An improved one‐pot preparation of [<sup>18</sup>F]FMISO based on solid phase extraction purification: Pitfalls on the analytical method reported in the Ph.Eur.'s monograph

Background [18F]fluoromisonidazole ([18F]FMISO, 1H-1-(3-[18F]fluoro-2-hydroxypropyl)-2-nitroimidazole) is a commonly used radiotracer for imaging hypoxic conditions in cells. Since hypoxia is prevalent in solid tumors, [18F]FMISO is in clinical application for decades to explore oxygen demand in cancer cells and the resulting impact on radiotherapy and chemotherapy. Results Since the introduction of [18F]FMISO as positron emission tomography imaging agent in 1986, a variety of radiosynthesis procedures for the production of this hypoxia tracer has been developed. This paper gives a brief overview on [18F]FMISO radiosyntheses published so far from its introduction until now. From a radiopharmaceutical chemist’s perspective, different precursors, radiolabeling approaches and purification methods are discussed as well as used automated radiosynthesizers, including cassette-based and microfluidic systems. Conclusion In a GMP compliant radiosynthesis using original cassettes for FASTlab we produced [18F]FMISO in 49% radiochemical yield within 48 min with radiochemical purities > 99% and molar activities > 500 GBq/µmol. In addition, we report an easy and efficient radiosynthesis of [18F]FMISO, based on in-house prepared FASTlab cassettes, providing the radiotracer for research and preclinical purposes in good radiochemical yields (39%), high radiochemical purities (> 99%) and high molar activity (> 500 GBq/µmol) in a well-priced option.

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Synthesis of [18F]FMISO, a hypoxia-specific imaging probe for PET, an overview from a radiochemist’s perspective

Knieß

Zessin

Mäding

et al. 2023

EJNMMI radiopharm. chem.

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[¹⁸F]Fluoromisonidazole synthesis method: development and optimization by cartridge purification

et al. 2023

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[18F]Fluoromisonidazole ([18F]FMISO) as nitroimidazole derivative with 18F radioisotope is a widely known and studied hypoxia marker for PET imaging. A number of automated synthesis modules and purification strategies for production of [18F]FMISO have been described in recent years. The goal of this work was to develop [18F]FMISO synthesis process with Synthera module with solid phase extraction (SPE) Sep-Pak purification cartridges. To adjust the reaction conditions we synthesized [18F]FMISO under different reaction conditions and using various reversed-phase (RP) purification cartridges (HLB light, HLB plus, tC18, C18 environmental, Chromafix PS-RP). The synthesis was performed by nucleophilic substitution of commercial 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonylpropanediol precursor and subsequent acidic hydrolysis. Further, the product mixture was purified by passing through the SPE cartridge. The produced [18F]FMISO was retained on the cartridge, while the impurities passed through the cartridge into a waste. The retained [18F]FMISO was then eluted with small amounts of ethanol in water and eluates were collected in the final product vial. The product sample was subjected to quality control tests, while for waste sample chemical and radiochemical tests were performed. We have developed an efficient synthesis method of [18F]FMISO with cartridge purification with good radiochemical yield (RCY) and high chemical and radiochemical purity in accordance with the Ph. Eur. Monograph for Fluoromisonidazole (18F) injection.

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Phase Transfer Catalysts and Role of Reaction Environment in Nucleophilc Radiofluorinations in Automated Synthesizers

Красикова

Orlovskaya

2021

Applied Sciences

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Incorporation of [18F]fluorine into PET radiotracer structure has traditionally been accomplished via nucleophilic pathways. The [18F]fluoride is generated in an aqueous solution via proton irradiation of oxygen-18 enriched water and must to be introduced into water-free organic solutions in order to generate reactive species. Thus nucleophilic 18F-fluorination traditionally included steps for [18F]fluoride concentration on the anion exchange resin, followed by removal of residual water via azeotropic distillation with MeCN, a time-consuming process associated with radioactivity losses and difficult automation. To circumvent this, several adsorption/elution protocols were developed based on the minimization of water content in traditional kryptofix-based [18F]fluoride eluents. The use of pre-dried KOH/kryptofix solutions, tertiary alcohols, and strong organic bases was found to be effective. Advances in transition metal-mediated SNAr approaches for radiolabeling of non-activated aromatic substrates have prompted development of alternative techniques for reactive [18F]fluoride species generation, such as organic solutions of non-basic alkyl ammonium and pyridinium sulfonates, etc. For radiofluorinations of iodonium salts precursors, a “minimalist” approach was introduced, avoiding the majority of pitfalls common to more complex methods. These innovations allowed the development of new time-efficient and convenient work-up procedures that are easily implementable in modern automated synthesizers. They will be the subject of this review.

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An improved one‐pot preparation of [¹⁸F]FMISO based on solid phase extraction purification: Pitfalls on the analytical method reported in the Ph.Eur.'s monograph

Cited by 3 publications

References 17 publications

Synthesis of [18F]FMISO, a hypoxia-specific imaging probe for PET, an overview from a radiochemist’s perspective

Synthesis of [18F]FMISO, a hypoxia-specific imaging probe for PET, an overview from a radiochemist’s perspective

[¹⁸F]Fluoromisonidazole synthesis method: development and optimization by cartridge purification

Phase Transfer Catalysts and Role of Reaction Environment in Nucleophilc Radiofluorinations in Automated Synthesizers

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An improved one‐pot preparation of [18F]FMISO based on solid phase extraction purification: Pitfalls on the analytical method reported in the Ph.Eur.'s monograph

Cited by 3 publications

References 17 publications

Synthesis of [18F]FMISO, a hypoxia-specific imaging probe for PET, an overview from a radiochemist’s perspective

Synthesis of [18F]FMISO, a hypoxia-specific imaging probe for PET, an overview from a radiochemist’s perspective

[18F]Fluoromisonidazole synthesis method: development and optimization by cartridge purification

Phase Transfer Catalysts and Role of Reaction Environment in Nucleophilc Radiofluorinations in Automated Synthesizers

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Product

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An improved one‐pot preparation of [¹⁸F]FMISO based on solid phase extraction purification: Pitfalls on the analytical method reported in the Ph.Eur.'s monograph

[¹⁸F]Fluoromisonidazole synthesis method: development and optimization by cartridge purification