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Efficient radiosynthesis of 2-[(18)f]fluoroadenosine: a new route to 2-[(18)f]fluoropurine nucleosides.

ABSTRACT: An efficient method to incorporate the fluorine-18 radionuclide in 2-nitropurine-based nucleosides was developed. The nucleophilic radiofluorination of the labeling precursor with [(18)F]KF under aminopolyether-mediated conditions (Kryptofix 2.2.2/K2CO3) followed by deprotection was straightforward and, after formulation, gave 2-[(18)F]fluoroadenosine, ready for injection with a radiochemical yield of 45 ± 5%, a radiochemical purity of >98%, and a specific radioactivity up to 148 GBq/?mol. A micropositron emission tomography imaging and biodistribution study on rodents was reported.

SUBMITTER: Marchand P

PROVIDER: S-EPMC4007834 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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Efficient radiosynthesis of 2-[(18)f]fluoroadenosine: a new route to 2-[(18)f]fluoropurine nucleosides.

Marchand Patrice P Lorilleux Christophe C Gilbert Gwénaëlle G Gourand Fabienne F Sobrio Franck F Peyronnet Damien D Dhilly Martine M Barré Louisa L

ACS medicinal chemistry letters 20100528 6

An efficient method to incorporate the fluorine-18 radionuclide in 2-nitropurine-based nucleosides was developed. The nucleophilic radiofluorination of the labeling precursor with [(18)F]KF under aminopolyether-mediated conditions (Kryptofix 2.2.2/K2CO3) followed by deprotection was straightforward and, after formulation, gave 2-[(18)F]fluoroadenosine, ready for injection with a radiochemical yield of 45 ± 5%, a radiochemical purity of >98%, and a specific radioactivity up to 148 GBq/μmol. A mic ...[more]

PMID: 24900201

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Project description:Background: Current 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.Procedures: The 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??L 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.Results: Starting 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/?mol. The miniature C18 cartridge enables efficient elution with only 150??L 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.Conclusions: This 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:The synthesis and isolation of a novel bimetallic species formed by reacting two equivalents of TMPLi with CuCl in the presence of Et2O are reported. X-ray crystallography reveals the Et2O-free tetranuclear aggregate (TMPCu)2(TMPLi)2 1, which formally results from the catenation of dimers of TMPLi and TMPCu. NMR spectroscopy confirms that, upon dissolution in hydrocarbon media, the crystals fail to form a conventional Gilman cuprate dimer. Instead they exhibit a spectrum which is consistent with that recently proposed for an isomer of dimeric Gilman cuprate. Moreover, while pre-isolated Gilman cuprate is inert to benzene solvent, this new isomer smoothly affects aromatic deprotonation to give mainly Ph(TMP)3Cu2Li2 3, which is formally a heterodimer of Gilman cuprate TMPCu(?-TMP)Li 2 and PhCu(?-TMP)Li 4. Attempts to synthesise 3 through explicit combination of pre-isolated 2 and 4 were successful; additionally, this permitted the preparation of Ph(TMP)3Cu3Li 5 and Ph(TMP)3CuLi3 7 when 4 was combined in 1?:?2 ratios with TMPCu or TMPLi, respectively. 5 was characterised as metallacyclic in the solid-state, its structural features resembling those in 3 but with reduced Li-? interactions. It also proved possible to perform Cu/Li exchange on 5 (using t BuOCu) to give a novel mixed organo(amido)copper species Ph(TMP)3Cu4 6. Remarkably, the unprecedented reactivity of 1 towards benzene is reproduced by heating a 1?:?1 mixture of TMPLi and TMPCu in the same solvent; this gives predominantly 3. On the other hand, mixtures which are rich in either Cu or Li can lead to the selective in situ formation of 5 or 7. Though crystallographic data on 7 could not be obtained, DFT calculations accurately corroborated the observed structures of 3 and 5 and could be used to support 7 having the same structure type, albeit with enhanced Li-? interactions. This was consistent with NMR spectroscopic data. However, in contrast to 3 and 5, for which 2D NMR spectroscopy indicated only conformational changes, 7 was additionally found to exhibit fluxionality in a manner consistent with a dissociative process.

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

Efficient radiosynthesis of 2-[(18)f]fluoroadenosine: a new route to 2-[(18)f]fluoropurine nucleosides.

Publications

Efficient radiosynthesis of 2-[(18)f]fluoroadenosine: a new route to 2-[(18)f]fluoropurine nucleosides.

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