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![Fig 2. Synthetic method for [18F]SFB.](publication/305313082/figure/fig11/AS:383855073742855@1468529589556/Synthetic-method-for-18FSFB_Q320.jpg)
In the field of positron emission tomography (PET) radiochemistry, compact microreactors provide reliable and reproducible synthesis methods that reduce the use of expensive precursors for radiolabeling and make effective use of the limited space in a hot cell. To develop more compact microreactors for radiosynthesis of 18F-labeled compounds requir...
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Context 1
... radiosynthesis of N-succinimidyl 4- [29][30][31][32][33][34][35][36] was selected as the model reaction for multistep syn- thesis evaluation because [ 18 F]SFB is a well-known prosthetic group for peptides, proteins, and antibodies in PET radiochemistry. The synthesis of [ 18 F]SFB requires the following three steps: 1) [ 18 F]fluorination of an aromatic precursor, i.e., 4-(tert-butoxycarbonyl)-N,N,N-trimethyl- phenylammonium triflate (1) [31], 2) hydrolysis of tert-butyl 4-[ 18 F]fluorobenzoate (2) with tetrapropylammonium hydroxide (TPAH), and 3) succinimidylation of the 4-[ 18 F]fluoroben- zoic acid (3) with O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TSTU) [30,31] (Fig 2). To date, attempts have been made to reduce the time required to syn- thesize [ 18 F]SFB and to improve the yields using modified commercial synthesizers and micro- wave synthetic technology; [34][35][36] however, further improvements are desired. ...
Context 2
... apply the three-step reaction of [ 18 F]SFB to a continuous-flow synthetic method using a single microfluidic chip, we initially examined 18 F-fluorination, which is the first step of radio- synthesis of [ 18 F]SFB (Fig 2). A solution of 1 in dimethyl sulfoxide (DMSO) was run into inlet A, and a mixture of [ 18 F]KF and Kryptofix 2.2.2 in DMSO was run into inlet B on the designed microfluidic chip (chip 1) pre-heated at 120°C (Fig 6a). ...
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Citations
... concentration and labeling). [38][39][40][41][42][43] Arima et al. did, however, report on a multi-component platform with a series of microchannel reactors to achieve each step of a [ 18 F]FDG synthesis ( Fig. 3f and g). 44 The group was able to develop a fully automated platform that incorporated pre-concentration and purification methods as well as silicon photomultiplier tubes to monitor radioactivity. ...
Current radiotracer production approaches restrict clinicians' access to a wide range of targeted probes. In this review, we assess the current state of microfluidic synthesis platforms with a view towards future dose-on-demand production.
... [24] Bovine serine albumin (BSA) and myoglobin proteins have been radiolabelled, within minutes, by amide covalent linkage using the activated ester reagent N-succinimidyl 4-[ 18 F] fluorobenzoate through coupling with lysine residues on the proteins. [25] In a similar vein, fluorescent BSA has been produced through in-flow lysine conjugation with fluorescein isothiocyanate. [26] A flow apparatus has also been employed to achieve biotin labelling of the antibody trastuzumab Fab. ...
The importance of bioconjugation reactions continues to grow for cell specific targeting and dual therapeutic plus diagnostic medical applications. This necessitates the development of new bioconjugation chemistries, in‐flow synthetic and analytical methods. With this goal, continuous flow bioconjugations were readily achieved with short residence times for strained alkyne substituted carbohydrate and therapeutic peptide biomolecules in reaction with azide and tetrazine substituted fluorophores. The strained alkyne substrates included substituted 2‐amino‐2‐deoxy‐α‐D‐glucopyranose, and the linear and cyclic peptide sequences QIRQQPRDPPTETLELEVSPDPAS‐OH and c(RGDfK) respectively. The catalyst and reagent‐free inverse electron demand tetrazine cycloadditions proved more favourable than the azide 1,3‐dipolar cycloadditions. Reaction completion was achieved with residence times of 5 min at 40 °C for tetrazine versus 10 min at 80 °C for azide cycloadditions. The use of a fluorogenic tetrazine fluorophore, in a glass channelled reactor chip, allowed for intra‐chip reaction monitoring by recording fluorescence intensities at various positions throughout the chip. As the Diels‐Alder reactions proceeded through the chip, the fluorescence intensity increased accordingly in real‐time. The application of continuous flow fluorogenic bioconjugations could offer an efficient translational access to theranostic agents.
... To address these challenges, microfluidic devices based on microTAS technology [6] can automatically process small volumes of reagents, minimize the processing time constraints and reagent costs [7,8]. The use of a microfluidic device for medicinal preparation allows accurate processing without human pipetting error, while radioisotope scattering and contamination can be suppressed within the enclosed microchannel space [9][10][11]. ...
