FDG Production Research Articles

Fully Automated Methods for [18F]FDG and [18F]-NaF Productions Using Explora FDG4: Validation and Reliability of Multi-subsequent Preparations for Clinical Applications

The worldwide usage of [18F]-sodium fluoride in clinical applications has increased the interest in the facility of its production. The development of a new automated method for multi-preparations of [18F]-NaF and [18F]FDG on an Explora FDG4 module is described. Explora FDG4 is one of the most widely used synthesizers for FDG production in daily routine use and is specifically designed to run up to four different productions with a single module. Therefore, slight modifications are carried out in order to increase the potential of the synthesizer to perform more radiopharmaceuticals. A fully automated method for multi-preparations of [18F]-NaF and [18F]FDG using Explora FDG4 was developed. Slight modifications to the Explora's hardware and software configuration were applied. A new elution vial for NaF preparation was installed and connected to the free position to MVP1. Quality control was carried out using the standard analytical methods applied for GMP production. This modification successfully provides preparation of [18F]-NaF without affecting the daily FDG production using one set preparation. [18F]-NaF was obtained in a high radiochemical yield (>90%, n=100) in 10 min total preparation time. The quality control results for both obtained products, FDG (RCP >95%) and NaF (RCP >98%), showed that the radiopharmaceuticals were in compliance with USP and Ph.Eur. specifications and compatible with clinical applications. A rapid and simple method for multi preparations of [18F]-NaF and [18F]FDG using a single Explora module was designed. Yet, the chemistry module has the potential to generate more radiopharmaceuticals to decrease the cost of preparation of [18F]-NaF compared to the cassette-based synthesizers, reducing radiation exposure resulting from manual preparations and increasing the reproducibility of [18F]-NaF preparation.

A cost effective method for the preparation of sodium fluoride [18F]NaF for PET-CT imaging by using an in-house designed module

We report the development of a manual module for the preparation of [18F]NaF for metastatic bone cancer imaging. By using this simple module, [18F]NaF production can be carried out inexpensively without using commercially available kits. The module can be used for making [18F]NaF from freshly irradiated H218O water or with left over activity in the target after [18F]FDG production. The product meets all quality control parameters.

Establishing the [18F]-FDG Production via Two Different Automated Synthesizers for Routine Clinical Studies: Our Institutional Experiences of 4 years.

Introduction:[18F]-Fluorodeoxyglucose ([18F]-FDG) is the most widely used positron-emission tomography tracer used for imaging in clinical studies such as early detection of cancer or its malignancies, quantifications, staging, and restaging of several malignancies. For clinical application, routine production of this tracer is mandatory in compliance to regulatory guidelines. Several dedicated commercial synthesizers are currently used for producing[18F]-FDG for clinical usage. Being at hospital radiopharmacy, it is our responsibility and duty to support the clinical service with uninterrupted production and supply of [18F]-FDG. This document describes the production of [18F]-FDG using two different automated synthesizers in terms of its production yield, time of synthesis, and analyze the quality control (QC) of the produced [18F]-FDG.Materials and Methods:The precursor, mannose triflate ultra-pure, authentic nonradioactive standard FDG and [18O]-water were obtained from ABX, Germany. Solvents and reagents were purchased from Sigma Aldrich India Ltd. and Fisher Scientific India Ltd., (Mumbai, Maharashtra, India).Results:The protocol developed for the synthesis with MPS-100 synthesizer yield of [18F]-FDG is approximate about 45% End of Bombardment (EOB) with synthesis time of around 35 min, whereas with F300E synthesizer it is around 60% with synthesis time of 25 min. The quality of the tracer produced by both synthesizers is at par with the QC parameter for clinical applications.Conclusions:Finally, we have developed the production using two automated synthesis modules which have the capability to produce [18F]-FDG, to do the patient studies in good yield and purity. Our protocol is simple, reproducible, and robust.

