Robust and Facile Automated Radiosynthesis of [18F]FSPG on the GE FASTlab

10.26434/chemrxiv.13434143.v2 ◽

2020 ◽

Author(s):

Richard Edwards ◽

Hannah Greenwood ◽

Timothy Witney

Keyword(s):

Large Scale ◽

Radiochemical Purity ◽

Radiochemical Yield ◽

Reaction Conditions ◽

Positron Emission ◽

Optimized Protocol ◽

Cancer Types ◽

Automated Procedures ◽

Phosphate Buffered Saline ◽

High Radioactivity

Purpose: (S)-4-(3-18F-Fluoropropyl)-ʟ-Glutamic Acid ([18F]FSPG) is a radiolabeled non-natural amino acid that is used for positron emission tomography (PET) imaging of the glutamate/cystine antiporter, system xC-, whose expression is upregulated in many cancer types. To increase the clinical adoption of this radiotracer, reliable and facile automated procedures for [18F]FSPG production are required. Here, we report a cassette-based method to produce [18F]FSPG at high radioactivity concentrations from low amounts of starting activity.Procedures: An automated synthesis and purification of [18F]FSPG was developed for the GE FASTlab. Optimization of the reaction conditions and automated manipulations were performed by measuring the isolated radiochemical yield of [18F]FSPG and by assessing radiochemical purity using radioHPLC. Purification of [18F]FSPG was conducted by trapping and washing of the radiotracer on MCX SepPak catridges, followed by a reverse elution of [18F]FSPG in phosphate-buffered saline. Subsequently, the [18F]FSPG obtained from the optimized process was used to image an animal model of non-small cell lung cancer.Results: The optimized protocol produced [18F]FSPG in 38.4 ± 2.6% RCY and 96% radiochemical purity. Small alterations, including the implementation of a reverse elution and an altered hypercarb cartridge, lead to significant improvements in radiotracer concentration from <10 MBq/mL to >100 MBq/mL. The improved radiotracer concentration allowed for the imaging of up to 20 mice, starting with just 1.5 GBq of [18F]fluoride.Conclusions: We have developed a robust and facile method for [18F]FSPG radiosynthesis in high radiotracer concentration, RCP and RCY. This cassette-based method enabled the production of [18F]FSPG at radioactive concentrations sufficient to facilitate large-scale preclinical experiments with a single prep of starting activity. The use of cassettes for an ‘out the box’ synthesis on a synthesis module routinely used for clinical production make the method amenable to rapid and widespread clinical translation.

Download Full-text

Robust and Facile Automated Radiosynthesis of [18F]FSPG on the GE FASTlab

10.26434/chemrxiv.13434143.v1 ◽

2020 ◽

Author(s):

Richard Edwards ◽

Hannah Greenwood ◽

Timothy Witney

Keyword(s):

Large Scale ◽

Radiochemical Purity ◽

Radiochemical Yield ◽

Reaction Conditions ◽

Positron Emission ◽

Optimized Protocol ◽

Cancer Types ◽

Automated Procedures ◽

Phosphate Buffered Saline ◽

High Radioactivity

Purpose: (S)-4-(3-18F-Fluoropropyl)-ʟ-Glutamic Acid ([18F]FSPG) is a radiolabeled non-natural amino acid that is used for positron emission tomography (PET) imaging of the glutamate/cystine antiporter, system xC-, whose expression is upregulated in many cancer types. To increase the clinical adoption of this radiotracer, reliable and facile automated procedures for [18F]FSPG production are required. Here, we report a cassette-based method to produce [18F]FSPG at high radioactivity concentrations from low amounts of starting activity.Procedures: An automated synthesis and purification of [18F]FSPG was developed for the GE FASTlab. Optimization of the reaction conditions and automated manipulations were performed by measuring the isolated radiochemical yield of [18F]FSPG and by assessing radiochemical purity using radioHPLC. Purification of [18F]FSPG was conducted by trapping and washing of the radiotracer on MCX SepPak catridges, followed by a reverse elution of [18F]FSPG in phosphate-buffered saline. Subsequently, the [18F]FSPG obtained from the optimized process was used to image an animal model of non-small cell lung cancer.Results: The optimized protocol produced [18F]FSPG in 38.4 ± 2.6% RCY and 96% radiochemical purity. Small alterations, including the implementation of a reverse elution and an altered hypercarb cartridge, lead to significant improvements in radiotracer concentration from <10 MBq/mL to >100 MBq/mL. The improved radiotracer concentration allowed for the imaging of up to 20 mice, starting with just 1.5 GBq of [18F]fluoride.Conclusions: We have developed a robust and facile method for [18F]FSPG radiosynthesis in high radiotracer concentration, RCP and RCY. This cassette-based method enabled the production of [18F]FSPG at radioactive concentrations sufficient to facilitate large-scale preclinical experiments with a single prep of starting activity. The use of cassettes for an ‘out the box’ synthesis on a synthesis module routinely used for clinical production make the method amenable to rapid and widespread clinical translation.

