Production Of Fluorine-18 Research Articles

New Method for 18FDG generating using Geant4/ Gate7

Fluorine 18-deoxyglucose is often used in Positron Emission Tomography devices. Positron Emission Tomography imaging is one of the useful tool which is used for cancer detection and its management. Positron Emission Tomography growth is limited due to problems that depend on the production of Fluorine-18. Imaging results are strongly depending on the information of nuclear reaction cross section data. This study is presented to calculate different quantities such as stopping power, CSDA range, simulated and distributed absorbed dose of Fluorine-18 in water. In order to access these goals, we use Geant4/Gate7 simulation and the Bethe-Bloch model. The results of this simulation and theoretical model presented are in good agreement with each other. The important point of this paper is the presentation of a theoretical approach in order to the production of Fluorine-18 using protons generated through the main D(d;p)Tand side 3 He(d;p)4 He nuclear fusion reaction in which uses Helium-3 is catalyzed.

18FDG Production in a PET Imaging Using a Proton Flux Produced by the D-D Fusion Reaction

Fluorine 18-deoxyglucose (18FDG) is often used in Positron Emission Tomography (PET). PET imaging is one of the valuable tools used for cancer detection and management. PET growth is limited due to problems that depend on the production of Fluorine-18. Imaging results are strongly dependent on the information of nuclear reaction cross-section data. This study calculates the stopping power, RCSDA, and the simulated and distributed absorbed dose of F-18, in water. We use the Geant4/Gate simulation and the Bethe-Bloch theory model to access these goals. The results of this simulation and this theory model agree with each other. The main point of this paper is the presentation of a theoretical approach to the production of Fluorine-18 by using protons production through the main nuclear fusion reaction D(d,p)T and the side fusion reaction 3 He(d,p)4 He uses helium-3 as a catalyzed.

In vivo production of fluorine-18 in a chicken egg tumor model of breast cancer for proton therapy range verification

Range verification of clinical protontherapy systems via positron-emission tomography (PET) is not a mature technology, suffering from two major issues: insufficient signal from low-energy protons in the Bragg peak area and biological washout of PET emitters. The use of contrast agents including 18O, 68Zn or 63Cu, isotopes with a high cross section for low-energy protons in nuclear reactions producing PET emitters, has been proposed to enhance the PET signal in the last millimeters of the proton path. However, it remains a challenge to achieve sufficient concentrations of these isotopes in the target volume. Here we investigate the possibilities of 18O-enriched water (18-W), a potential contrast agent that could be incorporated in large proportions in live tissues by replacing regular water. We hypothesize that 18-W could also mitigate the problem of biological washout, as PET (18F) isotopes created inside live cells would remain trapped in the form of fluoride anions (F-), allowing its signal to be detected even hours after irradiation. To test our hypothesis, we designed an experiment with two main goals: first, prove that 18-W can incorporate enough 18O into a living organism to produce a detectable signal from 18F after proton irradiation, and second, determine the amount of activity that remains trapped inside the cells. The experiment was performed on a chicken embryo chorioallantoic membrane tumor model of head and neck cancer. Seven eggs with visible tumors were infused with 18-W and irradiated with 8-MeV protons (range in water: 0.74 mm), equivalent to clinical protons at the end of particle range. The activity produced after irradiation was detected and quantified in a small-animal PET-CT scanner, and further studied by placing ex-vivo tumours in a gamma radiation detector. In the acquired images, specific activity of 18F (originating from 18-W) could be detected in the tumour area of the alive chicken embryo up to 9 h after irradiation, which confirms that low-energy protons can indeed produce a detectable PET signal if a suitable contrast agent is employed. Moreover, dynamic PET studies in two of the eggs evidenced a minimal effect of biological washout, with 68% retained specific 18F activity at 8 h after irradiation. Furthermore, ex-vivo analysis of 4 irradiated tumours showed that up to 3% of oxygen atoms in the targets were replaced by 18O from infused 18-W, and evidenced an entrapment of 59% for specific activity of 18F after washing, supporting our hypothesis that F- ions remain trapped within the cells. An infusion of 18-W can incorporate 18O in animal tissues by replacing regular water inside cells, producing a PET signal when irradiated with low-energy protons that could be used for range verification in protontherapy. 18F produced inside cells remains entrapped and suffers from minimal biological washout, allowing for a sharper localization with longer PET acquisitions. Further studies must evaluate the feasibility of this technique in dosimetric conditions closer to clinical practice, in order to define potential protocols for its use in patients.

