Scalable 18F Processing Conditions for Copper-Mediated Radiofluorination Chemistry Facilitate "Design of Experiments" (DoE) Optimization Studies and Afford an Improved Synthesis of [18F]Olaparib.

A convenient, scalable, and azeotropic drying free method for processing [18F]fluoride as base free [18F]TBAF is reported and applied to copper-mediated radiofluorination (CMRF) radiosyntheses. A central feature of this method is that a single production of [18F]TBAF can be divided into small aliquots that can be used to perform multiple small-scale reactions in DoE optimization studies. The results of these studies can then be reliably translated to full batch tracer productions using automated synthesizers. This processing technique was successfully applied to the manual DoE optimization, DoE study validation, and subsequent full-batch automation of the PARP-1 tracer [18F]olaparib. After DoE optimization, we were able to produce [18F]olaparib in high radiochemical yields via both manual (%RCY (CMRF step only) = 78 ± 6 %, n = 4) and automated (up to 80% radiochemical yield (%RCY); 41% activity yield (%AY)) radiosynthesis procedures. This work further demonstrates the power of the DoE approach for improving the radiochemical yields and radiosynthesis performance of clinically relevant tracer productions

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Scalable 18F Processing Conditions for Copper-Mediated Radiofluorination Chemistry Facilitate "Design of Experiments" (DoE) Optimization Studies and Afford an Improved Synthesis of [18F]Olaparib.

10.26434/chemrxiv.14547342 ◽

2021 ◽

Author(s):

Gregory D. Bowden ◽

Nantanat Chailanggar ◽

Bernd J. Pichler ◽

Andreas Maurer

Keyword(s):

Design Of Experiments ◽

Radiochemical Yield ◽

Small Scale ◽

Processing Conditions ◽

Single Production ◽

Activity Yield ◽

Radiochemical Yields ◽

Parp 1 ◽

18F Fluoride

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Novel late-stage radiosynthesis of 5-[18F]-trifluoromethyl-1,2,4-oxadiazole (TFMO) containing molecules for PET imaging

Scientific Reports ◽

10.1038/s41598-021-90069-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nashaat Turkman ◽

Daxing Liu ◽

Isabella Pirola

Keyword(s):

Late Stage ◽

Histone Deacetylases ◽

Radiochemical Purity ◽

Radiochemical Yield ◽

Single Step ◽

The Novel ◽

Molar Activity ◽

The Central Nervous System ◽

Class Iia Hdacs ◽

18F Fluoride

AbstractSmall molecules that contain the (TFMO) moiety were reported to specifically inhibit the class-IIa histone deacetylases (HDACs), an important target in cancer and the disorders of the central nervous system (CNS). However, radiolabeling methods to incorporate the [18F]fluoride into the TFMO moiety are lacking. Herein, we report a novel late-stage incorporation of [18F]fluoride into the TFMO moiety in a single radiochemical step. In this approach the bromodifluoromethyl-1,2,4-oxadiazole was converted into [18F]TFMO via no-carrier-added bromine-[18F]fluoride exchange in a single step, thus producing the PET tracers with acceptable radiochemical yield (3–5%), high radiochemical purity (> 98%) and moderate molar activity of 0.33–0.49 GBq/umol (8.9–13.4 mCi/umol). We validated the utility of the novel radiochemical design by the radiosynthesis of [18F]TMP195, which is a known TFMO containing potent inhibitor of class-IIa HDACs.

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Optimised GMP-compliant production of [18F]DPA-714 on the Trasis AllinOne module

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-021-00133-0 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Klaudia A. Cybulska ◽

Vera Bloemers ◽

Lars R. Perk ◽

Peter Laverman

Keyword(s):

Significant Degree ◽

Translocator Protein ◽

Positron Emission ◽

Leaving Group ◽

Inflammatory Processes ◽

Single Production ◽

Translocator Protein 18 Kda ◽

Radiochemical Yields ◽

Specific Ligand

Abstract Background The translocator protein 18 kDa is recognised as an important biomarker for neuroinflammation due to its soaring expression in microglia. This process is common for various neurological disorders. DPA-714 is a potent TSPO-specific ligand which found its use in Positron Emission Tomography following substitution of fluorine-19 with fluorine-18, a positron-emitting radionuclide. [18F]DPA-714 enables visualisation of inflammatory processes in vivo non-invasively. Radiolabelling of this tracer is well described in literature, including validation for clinical use. Here, we report significant enhancements to the process which resulted in the design of a fully GMP-compliant robust synthesis of [18F]DPA-714 on a popular cassette-based system, Trasis AllinOne, boosting reliability, throughput, and introducing a significant degree of simplicity. Results [18F]DPA-714 was synthesised using the classic nucleophilic aliphatic substitution on a good leaving group, tosylate, with [18F]fluoride using tetraethylammonium bicarbonate in acetonitrile at 100∘C. The process was fully automated on a Trasis AllinOne synthesiser using an in-house designed cassette and sequence. With a relatively small precursor load of 4 mg, [18F]DPA-714 was obtained with consistently high radiochemical yields of 55-71% (n=6) and molar activities of 117-350 GBq/µmol at end of synthesis. With a single production batch, starting with 31-42 GBq of [18F]fluoride, between 13-20 GBq of the tracer can be produced, enabling multi-centre studies. Conclusion To the best of our knowledge, the process presented herein is the most efficient [18F]DPA-714 synthesis, with advantageous GMP compliance. The use of a Trasis AllinOne synthesiser increases reliability and allows rapid training of production staff.