Performance analysis and operational experience of [18F]FDG production with cassette-type modules in four hospitals of Taiwan

The performance of FASTlab synthesizers and three-year operational experience at four hospitals in Taiwan were analyzed and summarized. [18F]FDG was daily produced with about 80% (EOB) of RCY and USP-compliant specification at four centers in Taiwan. The easiness to operate the cassette and high RCY of produced [18F]FDG are the main advantages for clinical use at the PET center of hospitals, but some underlying defects of the synthesizer or cassettes should be paid attention to and proactively scrutinized, such as cassette leakage and low tC18 trapping yield.

Historical and radiopharmaceutical relevance of [18F]FDG

The 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) is the most well-known radiopharmaceutical positron emitter, in both clinical and preclinical fields. Based on a literature review of research from the last 40 years, this paper focuses on the most important aspects of [18F]FDG production and its evolution over time. Possible future perspectives of this important radiotracer are also discussed.

Effect of IDH3a on glucose uptake in lung adenocarcinoma: A pilot study based on [18 F]FDG.

Subunit of isocitrate dehydrogenase 3 (IDH3a) as upstream of the hypoxia‐inducible factor was reported highly expressed in malignant tumors, playing an important role in glucose metabolism reprogramming. As one of rate‐limiting enzyme in the Krebs cycle, whether high expression of IDH3a affects glucose uptake in tumors has not been elucidated. This study was aimed to investigate the relationship between IDH3a expression and tumor glucose uptake. Sixty‐five patients who underwent 2‐[18F]‐2‐deoxy‐D‐glucose ([18F]‐FDG) positron emission tomography/computed tomography (PET/CT) imaging before surgery and pathologically diagnosed as lung adenocarcinoma were included. All patients were divided into high (n = 31) and low (n = 34) groups according IDH3a expression by immunohistochemistry. Comparatively higher [18F]‐FDG uptake was found in high IDH3a expression group. Glucose transporter 1 (GLUT1) level was demonstrated to correlate with IDH3a expression, but not for hexokinase 2 (HK2). Furthermore, A549 and H1299 cells experiment showed, the expression of p‐AKT and GLUT1 were significantly downregulated after IDH3a interference. The cellular uptake of [18F]‐FDG and lactate production were significantly reduced in treatment group. In summary, high expression of IDH3a in lung adenocarcinoma patients is associated with higher glucose uptake. IDH3a targets AKT‐GLUT1 pathway to affect glucose uptake and metabolites in lung adenocarcinoma.

An improved automated one-pot synthesis of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) based on a purification by cartridges

IntroductionO-(2-[18F]Fluoroethyl)-L-tyrosine ([18F]FET) is an established radiotracer used for oncology investigations by Positron Emission Tomography (PET). Main limitations to its widespread use are the synthesis itself (time; cost; radiochemical yield; complexity) and a troublesome and time-consuming HPLC purification. Aim of this work was to improve the preparation overall efficiency and, most important, to achieve an efficient and reliable purification by means of disposable cartridges. Methods[18F]FET was synthesized by direct nucleophilic radiofluorination of O-(2-tosyloxy-ethyl)-N-trityl-L-tyrosine t-butylester (TET) followed by acid hydrolysis with HCl. Several conditions and materials were tested for the synthesis and purification step. For the latter, a number of different commercial cartridges, varying in amount, particulate size and adsorbent, were examined. Best results were obtained by a combination of STRATA-X, tC18 and QMA cartridges. ResultsStarting from only 5 mg of TET, up to 11 GBq of injectable solutions of [18F]FET were produced within 36 min with 54–65% radiochemical yields and radiochemical purities >99%. No D-form was observed by chiral HPLC. Chemical purity was 1–2 order of magnitude below the limits imposed by the European Pharmacopoeia's monograph on [18F]FET.A radiochemical purity decrease by radiolysis, observed only on relatively large batches of [18F]FET, was efficiently suppressed by preloading in the receiving final vial a small amount of ethanol (<2% v/v). ConclusionsBy combining improvements to a known synthetic route with a novel cartridge-based purification, [18F]FET was obtained in a very efficient and reproducible way. The whole process was easily implemented on a commercial automated module presently used for [18F]FDG production. Advances in knowledge and implications for patient careA few drawbacks regarding the HPLC conditions recommended in the European Pharmacopoeia were highlighted. An alternative method able to cope with them is herein proposedThe simplified preparation herein described is expected to encourage a more widespread clinical use of [18F]FET.