Delicate animal experiments and microdose clinical trials using short-lived radioisotopes require rapid preparation with high accuracy and careful attention to safety within a limited timeframe. We have developed an open-style electrowetting on dielectric (EWOD) device containing dimple structures for the rapid preparation of radiolabelled reagents. The device was demonstrated by automatic preparation of a technetium diethylenetriamine pentaacetate ( 99m Tc-DTPA) with high chelation efficiency (99.7 ± 0.13%). Additionally, we demonstrated the single-photon emission computed tomography/computed tomography imaging of mouse kidney using the 99m Tc-DTPA prepared with the EWOD device. The obtained organ tomographic images were sufficient for the evaluation of mouse models for specific diseases. These results indicate that manual radiolabelling for a small amount of nuclear medicine can be replaced by a process using the proposed EWOD device as a human error reduction technique.
... Normally, the fine chemical industry (polymers and pharmaceutical) prefers batch processes for their simplicity and their flexibility as multipurpose systems. 1,2 Nevertheless, in the past few years, there is a tendency to shift to continuous processes 3,4 which allow the gain of several advantages over discontinuous systems, such as reduced volumes, higher productivities, automatization with simpler control, and most importantly, constant quality of the produced chemicals. 5,6 Among continuous reactors, tubular reactors guarantee a better heat exchange than continuous stirred tank reactors (CSTRs) due to a higher heat transfer area-to-volume ratio. ...
Plug flow behavior in tubular reactors is often highly desirable in industry, since it can ensure high productivity, good selectivity, and enhanced heat transfer. To achieve this, good radial mixing combined with poor axial mixing is required: these conditions are quite easy to obtain if the flow regime is turbulent, but they are much more challenging to achieve if the flow is laminar. In this work radial mixing and residence time distributions in a side-injected tubular reactor equipped with a series of Sulzer SMX static mixers were investigated using Computational Fluid Dynamics. It was found that even at low values of Reynolds number the reactor can efficiently satisfy the plug flow conditions, and operative diagrams were determined to foresee the reactor behavior.
... This type of microfluidic systems (glass or PDMS microchips) has been widely used to produce both drug nanosuspensions (Amani et al., 2014;Panagiotou et al., 2009;Rahimi et al., 2017;Schianti et al., 2011) and polymeric nanoparticles (Donno et al., 2017;Karnik et al., 2008). (Kimura et al., 2016) and (Feng et al., 2015), respectively) ...
... Recently, Kimura and his colleagues in Japan optimized the three-steps radiosynthesis of [ 18 F]SFB into a single continuous ow microuidic chip with 64% radiochemical yield. 29 One major downside of such owthrough radiosynthesizer is in their inability to perform solvent exchange reactions, and so part of the process must be carried out in conventional, macroscale apparatus. Bejot and co-workers have demonstrated the integration of solvent evaporation steps and achieved the synthesis of [ 18 F]SFB with 64% radiochemical yield within 25 min in a 60 mL batch microreactor with integrated valves and mechanical actuators to control the ow of reagents in and out of the reaction vessel. ...
An all-electronic, droplet-based batch microfluidic device, operated using the electrowetting on dielectric (EWOD) mechanism was developed for on-demand synthesis of N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB), the most commonly used ¹⁸F-prosthetic group for biomolecule labeling. In order to facilitate the development of peptides, and proteins as new diagnostic and therapeutic agents, we have diversified the compact EWOD microfluidic platform to perform the three-step radiosynthesis of [¹⁸F]SFB starting from the no carrier added [¹⁸F]fluoride ion. In this report, we established an optimal microliter droplet reaction condition to obtain reliable yields and synthesized [¹⁸F]SFB with sufficient radioactivity for subsequent conjugation to the anti-PSCA cys-diabody (A2cDb) and for small animal imaging. The three-step, one-pot radiosynthesis of [¹⁸F]SFB radiochemistry was adapted to a batch microfluidic platform with a reaction droplet sandwiched between two parallel plates of an EWOD chip, and optimized. Specifically, the ratio of precursor to base, droplet volume, reagent concentration, reaction time, and evaporation time were found be to be critical parameters. [¹⁸F]SFB was successfully synthesized on the EWOD chip in 39 ± 7% (n = 4) radiochemical yield in a total synthesis time of ∼120 min ([¹⁸F]fluoride activation, [¹⁸F]fluorination, hydrolysis, and coupling reaction, HPLC purification, drying and reformulation). The reformulation and stabilization step for [¹⁸F]SFB was important to obtain a high protein labeling efficiency of 33.1 ± 12.5% (n = 3). A small-animal immunoPET pilot study demonstrated that the [¹⁸F]SFB-PSCA diabody conjugate showed specific uptake in the PSCA-positive human prostate cancer xenograft. The successful development of a compact footprint of the EWOD radiosynthesizer has the potential to empower biologists to produce PET probes of interest themselves in a standard laboratory.