Download Full-text

Robust and Facile Automated Radiosynthesis of [18F]FSPG on the GE FASTlab

10.26434/chemrxiv.13434143 ◽

2020 ◽

Author(s):

Richard Edwards ◽

Hannah Greenwood ◽

Timothy Witney

Keyword(s):

Large Scale ◽

Radiochemical Purity ◽

Radiochemical Yield ◽

Reaction Conditions ◽

Positron Emission ◽

Optimized Protocol ◽

Cancer Types ◽

Automated Procedures ◽

Phosphate Buffered Saline ◽

High Radioactivity

Purpose: (S)-4-(3-18F-Fluoropropyl)-ʟ-Glutamic Acid ([18F]FSPG) is a radiolabeled non-natural amino acid that is used for positron emission tomography (PET) imaging of the glutamate/cystine antiporter, system xC-, whose expression is upregulated in many cancer types. To increase the clinical adoption of this radiotracer, reliable and facile automated procedures for [18F]FSPG production are required. Here, we report a cassette-based method to produce [18F]FSPG at high radioactivity concentrations from low amounts of starting activity.Procedures: An automated synthesis and purification of [18F]FSPG was developed for the GE FASTlab. Optimization of the reaction conditions and automated manipulations were performed by measuring the isolated radiochemical yield of [18F]FSPG and by assessing radiochemical purity using radioHPLC. Purification of [18F]FSPG was conducted by trapping and washing of the radiotracer on MCX SepPak catridges, followed by a reverse elution of [18F]FSPG in phosphate-buffered saline. Subsequently, the [18F]FSPG obtained from the optimized process was used to image an animal model of non-small cell lung cancer.Results: The optimized protocol produced [18F]FSPG in 38.4 ± 2.6% RCY and 96% radiochemical purity. Small alterations, including the implementation of a reverse elution and an altered hypercarb cartridge, lead to significant improvements in radiotracer concentration from <10 MBq/mL to >100 MBq/mL. The improved radiotracer concentration allowed for the imaging of up to 20 mice, starting with just 1.5 GBq of [18F]fluoride.Conclusions: We have developed a robust and facile method for [18F]FSPG radiosynthesis in high radiotracer concentration, RCP and RCY. This cassette-based method enabled the production of [18F]FSPG at radioactive concentrations sufficient to facilitate large-scale preclinical experiments with a single prep of starting activity. The use of cassettes for an ‘out the box’ synthesis on a synthesis module routinely used for clinical production make the method amenable to rapid and widespread clinical translation.

Download Full-text

Microfluidic Radiosynthesis of the Muscarinic M2 Imaging Agent [18F]FP-TZTP

Australian Journal of Chemistry ◽

10.1071/ch18266 ◽

2018 ◽

Vol 71 (10) ◽

pp. 811 ◽

Cited By ~ 2

Author(s):

Lidia Matesic ◽

Ivan Greguric ◽

Giancarlo Pascali

Keyword(s):

Radiochemical Purity ◽

Muscarinic Acetylcholine Receptor ◽

Reaction Times ◽

Radiochemical Yield ◽

Receptor Subtype ◽

Chemical Reagents ◽

Molar Activity ◽

Positron Emission ◽

Radiochemical Yields ◽

Pet Scans

3-(4-(3-[18F]Fluoropropylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine ([18F]FP-TZTP) is a selective 18F-radiotracer for the muscarinic acetylcholine receptor subtype M2, which can be used to perform positron emission tomography (PET) scans on patients with neurological disorders such as Alzheimer’s disease. [18F]FP-TZTP was produced using continuous-flow microfluidics, a technique that uses reduced amounts of chemical reagents, shorter reaction times and in general, results in higher radiochemical yields compared to currently used techniques. The optimal 18F-radiolabelling conditions consisted of a total flow rate of 40 µL min−1 and 190°C, which produced [18F]FP-TZTP in 26 ± 10 % radiochemical yield with a molar activity of 182 ± 65 GBq µmol−1 and >99 % radiochemical purity.

Download Full-text

On site production of [18F]PSMA-1007 using different [18F]fluoride activities: practical, technical and economical impact

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-021-00150-z ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Costantina Maisto ◽

Anna Morisco ◽

Roberta de Marino ◽

Elisabetta Squame ◽

Valentina Porfidia ◽

...