A two-center study for the quality control of [(18)F]FDG using FASTlab phosphate cassettes.

The GE FASTlab radiosynthesis module is routinely used for the production of [(18)F]FDG, utilizing the commercially available phosphate cassettes. Because of the observation of a white precipitate in the product vial before the product expiry time, we re-examined the quality of the produced [(18)F]FDG solution. Phosphate buffered [(18)F]FDG solution was synthesized on the FASTlab and analyzed at both National Taiwan University Hospital (NTUH) of Taiwan and Royal Brisbane and Women's Hospital (RBWH) of Australia. In addition to the standard product quality control (QC), the concentration of aluminum (Al(3+)) as probable cause of the precipitations in the [(18)F]FDG solution was analyzed by inductively coupled plasma mass spectrometry (ICP-MS at RBWH) and inductively coupled plasma optical emission spectrometry (ICP-OES at NTUH), and using three semi-quantitative methods at NTUH, Advantec(®) Alumi Check Test Strip, Quantofix(®) Aluminum Test Strip and MColortest™ Aluminum Test kit. The precipitates were observed in the [(18)F]FDG solution within 24 (NTUH) and 6 (RBWH) hours after the end of synthesis in 38-100% of the batches, dependent on the batch of the FASTlab cassettes. Addition of metal-free HCl(aq) to aliquots of [(18)F]FDG containing precipitate, followed by ICP-MS analysis revealed Al(3+) concentrations of 70-80ppm. Al(3+) concentrations of 10-12ppm were detected in [(18)F]FDG batches that did not show any precipitation. In contrast, less than 5ppm of the residual Al(3+) was detected by semi-quantitative methods in all batches. The US (USP), British (BP), European (EP) and Japanese (JP) pharmacopeias demand that [(18)F]FDG for injection should be clear and particulate free within the given shelf-life/expiration time. To avoid Al-phosphate precipitation within the product expiry time, FASTlab citrate cassettes, rather than phosphate cassettes, should be used for [(18)F]FDG production. Although testing for Al(3+) is not listed in the [(18)F]FDG monographs of the USP, BP and EP, residual Al(3+) levels should be considered in the interests of patient safety.

Measurement of activation products generated in the [18F]FDG production by a 9.6 MeV cyclotron

Gamma-ray spectrometry was used for the identification and quantification of the activation products induced during the production of [18F]FDG in a cyclotron with a beam of 9.6MeV protons, a silver target and Havar entrance window. Samples of the irradiated water collected before and after the 18F separation, and of the final product [18F]FDG were measured in the particular conditions of a beam current of 45 μA and an irradiation time of 25–30min The radionuclides 52Mn, 55Co, 56Co, 57Co, 58Co, 95Tc, 96Tc, and 109Cd were identified in the irradiated water samples, but not detected in the final [18]FDG product. The requirements for the transport of the recovered enriched water are also discussed.

A “dose on demand” Biomarker Generator for automated production of [18F]F− and [18F]FDG

The University of Oklahoma—College of Pharmacy has installed the first Biomarker Generator (BG75) comprising a self-shielded 7.5-MeV proton beam positive ion cyclotron and an aseptic automated chemistry production and quality control module for production of [18F]F− and clinical [18F]FDG. Performance, reliability, and safety of the system for the production of “dose on demand” were tested over several months. No-carrier-added [18F]F− was obtained through the 18O(p,n)18F nuclear reaction by irradiation (20–40min) of a >95% enriched [18O]H2O target (280μl) with a 7.5-MeV proton beam (3.5–5.0μA). Automated quality control tests were performed on each dose. The HPLC-based analytical methods were validated against USP methods of quality control. [18F]FDG produced by BG75 was tested in a mouse tumor model implanted with H441 human lung adenocarcinoma cells. After initial installment and optimization, the [18F]F− production has been consistent since March 2011 with a maximum production of 400 to 450mCi in a day. The average yield is 0.61mCi/min and 0.92mCi/min at 3.8µA and 5µA, respectively. The current target window has held up for over 25 weeks against >400 bombardment cycles. [18F]FDG production has been consistent since June 2012 with an average of six doses/day in an automated synthesis mode (RCY≈50%). The release criteria included USP-specified limits for pH, residual solvents (acetonitrile/ethanol), kryptofix, radiochemical purity/identity, and filter integrity test. The entire automated operation generated minimal radiation exposure hazard to the operator and environment. As expected, [18F]FDG produced by BG75 was found to delineate tumor volume in a mouse model of xenograft tumor. In summary, production and quality control of “[18F]FDG dose on demand” have been accomplished in an automated and safe manner by the first Biomarker Generator. The implementation of a cGMP quality system is under way towards the ANDA submission and first clinical use of [18F]FDG produced by BG75.

