Dataset Information

Automated Radiosynthesis of cis- and trans-4-[¹⁸F]Fluoro-l-proline Using [¹⁸F]Fluoride.

ABSTRACT: The positron emission tomography imaging agents cis- and trans-4-[¹⁸F]fluoro-l-proline are used for the detection of numerous diseases such as pulmonary fibrosis and various carcinomas. These imaging agents are typically prepared by nucleophilic fluorination of 4-hydroxy-l-proline derivatives, with [¹⁸F]fluoride, followed by deprotection. Although effective radiofluorination reactions have been developed, the overall radiosynthesis process is suboptimal due to deprotection methods that are performed manually, require multiple steps, or involve harsh conditions. Here we describe the development of two synthetic routes that allow access to precursors, which undergo highly selective radiofluorination reactions and rapid deprotection, under mild acidic conditions. These methods were found to be compatible with automation, avoiding manual handling of radioactive intermediates.

SUBMITTER: Morgan TEF

PROVIDER: S-EPMC8524414 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Automated Radiosynthesis of cis- and trans-4-[18F]Fluoro-l-proline Using [18F]Fluoride.

Morgan Timaeus E F TEF Riley Leanne M LM Tavares Adriana A S AAS Sutherland Andrew A

The Journal of organic chemistry 20210429 20

The positron emission tomography imaging agents cis- and trans-4-[18F]fluoro-l-proline are used for the detection of numerous diseases such as pulmonary fibrosis and various carcinomas. These imaging agents are typically prepared by nucleophilic fluorination of 4-hydroxy-l-proline derivatives, with [18F]fluoride, followed by deprotection. Although effective radiofluorination reactions have been developed, the overall radiosynthesis process is suboptimal due to ...[more]

PMID: 33913318

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Project description:BackgroundCurrent automated radiosynthesizers are generally optimized for producing large batches of PET tracers. Preclinical imaging studies, however, often require only a small portion of a regular batch, which cannot be economically produced on a conventional synthesizer. Alternative approaches are desired to produce small to moderate batches to reduce cost and the amount of reagents and radioisotope needed to produce PET tracers with high molar activity. In this work we describe the first reported microvolume method for production of [18F]Florbetaben for use in imaging of Alzheimer's disease.ProceduresThe microscale synthesis of [18F]Florbetaben was adapted from conventional-scale synthesis methods. Aqueous [18F]fluoride was azeotropically dried with K2CO3/K222 (275/383 nmol) complex prior to radiofluorination of the Boc-protected precursor (80 nmol) in 10 μL DMSO at 130 °C for 5 min. The resulting intermediate was deprotected with HCl at 90 °C for 3 min and recovered from the chip in aqueous acetonitrile solution. The crude product was purified via analytical scale HPLC and the collected fraction reformulated via solid-phase extraction using a miniature C18 cartridge.ResultsStarting with 270 ± 100 MBq (n = 3) of [18F]Fluoride, the method affords formulated product with 49 ± 3% (decay-corrected) yield,> 98% radiochemical purity and a molar activity of 338 ± 55 GBq/μmol. The miniature C18 cartridge enables efficient elution with only 150 μL of ethanol which is diluted to a final volume of 1.0 mL, thus providing a sufficient concentration for in vivo imaging. The whole procedure can be completed in 55 min.ConclusionsThis work describes an efficient and reliable procedure to produce [18F]Florbetaben in quantities sufficient for large-scale preclinical applications. This method provides very high yields and molar activities compared to reported literature methods. This method can be applied to higher starting activities with special consideration given to automation and radiolysis prevention.

Project description: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.ProceduresAn 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.ResultsThe 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.ConclusionsWe 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.

Dataset Information

Automated Radiosynthesis of cis- and trans-4-[¹⁸F]Fluoro-l-proline Using [¹⁸F]Fluoride.

Publications

Automated Radiosynthesis of <i>cis</i>- and <i>trans</i>-4-[<sup>18</sup>F]Fluoro-l-proline Using [<sup>18</sup>F]Fluoride.

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Dataset Information

Automated Radiosynthesis of cis- and trans-4-[18F]Fluoro-l-proline Using [18F]Fluoride.

Publications

Automated Radiosynthesis of &lt;i&gt;cis&lt;/i&gt;- and &lt;i&gt;trans&lt;/i&gt;-4-[&lt;sup&gt;18&lt;/sup&gt;F]Fluoro-l-proline Using [&lt;sup&gt;18&lt;/sup&gt;F]Fluoride.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Automated Radiosynthesis of cis- and trans-4-[¹⁸F]Fluoro-l-proline Using [¹⁸F]Fluoride.

Automated Radiosynthesis of <i>cis</i>- and <i>trans</i>-4-[<sup>18</sup>F]Fluoro-l-proline Using [<sup>18</sup>F]Fluoride.