A simplified protocol for the automated production of succinimidyl 4‐[<sup>18</sup>F]fluorobenzoate on an IBA Synthera module

Ackermann, Uwe; Yeoh, Shinn Dee; Sachinidis, John; Poniger, Stan; Scott, Andrew; Tochon-Danguy, Henri

doi:10.1002/jlcr.1892

Cited by 25 publications

(18 citation statements)

References 8 publications

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“…The synthesis of 18 F-SFB was successfully automated on Synthera after a 3-step, 1-pot synthesis. In comparison with Ackermann et al (23), our optimized synthesis protocol required a larger reaction volume for fluorination and no drying step after basic hydrolysis. The use of more than 4 mg of precursor resulted in more impurities with minor increase of labeling yield.…”

Section: Discussionmentioning

confidence: 91%

PET Imaging of Macrophage Mannose Receptor–Expressing Macrophages in Tumor Stroma Using ¹⁸F-Radiolabeled Camelid Single-Domain Antibody Fragments

et al. 2015

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Tumor-associated macrophages constitute a major component of the stroma of solid tumors, encompassing distinct subpopulations with different characteristics and functions. We aimed to identify M2-oriented tumor-supporting macrophages within the tumor microenvironment as indicators of cancer progression and prognosis, using PET imaging. This can be realized by designing 18 F-labeled camelid single-domain antibody fragments (sdAbs) specifically targeting the macrophage mannose receptor (MMR), which has been identified as an important biomarker on this cell population. Methods: Crossreactive anti-MMR sdAbs were generated after immunization of an alpaca with the extracellular domains of both human and mouse MMR. The lead binder was chosen on the basis of comparisons of binding affinity and in vivo pharmacokinetics. The PET tracer 18 F-fluorobenzoate (FB)-anti-MMR sdAb was developed using the prosthetic group N-succinimidyl-4-18 F-fluorobenzoate ( 18 F-SFB), and its biodistribution, tumor-targeting potential, and specificity in terms of macrophage and MMR targeting were evaluated in mouse tumor models. Results: Four sdAbs were selected after affinity screening, but only 2 were found to be cross-reactive for human and mouse MMR. The lead anti-MMR 3.49 sdAb, bearing an affinity of 12 and 1.8 nM for mouse and human MMR, respectively, was chosen for its favorable in vivo biodistribution profile and tumor-targeting capacity. 18 F-FB-anti-MMR 3.49 sdAb was synthesized with a 5%-10% radiochemical yield using an automated and optimized protocol. In vivo biodistribution analyses showed fast clearance via the kidneys and retention in MMRexpressing organs and tumor. The kidney retention of the fluorinated sdAb was 20-fold lower than a 99m Tc-labeled counterpart. Compared with MMR-and C-C chemokine receptor 2-deficient mice, significantly higher uptake was observed in tumors grown in wild-type mice, demonstrating the specificity of the 18 F tracer for MMR and macrophages, respectively. Conclusion: Anti-MMR 3.49 was denoted as the lead cross-reactive MMR-targeting sdAb. 18 F radiosynthesis was optimized, providing an optimal probe for PET imaging of the tumor-promoting macrophage subpopulation in the tumor stroma. Dur ing tumor development, myeloid cells are attracted to the tumor stroma. These infiltrating immune cells are versatile, adopting different activation states in response to a changing microenvironment, leading to subsets of tumor-associated macrophages (TAMs) with specialized functions (1,2). Two main morphologically distinct TAM subsets can be distinguished on the basis of major histocompatibility complex (MHC) class II expression levels in multiple mouse tumor models. Tumor promotion has been linked with an accumulation of M2-oriented MHC II low TAMs in lung and breast carcinoma (3,4). Accordingly, MHC II low TAMs were found to reside primarily in less oxygenated zones, express hypoxia-regulated genes, and facilitate the angiogenic switch (5). Interestingly, the macrophage mannose receptor (MMR, CD206), a typical M2...

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Section: Discussionmentioning

confidence: 91%

PET Imaging of Macrophage Mannose Receptor–Expressing Macrophages in Tumor Stroma Using ¹⁸F-Radiolabeled Camelid Single-Domain Antibody Fragments

