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

Abstract BackgroundProstate-Specific Membrane Antigen is overexpressed in prostate cancer and it is considered a good target for staging of primary and recurrences as well as for radioligand therapy. Different PSMA-analogues have been investigated, labeled with [68Ga], showing excellent imaging properties; although, only small amounts can be produced for single synthesis. Recently, a fluorinated PSMA-inhibitor, [18F]-PSMA-1007, has been introduced, ensuring large-scale productions. In this study, the radiosynthesis of [18F]-PSMA-1007 using low (A), medium (B) and high (C) starting activities of [18F]-Fluoride, has been fully tested. The following parameters radiochemical yield, radiochemical purity and stability of [18F]-PSMA-1007 have been measured in 65, consecutive batches to verify the effects of the three different conditions. In addition, the analysis of the costs for the production has been performed. ResultsThe radiochemical yield percentage for low and medium range of activities of [18F]-Fluoride was 52%, while for the high range it decreases to 40%. The radiochemical purity was 99% in all three tested starting activities. [18F]-PSMA-1007 did not show radiolysis up to 8 hours after the end of synthesis, confirming that the radiopharmaceutical is stable an suitable for PET studies in humans. Furthermore, stability studies performed in fetal bovine serum demonstrated radiochemical stability at 37°C for 120’. ConclusionsA starting activity of [18F]-Fluoride of 90 GBq (range B) enables a final amount of [18F]-PSMA-1007 of about 50 GBq, which is powerful for different choices: to perform up to 25 PET/CT scans in a referral institution for prostate cancer, and/or to supply the eventual peripheral PET centers.

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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.

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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.

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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.

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

Molecular Imaging and Biology ◽

10.1007/s11307-021-01609-w ◽

2021 ◽

Author(s):

Richard Edwards ◽

Hannah E. Greenwood ◽

Graeme McRobbie ◽

Imtiaz Khan ◽

Timothy H. Witney

Keyword(s):

Large Scale ◽

Radiochemical Purity ◽

Radiochemical Yield ◽

Automated Synthesis ◽

Molar Activity ◽

Positron Emission ◽

Optimized Protocol ◽

Cancer Types ◽

Automated Procedures ◽

Phosphate Buffered Saline

Abstract 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 using 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 radio-HPLC. Purification of [18F]FSPG was conducted by trapping and washing of the radiotracer on Oasis MCX SPE cartridges, 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 % radiochemical yield and >96 % radiochemical purity with a molar activity of 11.1 ± 7.7 GBq/μmol. Small alterations, including the implementation of a reverse elution and an altered Hypercarb cartridge, led 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, radiochemical yield, and radiochemical purity. 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 a cassette-based radiosynthesis on an automated synthesis module routinely used for clinical production makes the method amenable to rapid and widespread clinical translation.

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[18F]F-PSMA-1007 Radiolabelling without an On-Site Cyclotron: A Quality Issue

Pharmaceuticals ◽

10.3390/ph14070599 ◽

2021 ◽

Vol 14 (7) ◽

pp. 599

Author(s):

Valentina Di Iorio ◽

Stefano Boschi ◽

Anna Sarnelli ◽

Cristina Cuni ◽

David Bianchini ◽

...

Keyword(s):

Quality Assurance ◽

Radiochemical Purity ◽

Competent Authority ◽

Radiochemical Yield ◽

Synthesis Process ◽

Control Parameters ◽

Quality Issue ◽

Assurance System ◽

Quality Control Parameters ◽

Specific Membrane

Radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) has become the gold standard for PET imaging of prostate cancer. [68Ga]Ga-PSMA-11 has been the forerunner but a [18F]F-PSMA ligand has been developed because of the intrinsic advantages of Fluorine-18. Fluorine-18 labelled compounds are usually prepared in centers with an on-site cyclotron. Since our center has not an on-site cyclotron, we decided to verify the feasibility of producing the experimental 18F-labelled radiopharmaceutical [18F]F-PSMA-1007 with [18F]F- from different external suppliers. A quality agreement has been signed with two different suppliers, and a well-established and correctly implemented quality assurance protocol has been followed. The [18F]F- was produced with cyclotrons, on Nb target, but with different beam energy and current. Extensive validation of the [18F]F-PSMA-1007 synthesis process has been performed. The aim of this paper was the description of all the quality documentation which allowed the submission and approval of the Investigational Medicinal Product Dossier (IMPD) to the Competent Authority, addressing the quality problems due to different external suppliers. The result indicates that no significant differences have been found between the [18F]F- from the two suppliers in terms of radionuclidic and radiochemical purity and [18F]F- impacted neither the radiochemical yield of the labelling reaction nor the quality control parameters of the IMP [18F]F-PSMA-1007. These results prove how a correct quality assurance system can overcome some Regulatory Authorities issue that may represent an obstacle to the clinical use of F-18-labelled radiopharmaceuticals without an on-site cyclotron

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Radiosynthesis of a Novel PET Fluoronicotinamide for Melanoma Tumour PET Imaging; [18F]MEL050

Australian Journal of Chemistry ◽

10.1071/ch11048 ◽

2011 ◽

Vol 64 (7) ◽

pp. 873 ◽

Cited By ~ 7

Author(s):

Ivan Greguric ◽

Stephen Taylor ◽

Tien Pham ◽

Naomi Wyatt ◽

Cathy D. Jiang ◽

...