Keyword(s):

Large Scale ◽

Radiochemical Purity ◽

Radiochemical Yield ◽

Production Costs ◽

Positron Emission ◽

Good Target ◽

Fetal Bovine ◽

Imaging Properties ◽

Specific Membrane ◽

Psma Inhibitor

Abstract Background Prostate-specific membrane antigen is overexpressed in prostate cancer and it is considered a good target for positron emission tomography/computed tomography imaging of primary cancer and recurrent/metastatic disease, as well as for radioligand therapy. Different PSMA-analogues labeled with [68Ga]gallium have been investigated, showing excellent imaging properties; however, only small amounts can be produced for each radiolabeling. Recently, a [18F]fluoride labeled PSMA-inhibitor, [18F]PSMA-1007, has been introduced, and it has ensured large-scale productions, overcoming this limitation of [68Ga]PSMAs. In this study, PSMA-1007 has been labeled with low (A), medium (B) and high (C) starting activities of [18F]fluoride, in order to verify if radiochemical yield, radiochemical purity and stability of [18F]PSMA-1007 were affected. These parameters have been measured in sixty-five consecutive batches. In addition, the estimation of [18F]PSMA-1007 production costs is provided. Results The radiochemical yield for low and medium activities of [18F]fluoride was 52%, while for the high one it decreased to 40%. The radiochemical purity was 99% for all three activities. [18F]PSMA-1007 did not show radiolysis up to 8 h after the end of synthesis, confirming that the radiopharmaceutical is stable and suitable to perform diagnostic studies in humans for a long period of time after the end of radiolabeling. Furthermore, radiochemical stability was demonstrated in fetal bovine serum at 4 °C and 37 °C for 120′. Conclusions A starting activity of [18F]fluoride of 90 GBq (B) seems to be the best option enabling a final amount of about of 50 GBq of [18F]PSMA-1007, which is promising as it allows to: (a) perform a large number of scans, and/or (b) supply the radiopharmaceutical to any peripheral diagnostic centers in need.

Download Full-text

Click Chemistry Expedited Radiosynthesis: Sulfur [18F]fluoride Exchange of Aryl Fluorosulfates

10.26434/chemrxiv.10314647.v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Qinheng Zheng ◽

Hongtao Xu ◽

Hua Wang ◽

Wen-Ge Han Du ◽

Nan Wang ◽

...

Keyword(s):

Click Chemistry ◽

High Performance ◽

Isotopic Exchange ◽

Tumor Imaging ◽

Radiochemical Yield ◽

Exchange Method ◽

Molar Activity ◽

Positron Emission ◽

Sulfur Fluoride

The lack of simple, efficient [18F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [18F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated 18F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol–1) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [18F]fluorosulfate is demonstrated by the in vivo tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1).

Download Full-text

Novel late-stage radiosynthesis of 5-[18F]-trifluoromethyl-1,2,4-oxadiazole (TFMO) containing molecules for PET imaging

Scientific Reports ◽

10.1038/s41598-021-90069-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nashaat Turkman ◽

Daxing Liu ◽

Isabella Pirola

Keyword(s):

Late Stage ◽

Histone Deacetylases ◽

Radiochemical Purity ◽

Radiochemical Yield ◽

Single Step ◽

The Novel ◽

Molar Activity ◽

The Central Nervous System ◽

Class Iia Hdacs ◽

18F Fluoride

AbstractSmall molecules that contain the (TFMO) moiety were reported to specifically inhibit the class-IIa histone deacetylases (HDACs), an important target in cancer and the disorders of the central nervous system (CNS). However, radiolabeling methods to incorporate the [18F]fluoride into the TFMO moiety are lacking. Herein, we report a novel late-stage incorporation of [18F]fluoride into the TFMO moiety in a single radiochemical step. In this approach the bromodifluoromethyl-1,2,4-oxadiazole was converted into [18F]TFMO via no-carrier-added bromine-[18F]fluoride exchange in a single step, thus producing the PET tracers with acceptable radiochemical yield (3–5%), high radiochemical purity (> 98%) and moderate molar activity of 0.33–0.49 GBq/umol (8.9–13.4 mCi/umol). We validated the utility of the novel radiochemical design by the radiosynthesis of [18F]TMP195, which is a known TFMO containing potent inhibitor of class-IIa HDACs.

Download Full-text

Clinically Applicable Cyclotron-Produced Gallium-68 Gives High-Yield Radiolabeling of DOTA-Based Tracers

Biomolecules ◽

10.3390/biom11081118 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1118

Author(s):

Emma Jussing ◽

Stefan Milton ◽

Erik Samén ◽

Mohammad Mahdi Moein ◽

Lovisa Bylund ◽

...