Estimations of fluorine-18 production yields from 13-MeV proton bombardment of enriched water target

Fluorine-18 (18F) is a positron emitter frequently used in Positron Emission Tomography (PET) to assist in the staging of primary tumors, Recent research suggests that the positron emitting radionuclide can also be applied for pneumonia imaging caused by Covid-19 infection. In this work, a 13-MeV proton beam was theoretically bombarded to 99.5% enriched water (H2 18O) target to produce 18F radionuclide via (p, n) nuclear reaction. The CalcuYield code was used in the predictions of the F-18 production yields. Using the CalcuYield code, the 18F radioactivity yields were calculated at the end of bombardment (EOB) at various proton beam currents, irradiation time and proton beam doses. Based on the CalcuYield calculated results, the maximum EOB yield of 18F at 13 MeV proton energy was 60.073 mCi/µAh. At a proton dose of 60 µAh, the EOB yield could be achieved as high as 3784.393 mCi, which could be used to diagnose more than 500 patients. The calculations also found that for the same proton dose, increasing proton beam current would result in greater 18F radioactivity yield than increasing irradiation time. In addition, radionuclide impurities which could predictably be present in the target were mostly due to nuclear reactions between proton beam and havar window. The predicted radionuclide impurities include 96Tc, 55Fe, 59Ni, 56Co, 52Mn, 186Re and 58Cu which were due to (p, n) nuclear reactions. The total radionuclide impurity yield was found to be 0.793 mCi/µAh. Among the other impurities, 58Cu was expected to have the highest radioactivity yield at all irradiation parameters. These predicted results could be used as a reference for future 18F radionuclide production should a 13-MeV proton beam is employed.

Neutronic analysis of DECY-13 cyclotron target system as a neutron source for SAMOP

The Centre for Accelerator Science and Technology (PSTA) has developed a subcritical reactor for the molybdenum-99 (99Mo) production (SAMOP). This device requires an external neutron source. For experimental purposes, SAMOP is still driven by an external neutron source from a critical reactor, i.e. from the radial beam-port of the Kartini reactor. PSTA is also developing a 13 MeV cyclotron (DECY-13) for the production of fluorine-18 (18F) which can generate neutron as by-products. This cyclotron has an opportunity to be used as an external neutron source for the SAMOP. In this work, particle transport simulations have been carried out to determine the characteristics of the neutron produced by the DECY-13. The simulation results show that DECY-13 produces an average neutron flux of 2.6347 × 109 particles/cm2s and around 97% of them are the fast neutron. Based on the analysis, it concluded that the DECY 13 could be used as an external neutron source for the SAMOP by the addition of a neutron collimator.

Recycling of 18O enriched water used in 18F cyclotron production

A simple, effective, easy-handling and reliable method for recycling of [18O]H2O from fluorine-18 production, was developed based on co-precipitation, co-crystallization and distillation. Preliminary experiments with normal H2O were used to determine the optimal purification conditions, which were tested for purification of used [18O]H2O from a scientific and commercial 18F-production facility. The obtained recycled [18O]H2O had comparable quality to commercially available 18O enriched water. The loss of weight for enriched water was about only 7% and losses of 18O enrichment about 1.3% ± 0.2%. The method ensures elimination of radioisotopes (99.7% ± 0.1%), organic compounds (99.5% ± 0.1%) and trace metals (99.8% ± 0.1%) with special attention on radiation safety with dosimetry control checks and in total 1000 times mass reduction of the initial radioactive waste.

Production of Ga-68 with a General Electric PETtrace cyclotron by liquid target

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 Msolution 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 the68Zn(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 of68Ga amounts to (330 ± 20) MBq/µA, corresponding to a produced activity of68Ga at the EOB of (4.3 ± 0.3) GBq in a typical production run at 46 µA for 32 min. The radionuclidic purity of the68Ga 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 of68Ga by cyclotron irradiation of a liquid target, as a competitive alternative to the current production through the68Ge/68Ga generators.

