Improved synthesis of [ 18 F]FLETT via a fully automated vacuum distillation method for [ 18 F]2-fluoroethyl azide purification

Ackermann, Uwe; Plougastel, Lucie; Goh, Yit Wooi; Yeoh, Shinn Dee; Scott, Andrew M.

doi:10.1016/j.apradiso.2014.07.009

Cited by 9 publications

(11 citation statements)

References 11 publications

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“…[6] A disadvantage of this type of low-molecular-weight agent is its high volatility and the need for intermediate purification by distillation which is challenging to carry out in radiochemical laboratories. [6–7] To the best of our knowledge, 4-[ 18 F]fluorobenzyl azide is the only azido 18 F-arene used in PET imaging studies. [8] However, the preparation of 4-[ 18 F]fluorobenzyl azide involves laborious multi-step processes [8b, 8d] or utilization of a specialized flow device.…”

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confidence: 99%

Ortho‐Stabilized ¹⁸F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

et al. 2015

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Azido 18F-arenes are important and versatile building blocks for radiolabeling of biomolecules via Huisgen cycloaddition (‘click chemistry’) in positron emission tomography (PET). However, routine access of such clickable agents is challenged by inefficient multi-step and esoteric radiochemical approaches. Herein we describe a high-yielding direct radiofluorination for azido 18F-arenes by developing an oxygen ortho-stabilized iodonium derivative (OID). This OID strategy addresses an unmet need for a reliable azido 18F-arene clickable agent in bioconjugation reactions. A ssDNA aptamer is radiolabeled and visualized in a xenograft mouse model of human colon cancer by PET, which demonstrates a convenient and highly efficient way of labeling biomolecules and tracking them by OID approach.

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confidence: 99%

Ortho‐Stabilized ¹⁸F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

et al. 2015

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“…A fully automated Fig. 1 Initial HTS hit Chembridge 5219657, SAR optimized mTOR benzofuran reference compound 1 (mBRef-1) and proposed mTOR benzofuran PET compound 1 ([ 18 F]mBPET-1) procedure has been developed which allows convenient derivatisation of alkyne precursors with 2-[ 18 F]fluoroethylazide (Ackermann et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and validation of [18F]mBPET-1, a fluorine-18 labelled mTOR inhibitor derivative based on a benzofuran backbone

Wichmann

Goh

Parslow

et al. 2020

EJNMMI radiopharm. chem.

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Background: Targeted therapy of HER2 positive breast cancer has led to clinical success in some cases with primary and secondary resistance being major obstacles. Due to the substantial involvement of mTOR kinase in cell growth and proliferation pathways it is now targeted in combination treatments to counteract HER2 targeted therapy resistance. However, the selection of receptive patient populations for a specific drug combination is crucial. This work aims to develop a molecular probe capable of identifying patients with tumour populations which are receptive to RAD001 combination therapy. Based on the structure of a mTOR inhibitor specific for mTORC1, we designed, synthesised and characterised a novel benzofuran based molecular probe which suits late stage fluorination via Click chemistry. Results: Synthesis of the alkyne precursor 5 proceeded in 27.5% yield over 7 linear steps. Click derivatisation gave the non-radioactive standard in 25% yield. Radiosynthesis of [ 18 F]1-((1-(2-Fluoroethyl)-1H-1,2,3-triazol-4-yl) methyl)-4-((5-methoxy-2-phenylbenzofuran-4-yl) methyl) piperazine ([ 18 F]mBPET-1) proceeded over two steps which were automated on an iPhase FlexLab synthesis module. In the first step, 2-[ 18 F]fluoroethylazide ([ 18 F]6) was produced, purified by automated distillation in 60% non-decay-corrected yield and subjected to Click conditions with 5. Semipreparative RP-HPLC purification and reformulation gave [ 18 F]mBPET-1 in 40% ± 5% (n = 6) overall RCY with a process time of 90 min. Radiochemical purity was ≥99% at end of synthesis (EOS) and ≥ 98% after 4 h at room temperature. Molar activities ranged from typically 24.8 GBq/μmol (EOS) to a maximum of 78.6 GBq/μmol (EOS). Lipophilicity of [ 18 F]mBPET-1 was determined at pH 7.4 (logD 7.4 = 0.89). [ 18 F]mBPET-1 showed high metabolic stability when incubated with mouse S9 liver fractions which resulted in a 0.8% drop in radiochemical purity after 3 h. Cell uptake assays showed 1.3-1.9-fold increased uptake of the [ 18 F]mBPET-1 in RAD001 sensitive compared to insensitive cells across a panel of 4 breast cancer cell lines. Conclusion: Molecular targeting of mTOR with [ 18 F]mBPET-1 distinguishes mTOR inhibitor sensitive and insensitive cell lines. Future studies will explore the ability of [ 18 F]mBPET-1 to predict response to mTOR inhibitor treatment in in vivo models.

