Synthesis and Radiosynthesis of a Novel PET Fluorobenzyl Piperazine for Melanoma Tumour Imaging; [18F]MEL054

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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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.

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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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Clinical Translational Evaluation of Al18F-NOTA-FAPI for Fibroblast Activation Protein Targeted Tumour Imaging

10.21203/rs.3.rs-231262/v1 ◽

2021 ◽

Author(s):

Shuailiang Wang ◽

Xin Zhou ◽

Xiaoxia Xu ◽

Jin Ding ◽

Song Liu ◽

...

Keyword(s):

Cancer Patients ◽

Fibroblast Activation Protein ◽

Ct Imaging ◽

Whole Body ◽

Tumour Imaging ◽

Tumour Detection ◽

Fibroblast Activation ◽

Tumour Bearing ◽

Pet Ct ◽

18F Fdg

Abstract PurposeIn this study, a novel Al18F-NOTA-FAPI probe was developed for fibroblast activation protein (FAP) targeted tumour imaging, which was available to achieve curie level radioactivity by automatic synthesizer. The tumour detection efficacy of Al18F-NOTA-FAPI was further validated both in preclinical and clinical translational studies. MethodsThe radiolabeling procedure of Al18F-NOTA-FAPI was optimized. Cell uptake and competitive binding assay were completed with U87MG and A549 cell lines, to evaluate the affinity and specificity of Al18F-NOTA-FAPI probe. The biodistribution, pharmacokinetics, radiation dosimetry and tumour imaging efficacy of Al18F-NOTA-FAPI probe were researched with healthy Kunming (KM) and/or U87MG model mice. After the approval of ethical committee, Al18F-NOTA-FAPI probe was translated into clinical for the PET/CT imaging of first 10 cancer patients. ResultsThe radiolabeling yield of Al18F-NOTA-FAPI was 33.8 ± 3.2% through manually operation (n = 10), with the radiochemical purity over than 99% and the specific activity of 9.3-55.5 MBq/nmol. Whole body effective dose of Al18F-NOTA-FAPI was estimated to be 1.24E-02 mSv/MBq, lower than several other FAPI probes ( 68Ga-FAPI-04, 68Ga-FAPI-46 and 68Ga-FAPI-74). In U87MG tumour bearing mice, Al18F-NOTA-FAPI showed good tumor detection efficacy from the results of micro PET/CT imaging and biodistribution studies. In organ biodistribution study of human patients, Al18F-NOTA-FAPI showed lower SUVmean than 2-[18F]FDG in most organs, especially in liver (1.1 ± 0.2 vs. 2.0 ± 0.9), brain (0.1 ± 0.0 vs. 5.9 ± 1.3), and bone marrow (0.9 ± 0.1 vs. 1.7 ± 0.4). Meanwhile, Al18F-NOTA-FAPI do not show extensive bone uptakes, and was able to find out more tumour lesions than 2-[18F]FDG in the PET/CT imaging of several patients. ConclusionAl18F-NOTA-FAPI probe was successfully fabricated and applied in fibroblast activation protein targeted tumour PET/CT imaging, which showed excellent imaging quality and tumour detection efficacy in U87MG tumour bearing mice as well as in human cancer patients.

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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.

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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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Synthesis of 18F-labelled 2-fluoroethyl-nitrosoureas

Canadian Journal of Chemistry ◽

10.1139/v84-359 ◽

1984 ◽

Vol 62 (11) ◽

pp. 2107-2112 ◽

Cited By ~ 14

Author(s):

Simin Farrokhzad ◽

Mirko Diksic ◽

Lucas Y. Yamamoto ◽

William Feindel

Keyword(s):

Radiochemical Purity ◽

Specific Activity ◽

Radiochemical Yield ◽

Nucleophilic Attack ◽

Aziridine Ring ◽

Geometrical Isomers ◽

Isomeric Mixture

18F-labelled 1,3-bis-(2-fluoroethyl) nitrosourea (18F-BFNU) (9) and 1-(2-chloroethyl)-3-(2-fluoroethyl) nitrosourea (18F-CFNU) (isomeric mixture, 11,12) were synthesized by nucleophilic attack of 18F-labelled tetra-n-butylammonium fluoride on the aziridine ring of 1,3-substituted ureas. Diethyleneurea (DEU) (5), 1-(2-fluoroethyl)-3-ethyleneurea (FEU) (7), and 1-(2-chloroethyl)-3-ethyleneurea (CEU) (14) were used as starting materials in the synthesis. Nitrosation of 18F-labelled 1,3-bis-(2-fluoroethyl) urea (18F-BFU) (6) produced 18F-BFNU with a radiochemical yield of 5–10%. Nitrosation of 18F-labelled 1-(2-chloroethyl)-3-(2-fluoroethyl) urea (18F-CFU) (15) gave 18F-CFNU as a mixture of two isomers. Geometrical isomers of CFNU were separated by hplc, and the radiochemical yield of the two isomers ranged from 8% to 15%, with a radiochemical purity exceeding 96%. Syntheses, which took about 60 min, yielded products with specific activity of 680 mCi/mmol when n-Bu4N+F− was used, or 300 mCi/mmol when HF was used to complete the opening of the aziridine ring.

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