Futureproofing [18F]Fludeoxyglucose manufacture at an Academic Medical Center

BackgroundWe recently upgraded our [18F]fludeoxyglucose (FDG) production capabilities with the goal of futureproofing our FDG clinical supply, expanding the number of batches of FDG we can manufacture each day, and improving patient throughput in our nuclear medicine clinic. In this paper we report upgrade of the synthesis modules to the GE FASTLab 2 platform (Phase 1) and cyclotron updates (Phase 2) from both practical and regulatory perspectives. We summarize our experience manufacturing FDG on the FASTLab 2 module with a high-yielding self-shielded niobium (Nb) fluorine-18 target.ResultsFollowing installation of Nb targets for production of fluorine-18, a 55 μA beam for 22 min generated 1330 ± 153 mCi of [18F]fluoride. Using these cyclotron beam parameters in combination with the FASTLab 2, activity yields (AY) of FDG were 957 ± 102 mCi at EOS, corresponding to 72% non-corrected AY (n = 235). Our workflow, inventory management and regulatory compliance have been greatly simplified following the synthesis module and cyclotron upgrades, and patient wait times for FDG PET have been cut in half at our nuclear medicine clinic.ConclusionsThe combination of FASTlab 2 and self-shielded Nb fluorine-18 targets have improved our yield of FDG, and enabled reliable and repeatable manufacture of the radiotracer for clinical use.

Microfluidic radiosynthesis of [18F]FEMPT, a high affinity PET radiotracer for imaging serotonin receptors.

Continuous-flow microfluidics has shown increased applications in radiochemistry over the last decade, particularly for both pre-clinical and clinical production of fluorine-18 labeled radiotracers. The main advantages of microfluidics are the reduction in reaction times and consumption of reagents that often result in increased radiochemical yields and rapid optimization of reaction parameters for 18F-labeling. In this paper, we report on the two-step microfluidic radiosynthesis of the high affinity partial agonist of the serotonin 1A receptor, [18F]FEMPT (pKi = 9. 79; Ki = 0.16 nM) by microfluidic radiochemistry. [18F]FEMPT was obtained in ≈7% isolated radiochemical yield and in >98% radiochemical and chemical purity. The molar activity of the final product was determined to be >148 GBq/µmol (>4 Ci/µmol).

Dependence of 18F Production Yield and Radioactive Impurities on Proton Irradiation Dose

Radiation safety for patients during positron emission tomography (PET) procedures is affected by the amount of radioactive impurities generated during production of fluorine-18 (18F) radionuclide. In this investigation, the dependence of 18F production yield and radioactive impurities on proton irradiation dose is discussed. Enriched water (H2O18) target was bombarded perpendicularly by 11-MeV proton beams at various proton doses. Experimental results indicated that the 18F radioactivity yield and the amount of 56Co and Ag110m radioactive impurities depend strongly on the proton dose. In the proton dose range between 2 μAhr and 20 μAhr, the radioactive impurities increased with increasing proton dose. There was no significant difference in the radioactivity yield of both 56Co and Ag110m impurities at low proton dose between 2 and 10 μAhr. However a huge difference was recorded when the dose was increased above 10 μAhr. The experimental data can be used to predict the amount of impurities generated during 18F production at proton dose of higher than 20 μAhr.

Use of a TLD-based multisphere spectrometry system to measure the neutron spectra around a not-self-shielded PET cyclotron: Preliminary results

In the present work, we utilized the BSS system with TLD-600 and TLD-700 to measure the neutron spectra around the GE-PETtrace 8 cyclotron of the Development Centre of Nuclear Technology (CDTN/CNEN) in Belo Horizonte, Brazil. The cyclotron is capable of accelerating protons up to 16.5MeV, to production of fluorine-18. Four points inside the bunker of the cyclotron were studied. Two points in front of the primary radiation beam and other two opposed to the primary radiation beam. The measurements were unfolded with the BUMS and the NSDUAZ computer codes. The dosimetric quantities obtained were in agreement with the other published data and were coherent with the expected from theoretical estimates obtained from source term informed by the manufacturer of the cyclotron.