et al. 2015

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“…The multistep synthesis of [ 18 F]SFB has been reported in conventional macroscale radiosynthesizers with radiochemical yields (RCYs) ranging from 20-77% within 30-90 min. [14][15][16] Over the years, many research studies have been devoted to improving the laborious multistep and multi-pot 12,13,16 synthesis of [ 18 F]SFB, ultimately leading to a convenient and shorter three-step, onepot procedure. 14,15,17 Following the uorination step, an organic base is used in the hydrolysis step to yield the uorobenzoic acid ([ 18 F]FBA) intermediate.…”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16] Over the years, many research studies have been devoted to improving the laborious multistep and multi-pot 12,13,16 synthesis of [ 18 F]SFB, ultimately leading to a convenient and shorter three-step, onepot procedure. 14,15,17 Following the uorination step, an organic base is used in the hydrolysis step to yield the uorobenzoic acid ([ 18 F]FBA) intermediate. Due to the sensitivity of the nal coupling reaction with the acylation agent (TSTU or HSTU), an additional azeotropic evaporation is performed at the end of the hydrolysis step to achieve a high coupling efficiency.…”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20][21] The improved synthesis has been implemented on conventional automated radiosynthesizers (e.g., IBA Synthera and Soe ELYXYS FLEX/CHEM) with 69-85% RCY. 14,22 Though [ 18 F]SFB can be convenient reacted with peptides or proteins to produce imaging probes, it is not widely available due to insufficient demand. The radiosynthesis of [ 18 F]SFB can only be performed in a specialized radiochemistry laboratory and requires an expensive automated synthesizer, and a hot cell for operation of the synthesizer.…”

Section: Introductionmentioning

confidence: 99%

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On-demand radiosynthesis of N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) on an electrowetting-on-dielectric microfluidic chip for ¹⁸F-labeling of protein

et al. 2019

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“…Despite recent advances in [ 18 F]SFB production, this route still is time consuming and requires numerous synthesis steps, whereas the [ 18 F]FB route is slightly shorter …”

Section: Introductionmentioning

confidence: 99%

Fully automated synthesis and coupling of [¹⁸F]FBEM to glutathione using the iPHASE FlexLab module

Ackermann

Plougastel

Wichmann

et al. 2014

Labelled Comp Radiopharmac

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Site-specific radiolabelling of peptides or antibodies using [(18) F]FBEM is often preferred over non-site-specific radiolabelling with [(18) F]SFB because it does not affect the affinity of the antibody to its target. Unfortunately, the synthesis of [(18) F]FBEM and its conjugation to thiol containing macromolecules requires some manual intervention, which leads to radiation exposure of the radiochemist. In this publication, we report on the complete automation of [(18) F]FBEM production and its subsequent conjugation to glutathione using a slightly modified iPHASE FlexLab module. [(18) F]FBEM was produced in 1.185 ± 0.168 GBq (15-20%; n = 10; 0.75 ± 0.106 GBq non-decay corrected) with a specific activity of 57 ± 10 GBq/µmol. Radiochemical purity was 97 ± 1% and the synthesis time including HPLC purification and reformulation was 70 min. After evaporation to dryness, [(18) F]FBEM was conjugated to glutathione in PBS buffer pH 7.4 in quantitative yields. This fully automated method does not require any manual intervention and therefore reduces the radiation exposure to the operator.

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A simplified protocol for the automated production of succinimidyl 4‐[¹⁸F]fluorobenzoate on an IBA Synthera module

Cited by 25 publications

References 8 publications

PET Imaging of Macrophage Mannose Receptor–Expressing Macrophages in Tumor Stroma Using ¹⁸F-Radiolabeled Camelid Single-Domain Antibody Fragments

PET Imaging of Macrophage Mannose Receptor–Expressing Macrophages in Tumor Stroma Using ¹⁸F-Radiolabeled Camelid Single-Domain Antibody Fragments

On-demand radiosynthesis of N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) on an electrowetting-on-dielectric microfluidic chip for ¹⁸F-labeling of protein

Fully automated synthesis and coupling of [¹⁸F]FBEM to glutathione using the iPHASE FlexLab module

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A simplified protocol for the automated production of succinimidyl 4‐[18F]fluorobenzoate on an IBA Synthera module

Cited by 25 publications

References 8 publications

PET Imaging of Macrophage Mannose Receptor–Expressing Macrophages in Tumor Stroma Using 18F-Radiolabeled Camelid Single-Domain Antibody Fragments

PET Imaging of Macrophage Mannose Receptor–Expressing Macrophages in Tumor Stroma Using 18F-Radiolabeled Camelid Single-Domain Antibody Fragments

On-demand radiosynthesis of N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) on an electrowetting-on-dielectric microfluidic chip for 18F-labeling of protein

Fully automated synthesis and coupling of [18F]FBEM to glutathione using the iPHASE FlexLab module

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A simplified protocol for the automated production of succinimidyl 4‐[¹⁸F]fluorobenzoate on an IBA Synthera module

PET Imaging of Macrophage Mannose Receptor–Expressing Macrophages in Tumor Stroma Using ¹⁸F-Radiolabeled Camelid Single-Domain Antibody Fragments

PET Imaging of Macrophage Mannose Receptor–Expressing Macrophages in Tumor Stroma Using ¹⁸F-Radiolabeled Camelid Single-Domain Antibody Fragments

On-demand radiosynthesis of N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) on an electrowetting-on-dielectric microfluidic chip for ¹⁸F-labeling of protein

Fully automated synthesis and coupling of [¹⁸F]FBEM to glutathione using the iPHASE FlexLab module