Testing which is the fitter position sensor for a cyclotron liquid target

The [18F]FDG has 109.7min half-life, there is a period about 6h between the beginning of [18O]H2O irradiation until the PET–CT exam. Any fail in production chain will result in delay to the PET–CT exam. The absence of the position signs from [18O]H2O target valve may result in 18F production loss. Three types of position sensors were tested. After finding the fitter sensor it was possible to reduce the incidence of fails, increasing the reliability in [18F]FDG production chain.

FDG-PET and FDG production at Wattanosoth Hospital

FDG-PET or Positron Emission Tomography with Fluorode- oxyglucose (fluorine-18-2-fluoro-2-deoxy-D-glucose [FDG]) for oncologic imaging both detects and effectively monitors the therapy of many malignancies. FDG-PET improves the detection and staging of cancer, disease management, therapy selection, and the assessment of appropriate therapeutic responses. Besides the use of FDG-PET in oncology, it can also be used in neurology and cardiology. The clinical use of FDG-PET has flourished over the past 15 years. This article is not meant to be exhaustive, but rather to give an overview and to share some information and experience of FDG-PET and FDG production at Wattanosoth Hospital. It will touch briefly on all aspects of FDG-PET and its production, namely an overview of radioisotope production of F-18, FDG synthesis and quality control.

Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo

Cancer cells convert glucose preferentially to lactate even in the presence of oxygen (aerobic glycolysis–Warburg effect). New concepts in cancer treatment aim at inhibition of aerobic glycolysis. Pyruvate dehydrogenase converts pyruvate to acetylCoA thus preventing lactate formation. Therefore, the aim of this study was to evaluate compounds that could activate pyruvate dehydrogenase in cancer cells. We investigated the effects of (R)-(+)-α-lipoic acid (LPA) and dichloroacetate (DCA), possible activators of pyruvate dehydrogenase, on suppression of aerobic glycolysis and induction of cell death. The neuroblastoma cell lines Kelly, SK-N-SH, Neuro-2a and the breast cancer cell line SkBr3 were incubated with different concentrations (0.1–30 mM) of LPA and DCA. The effects of both compounds on cell viability/proliferation (WST-1 assay), [18F]-FDG uptake, lactate production and induction of apoptosis (flow cytometric detection of caspase-3) were evaluated. Furthermore, NMRI nu/nu mice that had been inoculated s.c. with SkBr3 cells were treated daily for four weeks with LPA (i.p, 18.5 mg/kg) starting at day 7 p.i.. Tumor development was measured with a sliding calliper and monitored via [18F]-FDG-PET. Residual tumors after therapy were examined histopathologically. These data suggests that LPA can reduce (1) cell viability/proliferation, (2) uptake of [18F]-FDG and (3) lactate production and increase apoptosis in all investigated cell lines. In contrast, DCA was almost ineffective. In the mouse xenograft model with s.c. SkBr3 cells, daily treatment with LPA retarded tumor progression. Therefore, LPA seems to be a promising compound for cancer treatment.