Labeling Strategies with F-18 for Positron Emission Tomography Imaging

The labeling of probes with fluorine-18 [(18)F, β(+); 96.7%] continues to play a considerably important role in the development of positron emission tomography (PET) as a modality for both clinical research and clinical diagnoses. This review summarizes the strategies and recent developments in the fluorine-18 labeling of probes for PET imaging. Problems and issues relating to the practical production of fluorine-18 currently in widespread use are also discussed.

Fluorine-18 Chemistry for PET: A Concise Introduction

Fluorine-18 is the most important radionuclide used in positron emission tomography (PET) today, largely due to its attractive physical and nuclear characteristics. Agents such as the clinical oncology tracer 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), the most widely used PET-radiopharmaceutical, are driving an increasing interest in the chemistry of radiopharmaceuticals utilizing fluorine-18. This review outlines the methods for production of fluorine-18, and the development of agents for performing radiofluorination reactions. With a few exceptions, radiofluorinations can be classified as either electrophilic or nucleophilic. The electrophilic reactions mainly use molecular [18F]fluorine of moderately low specific radioactivity, or reagents prepared from it, and include additions to alkenes, reactions with carbanions and especially fluorodehydrogenation and fluorodemetallation. The nucleophilic reactions usually involve no-carrier-added (high-specific- radioactivity) [18F]fluoride as its K[18F]F-K222 complex and include SN2-type substitutions in the aliphatic series and SNAr-type substitutions in the aromatic and heteroaromatic series. Key examples from each class of radiofluorination reaction will be described, highlighting the potential of this radioisotope in the design and preparation of fluorine-18- labeled probes for PET imaging.

Analysis of metal radioisotope impurities generated in [ 18O]H 2O during the cyclotron production of fluorine-18

We show the separation of metal radioistope impurities using capillary electrophoresis (CE). The methodology used is an improvement of existent protocols for separation of stable metal ions. Production of fluorine-18 using [ 18O]H 2O-enriched water encased in a titanium target body results in the production of several metal radioisotope impurities. Optimisation of the conditions for CE separation of the metal radioisotope impurities incorporated the use of 6 mM 18-Crown-6 in combination with 12 mM glycolic acid as complexing agents within the running buffer (10 mM pyridine, pH 4.0). Using this optimised procedure, we were able to separate and detect a number of metal radioisotopes, including chromium, cobalt, manganese, vanadium and berillium, within the fM concentration range.

Radiohalogen targetry at the University of Wisconsin

Over the last two years, the University of Wisconsin has developed new target systems for the production of fluorine-18, bromine-76 and iodine-124. These new systems include the successful replacement of a double-foiled silver water target for the production of [18F]–F− with a niobium body, isolated from the cyclotron vacuum by a single grid supported entrance foil. This manuscript highlights the success of our 18F-fluoride target over its two years of maintenance free operation. A new solid target system for the production of long-lived halogens, with specific reference to iodine-124, is also introduced.

Radiopharmaceutical chemistry for positron emission tomography

Radiopharmaceutical chemistry includes the selection, preparation, and preclinical evaluation of radiolabeled compounds. This paper describes selection criteria for candidates for positron emission tomography (PET) investigations. Practical aspects of nucleophilic and electrophilic 18F-fluorinations and 11C-methylations are described. These aspects include production of fluorine-18 and carbon-11, workup of fluorine-18, 18F radiochemistry, production of [ 11C]methyl iodide and triflate, and 11C-methylation radiochemistry.

