion, alloying) of materials being activated and final products with the support at high temperatures. The thermal, hydrodynamic, and strength characteristics of zinc and tellurium (elemental Te) cyclotron targets were evaluated. For commercial target assembly of the COSTIS system, the operation parameters of the process for preparing 124I from elemental tellurium using the derived beams of IBA Cyclone 18/9 or MGTs- 20 accelerators were determined.

PET Tracers and Radiochemistry

This paper provides a brief review of the radiochemistry of radiopharmaceuticals used in positron emission tomography (PET). It includes some history of PET, the basic formation of radionuclides in a cyclotron target, the processing of the precursor molecules into a useful PET radiotracer and the clinical significance and outlook for PET radiotracers. This review is based on a series of recent books and articles outlining the fundamental goals of PET and how radiochemistry plays a part in achieving these goals. It is also drawn from the literature that has been developed in PET over the last 30 years since PET became a research and valuable clinical tool. PET is a growing field and the clinical applications of the chemistry and technology have just begun to be explored. There is a great deal left to do in order to explore the full potential of PET in the clinic.