Automated synthesis of hypoxia imaging agent [18F]FMISO based upon a modified Explora FDG4 module

A new automated synthesis procedure of 1-H-1-(3-[18F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([18F]FMISO), a specific hypoxia imaging agent with great significances for the noninvasive, dynamic hypoxia evaluation of cancer, was developed by modifying Explora FDG4 module, a commercial [18F]FDG production system, in this study. Its radiochemical synthesis was carried out via two sequent reaction steps, i.e. the nucleophilic displacement of labeling precursor 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydropyranyl-3-O-tosyl-propanediol (NITTP) with activated 18F- ion at 100 °C for 8 minutes, and the following hydrolysis with 1M HCl at 100 °C for 5 minutes and neutralization with 1M NaOH. Two-pot reaction with two independent separations was adopted to assure the good separation of final product via solid phase extraction (SPE) based upon combined Sep-pak cartridges instead of high performance liquid chromatography (HPLC). This fast, reliable preparation route of 18F-FMISO could complete within 50 minutes with about 55% of high radiochemical yield (with decay correction) and more than 98% of good radiochemical purity. The modified module could perform multiple runs of production of [18F]FMISO.

Two years of experience with the [18F]FDG production module

Chemistry module for a conventional [18F]FDG production by using tetrabutylammonium bicarbonate (TBA) and an acidic hydrolysis has been manufactured and evaluated. In this experiment, 75mM (pH 7.5–7.8) of TBA solution and a ca. 2-curies order of [18F]-fluoride have been used for the evaluation. The commercial acidic purification cartridge was purchased from GE or UKE. The operation system (OS) was programmed with Lab-View which was selected because of its easy customization of the OS. Small sized solenoid valves (Burkert; type 6124) were selected to reduce the module dimensions (W 350×D 270×H 250). The total time for the synthesis of [18F]FDG was 30±3min. The production yield of [18F]FDG was 60±2% on an average at EOS, with the decay uncorrected. This experimental data show that the traditional chemistry module can provide a good [18F]FDG production yield by optimizing the operational conditions. The radiochemical purity, radionuclidic purity, acidity, residual solvent, osmolality and endotoxin were determined to assess the quality of [18F]FDG. The examined contents for the quality control of [18F]FDG were found to be suitable for a clinical application.

A study on the [ 18F]FDG production efficiency of the MINItrace™ cyclotron in Shin Kong Memorial Hospital

The Cyclotron Center of Shin Kong Memorial Hospital is the most active [ 18F]FDG producer in Taiwan. Any improvement of the production efficiency of the MINItrace™ cyclotron is valuable. A theoretical activity of [ 18F]FDG has been calculated from the proton stopping power and the interaction cross-section of the 18O(p,n) 18F reaction to estimate the efficiency of the production process. A high-sensitivity moderated 3He neutron detector was installed to investigate the real-time condition of the target irradiation by monitoring the associated neutron production. Based on the results of this study, a graphical user interface program has been developed for operators to arrange the operation conditions and to analyze the performance of the production process.

Routine quality control of recycled target [ 18O]water by capillary electrophoresis and gas chromatography

Recycling of [ 18O]water for [ 18F]fluoride production can be accomplished with reliable results. We have developed sensitive, robust, and rapid analyses of impurities in [ 18O]water. Anions were quantitated by capillary electrophoresis and organic residuals were quantitated by gas chromatography using methods with excellent reproducibility and linearity. Kryptofix 222 (K-222) was quantitated by a sensitive LC-MS-MS technique. Isotopic composition was determined by GC-MS with satisfactory accuracy and precision. These methods were employed to evaluate recovered [ 18O]water purified by a novel electrolysis method. 2-[ 18F]FDG yields using purified [ 18O]water with very low levels of impurities are indistinguishable from newly purchased [ 18O]water. High (> 300 ppm) carbonate concentration reduces the fluoride trapping efficiency of QMA. The analyses of anions, organics, and isotopic enrichment were applied routinely for quality control of [ 18O]water to predict a satisfactory outcome of 2-[ 18F]FDG production.

Adduct of 2-[ 18F]FDG and 2-nitroimidazole as a putative radiotracer for the detection of hypoxia with PET: synthesis, in vitro- and in vivo-characterization

A new sugar-coupled 2-nitroimidazole derivative ([ 18F] 1 ) has been prepared in good radiochemical yields starting from peracetylated 2-[ 18F]FDG obtained from an automated 2-[ 18F]FDG production module. The corresponding glucose derivative 2 has proved to be able to inhibit 2-[ 18F]FDG uptake into tumor cells in a concentration dependent way. However, [ 18F] 1 failed to show a retention in hypoxic tumor tissue thus excluding itself from further investigations.