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GMP production of 6-[18F]Fluoro-l-DOPA for PET/CT imaging by different synthetic routes: a three center experience

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-021-00135-y ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Valdemar L. Andersen ◽

Mikkel A. Soerensen ◽

Johan Hygum Dam ◽

Niels Langkjaer ◽

Henrik Petersen ◽

...

Keyword(s):

Radiochemical Yield ◽

Ct Imaging ◽

University Hospital ◽

Dopamine Synthesis ◽

Congenital Hyperinsulinism ◽

Molar Activity ◽

Time Period ◽

Pet Ct ◽

Synthetic Routes ◽

Radiochemical Yields

Abstract Background The radiofluorinated levodopa analogue 6-[18F]F-l-DOPA (3,4-dihydroxy-6-18F-l-phenylalanine) is a commonly employed radiotracer for PET/CT imaging of multiple oncological and neurological indications. An unusually large number of different radiosyntheses have been published to the point where two different Ph. Eur. monographs exist depending on whether the chemistry relies on electrophilic or nucleophilic radiosubstitution of appropriate chemical precursors. For new PET imaging sites wishing to adopt [18F]FDOPA into clinical practice, selecting the appropriate production process may be difficult and dependent on the clinical needs of the site. Methods Data from four years of [18F]FDOPA production at three different clinical sites are collected and compared. These three sites, Aarhus University Hospital (AUH), Odense University Hospital (OUH), and Herlev University Hospital (HUH), produce the radiotracer by different radiosynthetic routes with AUH adopting an electrophilic strategy, while OUH and HUH employ two different nucleophilic approaches. Production failure rates, radiochemical yields, and molar activities are compared across sites and time. Additionally, the clinical use of the radiotracer over the time period considered at the different sites are presented and discussed. Results The electrophilic substitution route suffers from being demanding in terms of cyclotron operation and maintenance. This challenge, however, was found to be compensated by a production failure rate significantly below that of both nucleophilic approaches; a result of simpler chemistry. The five-step nucleophilic approach employed at HUH produces superior radiochemical yields compared to the three-step approach adopted at OUH but suffers from the need for more comprehensive synthesis equipment given the multi-step nature of the procedure, including HPLC purification. While the procedure at OUH furnishes the lowest radiochemical yield of the synthetic routes considered, it produces the highest molar activity. This is of importance across the clinical applications of the tracer discussed here, including dopamine synthesis in striatum of subjects with schizophrenia and congenital hyperinsulinism in infants. Conclusion For most sites either of the two nucleophilic substitution strategies should be favored. However, which of the two will depend on whether a given site wishes to optimize the radiochemical yield or the ease of the use.

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Single center experience on the production of fluorine-18 radiopharmaceuticals using a 7.5 MeV cyclotron: capabilities and challenges

SN Applied Sciences ◽

10.1007/s42452-020-2695-2 ◽

2020 ◽

Vol 2 (5) ◽

Author(s):

Andreas Fesas ◽

Mohammad Reza Pourkhessalian ◽

Alexis Vrachimis

Keyword(s):

Radiochemical Yield ◽

Low Energy ◽

Third Party ◽

Single Center ◽

Single Patient ◽

Remote Site ◽

On Demand ◽

Single Center Experience ◽

Radiochemical Yields ◽

House Production

Abstract A plethora of cyclotron options have been developed to fulfil the demands of nuclear medicine industries in PET and SPECT radioisotopes. As a remote site, the difficulties of transporting fluorine 18 radiopharmaceuticals for PET examinations were overcome by the installation of a 7.5 MeV cyclotron for in-house production. The addition of a third-party synthesis module enabled the synthesis of 7 additional radiotracers according to a ‘’dose on demand’’ principle. Radiochemical yield is considered the primary factor in producing sufficient activity for a single patient dose, since low energy cyclotrons can only offer low initial activities. We hereby report the average radiochemical yields, synthesis times and doses per production for [18F]FDG, [18F]PSMA-1007, [18F]DOPA, [18F]FET, [18F]FLT, [18F]FMISO, [18F]Choline and [18F]FES using a BG75 cyclotron and a Neptis Mosaic-RS. Additionally, the presence of radionuclidic impurities in the final product was examined.