Keyword(s):

Total Synthesis ◽

Large Scale ◽

Radiochemical Purity ◽

Specific Activity ◽

Phase 1 ◽

Radiochemical Yield ◽

Synthesis Time ◽

Clinical Phase ◽

One Step ◽

No Carrier Added

[18F]6-Fluoro-N-[2-(diethylamino)ethyl]nicotinamide [18F]MEL050 is a novel nicotinamide-based radiotracer, designed to target random metastatic dissemination of melanoma tumours by targeting melanin. Preclinical studies suggest that [18F]MEL050 has an excellent potential to improve diagnosis and staging of melanoma. Here we report the radiochemical optimization conditions of [18F]MEL050 and its large scale automated synthesis using a GE FXFN automated radiosynthesis module for clinical, phase-1 investigation. [18F]MEL050 was prepared via a one-step synthesis using no-carrier added K[18F]F-Krytpofix® 222 (DMSO, 170°C, 5 min) followed by HPLC purification. Using 6-chloro-N-[2-(diethylamino)ethyl]nicotinamide as precursor, [18F]MEL050 was obtained in 40–46% radiochemical yield (non-decay corrected), in greater than 99.9% radiochemical purity and specific activity ranging from 240 to 325 GBq μmol–1. Total synthesis time including formulation was 40 min and [18F]MEL050 was stable (99.8%) in PBS for 6 h.

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Microfluidic Preparation of 89Zr-Radiolabelled Proteins by Flow Photochemistry

Molecules ◽

10.3390/molecules26030764 ◽

2021 ◽

Vol 26 (3) ◽

pp. 764

Author(s):

Daniel F. Earley ◽

Amaury Guillou ◽

Dion van der Born ◽

Alex J. Poot ◽

Jason P. Holland

Keyword(s):

Positron Emission Tomography ◽

Human Serum Albumin ◽

Radiochemical Purity ◽

Flow Reactor ◽

Radiochemical Yield ◽

Emission Tomography ◽

Flow Process ◽

Automated Production ◽

Desferrioxamine B ◽

Positron Emission

89Zr-radiolabelled proteins functionalised with desferrioxamine B are a cornerstone of diagnostic positron emission tomography. In the clinical setting, 89Zr-labelled proteins are produced manually. Here, we explore the potential of using a microfluidic photochemical flow reactor to prepare 89Zr-radiolabelled proteins. The light-induced functionalisation and 89Zr-radiolabelling of human serum albumin ([89Zr]ZrDFO-PEG3-Et-azepin-HSA) was achieved by flow photochemistry with a decay-corrected radiochemical yield (RCY) of 31.2 ± 1.3% (n = 3) and radiochemical purity >90%. In comparison, a manual batch photoreactor synthesis produced the same radiotracer in a decay-corrected RCY of 59.6 ± 3.6% (n = 3) with an equivalent RCP > 90%. The results indicate that photoradiolabelling in flow is a feasible platform for the automated production of protein-based 89Zr-radiotracers, but further refinement of the apparatus and optimisation of the method are required before the flow process is competitive with manual reactions.

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An Automated and Putatively Versatile Approach for Labeling Peptides with Fluorine-18 Using the FastlabTM Synthesizer; Exemplified with Glu-the CO-Lys Pharmacophore

10.21203/rs.3.rs-1148758/v1 ◽

2021 ◽

Author(s):

Dag Erlend Olberg ◽

Raphaël Hoareau ◽

Tore Bach-Gansmo ◽

Paul Cumming

Keyword(s):

Emission Tomography ◽

High Yield ◽

Prosthetic Group ◽

Positron Emission ◽

One Step ◽

Positron Emitters ◽

Synthesis Yield ◽

Imaging Properties ◽

Specific Membrane ◽

Spe Purification

Abstract Background: Noninvasive molecular imaging using peptides and biomolecules labelled with positron emitters has become important for detection of cancer and other diseases with PET (positron emission tomography). The positron emitting radionuclide fluorine-18 is widely available in high yield from cyclotrons and has favorable decay (t1/2 109.7 min) and imaging properties. 18F-Labelling of biomolecules and peptides for use as radiotracers is customarily achieved in a two-step approach, which can be challenging to automate. 6-[18F]Fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester ([18F]F-Py-TFP) is a versatile 18F-prosthetic group for this purpose, which can be rapidly be produced in an one-step approach on solid support. This work details an automated procedure on the cassette-based GE FASTlabTM platform for the labeling of a peptidomimetic, exemplified by the case of using the Glu-CO-Lys motif to produce [18F]DCFPyL, a ligand targeting the prostate specific membrane antigen (PSMA). Results: From fluorine-18 delivery a fully automated two-step radiosynthesis of [18F]DCFPyL was completed in 56 min with an overall end of synthesis yield as high as 37% using SPE purification on the GE FASTlabTM platform. Conclusions: Putatively, this radiolabeling methodology is inherently amenable to automation with a diverse set of synthesis modules, and it should generalize for production of a broad spectrum of biomolecule-based radiotracers for use in PET imaging.

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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.

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