... Synthesis systems not equipped with on-chip purification methods typically utilize semi-preparatory-and analyticalscale high-performance liquid chromatography (HPLC) equipped with both UV and radiation detection [11,38,55]. However, instead of using HPLC, there are several reports of custom designed mini-cartridges akin to the concentration cartridges employed by previous fluoride concentrating step for purification [23,38,56]. ...
The current utilization of positron emission tomography (PET) imaging is limited due to the high costs associated with production facility start-up and operations; subsequently, there has been a movement towards microfluidic synthesis of radiolabeled imaging pharmaceuticals (tracers). In this review, we summarize the current status of microfluidic radiosynthesis units for producing fluorine-18 labeled PET imaging tracers, including a discussion of the relative strengths and weaknesses of such devices. In addition, we provide a brief overview of the radiotracers that have been produced using microfluidic devices to date. Finally, we discuss the prospects for the future of this field, including the potential of newly envisioned devices developed that may allow operators to easily synthesize specialized tracers for individual patient doses.
... During the last decade, microfluidics and Lab on Chip technologies have been successfully applied to radiochemistry [17][18][19][20][21][22] with advantages in terms of yields, speed, safety and low reagent consumption [23][24][25][26][27][28][29][30][31]. In a pioneering work from Lee et al. [32] a PDMS microchamber was used to allow solvent exchange (from water to acetonitrile and vice versa) during the production of 2-deoxy-2-fluoro-D-glucose (FDG). ...
A pervaporation process was implemented into microfluidic chips to purify radiopharmaceuticals for Positron Emission Tomography in continuos-flow. The chip consists of a serpentine microreactor interfaced to a polydimethylsiloxane (PDMS) 10 μm thick membrane. Thanks to different volatility of the components present in the radiopharmaceutical matrix, ethanol (EtOH) is readily removed under gentle heating and nitrogen flow conditions. Three classes of chips with different membrane surface areas (S) and internal volumes (V) have been produced and quantified their pervaporative efficiency at different residence times (Rt) and temperatures. Higher S/V chips (̴ 70 mm⁻¹) apperared the most efficient at a very low residence time (Rt ̴ 10 s) allowing reduction of 67% at 80 °C. Chips of intermediate S/V ratios (̴ 30 mm⁻¹) decreased the EtOH amount up to ̴ 90% at longer residence time (Rt ≥ 26 s). The halving of EtOH concentration in a solution of a radiotracer was obtained at 50 °C with Rt of 25 s. After the pervaporation treatment, the EtOH content in the final radiopharmaceutical formulation was demonstrated to be reduced below 10% v/v as required by the European Pharmacopea current edition.
... For instance, some articles have described various flow-through microfluidic devices for on-chip pre-concentration of [ 18 F] fluoride. [10][11][12] Moreover, numerous publications have reported the investigation of utilizing a microfluidic chip to enable an efficient radiochemical labeling reaction. [13][14][15][16][17][18][19][20] As a result, there is an opportunity to integrate all the essential modules onto a single microfluidic chip, enabling the synthesis of PET tracers from the very beginning (radioactive [ 18 F]fluoride mixture) to the final stage (radiotracer ready for injection). ...
Herein, we report the development of a simple, high-throughput and efficient microfluidic system for synthesizing radioactive [18F]fallypride, a PET imaging radiotracer widely used in medical research. The microfluidic chip contains...
... The advantages of using microfluidic systems to produce 18 F-radiotracers, namely shorter reaction times, reduced amounts of chemical reagents, and higher radiochemical yields, [10,11] are contributing to the rising interest in the use of this technology. [12][13][14] Using the commercially available Advion NanoTek microfluidic synthesis system, we attached a custom-made electrical board to modify the system to incorporate HPLC and solid phase extraction (SPE) purification and subsequent formulation. [15] This customised system has produced a range of 18 F-radiotracers including [ 18 F]CB102, [ 18 F]fluoroalkylcholines, [15] and [ 18 F]MEL050. ...
3-(4-(3-[¹⁸F]Fluoropropylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine ([¹⁸F]FP-TZTP) is a selective ¹⁸F-radiotracer for the muscarinic acetylcholine receptor subtype M2, which can be used to perform positron emission tomography (PET) scans on patients with neurological disorders such as Alzheimer's disease. [¹⁸F]FP-TZTP was produced using continuous-flow microfluidics, a technique that uses reduced amounts of chemical reagents, shorter reaction times and in general, results in higher radiochemical yields compared to currently used techniques. The optimal ¹⁸F-radiolabelling conditions consisted of a total flow rate of 40 μL min⁻¹ and 190°C, which produced [¹⁸F]FP-TZTP in 26 ± 10 % radiochemical yield with a molar activity of 182 ± 65 GBq μmol⁻¹ and >99 % radiochemical purity.