A water target with beam sweep for routine fluorine-18 production

Fluorine-18 ( 18F) production with 18O-enriched water targets is well established world-wide. Heat transfer is still a critical point, however, when high beam currents are used to increase the amount of radioactivity per batch within an adequate irradiation period. The technique of beam sweep formerly used in Hannover for all targets has been adapted for this water target again. A titanium target with a beam sweep of up to 3 cm in the horizontal plane was designed to keep the total amount of enriched water low (2.06 ml), to allow beam currents of 30 μA for 1 h on a daily schedule and thereby to extend maintenance periods to more than 6 months. The design had to take into account that the target must be mounted on a target ladder with five additional positions and that the beam is carried by a 5.50 m beam line from a variable energy, multi-particle cyclotron (mc35, Scanditronix) to the target. The target has been in use for more than 130 consecutive runs with beam currents of about 30 μA at a target pressure of up to 15 bar without any maintenance. The mean value of the recovered radioactivity has reached 91.9±7.7% of the theoretically expected value at the end of bombardment (EOB).

Cryogenic target design considerations for the production of [ 18F]fluoride from enriched [ 18O]carbon dioxide

Four cryogenic target designs are described for the production of fluorine-18 in the chemical form of fluoride using oxygen-18-enriched carbon dioxide gas utilizing the 18O(p,n) 18F nuclear reaction. The targets are conical in shape and made of copper or silver and the carbon dioxide is frozen into the cone at liquid nitrogen temperatures. Three of the targets (2 copper and 1 silver) have four cooling fins extending radially and are different lengths, and one target has only a single heat sink at the rear of the cone. The targets with four cooling fins could be run with 17.4 MeV protons incident on the target material at a beam current of 25 μA with no detectable volatilization of the target material, although yields did decrease slightly when compared with lower current runs. The target with the single cooling block showed volatilization at about 8 μA. The two copper targets of different lengths did not show a difference in the volatilization of the target material at the beam current limit of our cyclotron (25 μA). The shorter target did maintain production with a lower amount of gas frozen into the target, while the longer target maintained production at higher beam currents. Targets of this type are compatible with low energy, high current accelerators because very thin windows may be used.

Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine: a new positron emission tomography ligand for nicotinic receptors.

The lead compound of a new series of 3-pyridyl ethers, the azetidine derivative A-85380 (3-[(S)-2-azetidinylmethoxy]pyridine), is a potent and selective ligand for the human alpha4beta2 nicotinic acetylcholine receptor (nAChR) subtype. In vitro, the fluoro derivative of A-85380 (2-fluoro-3-[(S)-2-azetidinylmethoxy]pyridine or F-A-85380) competitively displaced [3H]cytisine or [3H]epibatidine with Ki values of 48 and 46 pM, respectively. F-A-85380 has been labeled with the positron emitter fluorine-18 (t1/2 (half-life) = 110 min) by no-carrier-added nucleophilic aromatic substitution by K[18F]F-K222 complex with (3-[2(S)-N-(tert-butoxycarbonyl)-2-azetidinylmethoxy]pyridin-2-yl) tri methylammonium trifluoromethanesulfonate as a highly efficient labeling precursor, followed by TFA removal of the Boc protective group. The total synthesis time was 50-53 min from the end of cyclotron fluorine-18 production (EOB). Radiochemical yields, with respect to initial [18F]fluoride ion radioactivity, were 68-72% (decay-corrected) and 49-52% (non-decay-corrected), and the specific radioactivities at EOB were 4-7 Ci/micromol (148-259 GBq/micromol). In vivo characterization of [18F]F-A-85380 showed promising properties for PET imaging of central nAChRs. This compound does not bind in vivo to alpha7 nicotinic or 5HT3 receptors. Moreover, its cerebral uptake can be modulated by the synaptic concentration of the endogenous ligand acetylcholine. The preliminary PET experiments in baboons with [18F]F-A-85380 show an accumulation of the radiotracer in the brain within 60 min. In the thalamus, a nAChR-rich area, uptake of radioactivity reached a maximum at 60 min (4% I.D./100 mL of tissue). [18F]F-A-85380 appears to be a suitable radioligand for brain imaging nAChRs with PET.

Designs and use of silver [ 18O]water targets for [ 18F]fluoride production

A series of targets for production of fluorine-18 from enriched [ 18O]water were constructed using a double-foil design and silver spacers. The final target was provided standard with Scanditronix MC-17 cyclotrons and has been used for many years. Years of operating experience and production data are drawn upon to discuss features of the designs, and also the handling and methods of routine use of a double-foil low-pressure target as they relate to target performance.