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Novel Mechanical Characterization of Austenite and Ferrite Phases within Duplex Stainless Steel

Metals ◽

10.3390/met10101352 ◽

2020 ◽

Vol 10 (10) ◽

pp. 1352

Author(s):

Hossein Besharatloo ◽

Marcel Carpio ◽

José-María Cabrera ◽

Antonio Manuel Mateo ◽

Gemma Fargas ◽

...

Keyword(s):

Stainless Steel ◽

Duplex Stainless Steel ◽

High Speed ◽

Mapping Technique ◽

Small Scale ◽

Processing Conditions ◽

Excellent Correlation ◽

Electron Backscattered Diffraction ◽

Interphase Boundaries

The microstructure and micromechanical properties of the constitutive phases of a particular duplex stainless steel in various processing conditions have been characterized. Hardness (H), elastic modulus (E) and H/E cartography maps were obtained by using a high-speed nanoindentation mapping technique. Small-scale H and E evolution at different processing conditions has been investigated by statistical analysis of a large number of nanoindentations (10,000 imprints per sample). Two mechanically distinct phases, ferrite (α) and austenite (γ), were deconvoluted from this dataset using Ulm and Constantinides’ method, with the remaining values assigned to a third mechanical phase linked to composite-like (containing α/γ interphase boundaries) regions. These mechanical property phase assessments were supplemented by overlaying crystallographic phase maps obtained by electron backscattered diffraction. An excellent correlation between microstructure and small-scale mechanical properties was achieved, especially when considering the ratio H/E.

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TO THE ISSUE OF AUTOMATION OF THE DESIGNING-MANUFACTURING PROCESS OF PARTS IN SMALL-SCALE AND SINGLE PRODUCTION

Modern Technologies in Science and Education MTSE-2020, Vol.6 ◽

10.21667/978-5-6044782-4-0-140-145 ◽

2020 ◽

Author(s):

S.B. Arzamastcev ◽

◽

N.V. Gribov ◽

O.V. Milovzorov ◽

◽

...

Keyword(s):

Manufacturing Process ◽

Small Scale ◽

Single Production

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Effect of Hub Configuration on the Performance of Mixed Flow Turbine for Micro Hydropower in Pipes

10.1115/fedsm2021-63691 ◽

2021 ◽

Author(s):

Seungsoo Jang ◽

Ji-Hun Song ◽

Youn-Jea Kim

Keyword(s):

Numerical Analysis ◽

Design Of Experiments ◽

Guide Vane ◽

Environmental Issues ◽

Cross Sectional Area ◽

Small Scale ◽

Sectional Area ◽

Mixed Flow ◽

Cross Sectional ◽

Waste Energy

Abstract As environmental issues have been on the rise recently, the demand for hydropower is increasing. Micro hydropower in pipes is highly safe, sustainable, and easy to introduce. In this study, a mixed flow turbine is introduced to collect waste energy in pipes, and numerical analysis was conducted to estimate the performance. Efficiency was adopted as an indicator to evaluate the performance, and the performance of three different hub configurations, which are conical, convex, and concave, was investigated. The hydroturbine used in this study was modeled except for the guide vane due to the small scale, and the blade was designed using design of experiments. As a result, three different hub configurations have the best efficiency point between rotational speeds of 3000 rpm and 3200 rpm. The convex hub showed the highest efficiency, which was 1.60% and 3.63% higher than the conical and concave hub, respectively. It is related to the variation in the cross-sectional area of the flow path of the runner depending on the hub configuration. Consequently, the convex hub configuration showed the best performance.

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Microfluidic radiosynthesis of [18F]FEMPT, a high affinity PET radiotracer for imaging serotonin receptors

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.13.285 ◽

2017 ◽

Vol 13 ◽

pp. 2922-2927 ◽

Cited By ~ 3

Author(s):

Thomas Lee Collier ◽

Steven H Liang ◽

J John Mann ◽

Neil Vasdev ◽

J S Dileep Kumar

Keyword(s):

Serotonin Receptors ◽

Continuous Flow ◽

Partial Agonist ◽

Reaction Times ◽

Radiochemical Yield ◽

Reaction Parameters ◽

High Affinity ◽

Molar Activity ◽

Chemical Purity ◽

Radiochemical Yields

Continuous-flow microfluidics has shown increased applications in radiochemistry over the last decade, particularly for both pre-clinical and clinical production of fluorine-18 labeled radiotracers. The main advantages of microfluidics are the reduction in reaction times and consumption of reagents that often result in increased radiochemical yields and rapid optimization of reaction parameters for 18F-labeling. In this paper, we report on the two-step microfluidic radiosynthesis of the high affinity partial agonist of the serotonin 1A receptor, [18F]FEMPT (pK i = 9. 79; K i = 0.16 nM) by microfluidic radiochemistry. [18F]FEMPT was obtained in ≈7% isolated radiochemical yield and in >98% radiochemical and chemical purity. The molar activity of the final product was determined to be >148 GBq/µmol (>4 Ci/µmol).

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