Keyword(s):

Metal Ion ◽

Metal Content ◽

Gamma Spectroscopy ◽

Radiochemical Yield ◽

High Yield ◽

Automated Synthesis ◽

Molar Activity ◽

Icp Ms ◽

Gallium 68 ◽

Fe Impurities

By using solid targets in medical cyclotrons, it is possible to produce large amounts of 68GaCl3. Purification of Ga3+ from metal ion impurities is a critical step, as these metals compete with Ga3+ in the complexation with different chelators, which negatively affects the radiolabeling yields. In this work, we significantly lowered the level of iron (Fe) impurities by adding ascorbate in the purification, and the resulting 68GaCl3could be utilized for high-yield radiolabeling of clinically relevant DOTA-based tracers. 68GaCl3 was cyclotron-produced and purified with ascorbate added in the wash solutions through the UTEVA resins. The 68Ga eluate was analyzed for radionuclidic purity (RNP) by gamma spectroscopy, metal content by ICP-MS, and by titrations with the chelators DOTA, NOTA, and HBED. The 68GaCl3eluate was utilized for GMP-radiolabeling of the DOTA-based tracers DOTATOC and FAPI-46 using an automated synthesis module. DOTA chelator titrations gave an apparent molar activity (AMA) of 491 ± 204 GBq/µmol. GMP-compliant syntheses yielded up to 7 GBq/batch [68Ga]Ga-DOTATOC and [68Ga]Ga-FAPI-46 (radiochemical yield, RCY ~ 60%, corresponding to ten times higher compared to generator-based productions). Full quality control (QC) of 68Ga-labelled tracers showed radiochemically pure and stable products at least four hours from end-of-synthesis.

Download Full-text

Advances in the automated synthesis of 6-[18F]Fluoro-L-DOPA

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-021-00126-z ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Ângela C. B. Neves ◽

Ivanna Hrynchak ◽

Inês Fonseca ◽

Vítor H. P. Alves ◽

Mariette M. Pereira ◽

...

Keyword(s):

Large Scale ◽

Neuroendocrine Tumours ◽

Radiochemical Yield ◽

Clinical Applications ◽

Clinical Use ◽

Molar Activity ◽

Neuropsychiatric Diseases ◽

Recent Developments ◽

Key Issues ◽

Improved Methods

AbstractThe neurotracer 6-[18F] FDOPA has been, for many years, a powerful tool in PET imaging of neuropsychiatric diseases, movement disorders and brain malignancies. More recently, it also demonstrated good results in the diagnosis of other malignancies such as neuroendocrine tumours, pheochromocytoma or pancreatic adenocarcinoma.The multiple clinical applications of this tracer fostered a very strong interest in the development of new and improved methods for its radiosynthesis. The no-carrier-added nucleophilic 18F-fluorination process has gained increasing attention, in recent years, due to the high molar activities obtained, when compared with the other methods although the radiochemical yield remains low (17–30%). This led to the development of several nucleophilic synthetic processes in order to obtain the product with molar activity, radiochemical yield and enantiomeric purity suitable for human PET studies.Automation of the synthetic processes is crucial for routine clinical use and compliance with GMP requirements. Nevertheless, the complexity of the synthesis makes the production challenging, increasing the chance of failure in routine production. Thus, for large-scale clinical application and wider use of this radiopharmaceutical, progress in the automation of this complex radiosynthesis is of critical importance.This review summarizes the most recent developments of 6-[18F]FDOPA radiosynthesis and discusses the key issues regarding its automation for routine clinical use.

Download Full-text

Fully-Automated Synthesis of 177Lu Labelled FAPI Derivatives On The Module Modular Lab-Eazy

10.21203/rs.3.rs-292849/v1 ◽

2021 ◽

Author(s):

Kurtulus Eryilmaz ◽

Benan KILBAS

Keyword(s):

Quality Control ◽

Chromatographic Analysis ◽

Radiochemical Purity ◽

Radiochemical Yield ◽

Automated System ◽

Automated Synthesis ◽

Modular Approach ◽

Stability Studies ◽

European Pharmacopoeia ◽

First Time

Abstract Backround: To the best of our knowledge, manually production of [177Lu]Lu-FAPI radiopharmaceutical derivatives has been only described in literature. In this work, a fully-automated [177Lu]Lu-FAPI synthesis has been well designed for the first time using commercially available synthesis module. In addition to the development of an automated system with disposable cassette, quality control (QC) and stability studies were comprehensively employed. Results A fully automated synthesis of [177Lu]Lu-FAPI derivatives was achieved on the Modular Lab Eazy (ML Eazy) with high radiochemical yield (85–90%). Chromatographic analysis indicated the formation of radiosynthesis with an absolute radiochemical purity (99%). Stability experiments clarified the durability of the products within 4 days. All obtained specifications are consistent to European Pharmacopoeia. Conclusion A fully automated synthesis of [177Lu]Lu-FAPI radiopharmaceuticals were accomplished regarding quality control standards and quality assurance by using commercially available a modular approach namely ML Eazy with disposable customized cassette and template.

Download Full-text