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“…Unfortunately to date automated procedures have primarily focused on small molecules or the production of prosthetic groups. 4 Several automated syntheses of 18 35 The radiochemical yields for these automated productions are comparable, if not better than the analogous manual protocols. [32][33][34][35] Automated protocols capable of generating 18 Fpeptides from uorine-18 without manual interventions are less prevalent, as multiple purications are typically needed for both the intermediate 18 F-prosthetic and the nal 18 F-peptide radiotracer.…”

Section: Introductionmentioning

confidence: 99%

“…4 Several automated syntheses of 18 35 The radiochemical yields for these automated productions are comparable, if not better than the analogous manual protocols. [32][33][34][35] Automated protocols capable of generating 18 Fpeptides from uorine-18 without manual interventions are less prevalent, as multiple purications are typically needed for both the intermediate 18 F-prosthetic and the nal 18 F-peptide radiotracer. 4,31 For example, Thonon et al, used the FASTLab™ GE synthesis module for the production of [ 18 F]SFB via both a one-and two-pot method, followed by coupling to an RGD peptide (PRGD2).…”

Section: Introductionmentioning

confidence: 99%

Fully automated peptide radiolabeling from [¹⁸F]fluoride

et al. 2019

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The biological properties of receptor-targeted peptides have made them popular diagnostic imaging and therapeutic agents. Typically, the synthesis of fluorine-18 radiolabeled receptor-targeted peptides for positron emission tomography (PET) imaging is a time consuming, complex, multi-step synthetic process that is highly variable based on the peptide. The complexity associated with the radiolabeling route and lack of robust automated protocols can hinder translation into the clinic. A fully automated batch production to radiolabel three peptides (YGGFL, cRGDyK, and Pyr-QKLGNQWAVGHLM) from fluorine-18 using the ELIXYS FLEX/CHEM® radiosynthesizer in a two-step process is described. First, the prosthetic group, 6-[ 18 F]fluoronicotinyl-2,3,5,6-tetrafluorophenyl ester ([ 18 F]FPy-TFP) was synthesized and subsequently attached to the peptide. The [ 18 F]FPy-peptides were synthesized in 13-26% decay corrected yields from fluorine-18 with high molar activity 1-5 Ci mmol À1 and radiochemical purity of >99% in an overall synthesis time of 97 AE 3 minutes.

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Improved synthesis of [ 18 F]FLETT via a fully automated vacuum distillation method for [ 18 F]2-fluoroethyl azide purification

Cited by 9 publications

References 11 publications

Ortho‐Stabilized ¹⁸F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

Ortho‐Stabilized ¹⁸F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

Synthesis and validation of [18F]mBPET-1, a fluorine-18 labelled mTOR inhibitor derivative based on a benzofuran backbone

Fully automated peptide radiolabeling from [¹⁸F]fluoride

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Improved synthesis of [ 18 F]FLETT via a fully automated vacuum distillation method for [ 18 F]2-fluoroethyl azide purification

Cited by 9 publications

References 11 publications

Ortho‐Stabilized 18F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

Ortho‐Stabilized 18F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

Synthesis and validation of [18F]mBPET-1, a fluorine-18 labelled mTOR inhibitor derivative based on a benzofuran backbone

Fully automated peptide radiolabeling from [18F]fluoride

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Ortho‐Stabilized ¹⁸F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

Ortho‐Stabilized ¹⁸F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

Fully automated peptide radiolabeling from [¹⁸F]fluoride