A “dose on demand” Biomarker Generator for automated production of [18F]F− and [18F]FDG

Awasthi, Vibhudutta; Watson, Joseph C.; Gali, Hariprasad; Matlock, Greg; McFarland, Aaron; Bailey, J. E.; Anzellotti, Atilio

doi:10.1016/j.apradiso.2014.02.015

Cited by 30 publications

(33 citation statements)

References 9 publications

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“…Several efforts are underway to develop integrated QC testing instruments that automatically perform and document all of the required tests and calibrations, e.g. QC-1 [19] (Munster, Germany), Trace-ability [20] (Culver City, CA USA), and ABT Molecular Imaging Inc. [21, 22] (Louisville, TN USA). While potentially alleviating the labor burden, these systems are still based on conventional, macroscale instruments linked into an integrated system along with a sample distribution mechanism.…”

Section: Introductionmentioning

confidence: 99%

Toward miniaturized analysis of chemical identity and purity of radiopharmaceuticals via microchip electrophoresis

Cheung

et al. 2018

Anal Bioanal Chem

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Miniaturized synthesis of positron emission tomography (PET) tracers is poised to offer numerous advantages including reduced tracer production costs and increased availability of diverse tracers. While many steps of the tracer production process have been miniaturized, there has been relatively little development of microscale systems for the quality control (QC) testing process that is required by regulatory agencies to ensure purity, identity, and biological safety of the radiotracer before use in human subjects. Every batch must be tested, and in contrast with ordinary pharmaceuticals, the whole set of tests of radiopharmaceuticals must be completed within a short-period of time to minimize losses due to radioactive decay. By replacing conventional techniques with microscale analytical ones, it may be possible to significantly reduce instrument cost, conserve lab space, shorten analysis times, and streamline this aspect of PET tracer production. We focus in this work on miniaturizing the subset of QC tests for chemical identity and purity. These tests generally require high-resolution chromatographic separation prior to detection to enable the approach to be applied to many different tracers (and their impurities), and have not yet, to the best of our knowledge, been tackled in microfluidic systems. Toward this end, we previously explored the feasibility of using the technique of capillary electrophoresis (CE) as a replacement for the "gold standard" approach of using high-performance liquid chromatography (HPLC) since CE offers similar separating power, flexibility, and sensitivity, but can readily be implemented in a microchip format. Using a conventional CE system, we previously demonstrated the successful separation of non-radioactive version of a clinical PET tracer, 3'-deoxy-3'-fluorothymidine (FLT), from its known by-products, and the separation of the PET tracer 1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)-cytosine (D-FAC) from its α-isomer, with sensitivity nearly as good as HPLC. Building on this feasibility study, in this paper, we describe the first effort to miniaturize the chemical identity and purity tests by using microchip electrophoresis (MCE). The fully automated proof-of-concept system comprises a chip for sample injection, a separation capillary, and an optical detection chip. Using the same model compound (FLT and its known by-products), we demonstrate that samples can be injected, separated, and detected, and show the potential to match the performance of HPLC. Addition of a radiation detector in the future would enable analysis of radiochemical identity and purity in the same device. We envision that eventually this MCE method could be combined with other miniaturized QC tests into a compact integrated system for automated routine QC testing of radiopharmaceuticals in the future. Graphical abstract Miniaturized quality control (QC) testing of batches of radiopharmaceuticals via microfluidic analysis. The proof-of-concept hybrid microchip electrophoresis (MCE) device demonstrated the fea...

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Section: Introductionmentioning

confidence: 99%

Toward miniaturized analysis of chemical identity and purity of radiopharmaceuticals via microchip electrophoresis

Cheung

et al. 2018

Anal Bioanal Chem

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“…Chemie allowing the dose-on-demand preparation of these small molecules on site. [32] Scheme 3shows the automated synthesis of the 18 F-labeled hypoxia imaging positron emission tomography (PET) tracer [ 18 F]FAZA (9). In the first step, [ 18 F]fluoride was flushed from an ion exchange cartridge into the reaction vial containing potassium carbonate Kryptofix 2.2.2.…”

Section: Methodsmentioning

confidence: 99%

The Molecular Industrial Revolution: Automated Synthesis of Small Molecules

2018

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The eighteenth and nineteenth centuries marked a sweeping transition from manual to automated manufacturing on the macroscopic scale. This enabled an unmatched period of human innovation that helped drive the Industrial Revolution. The impact on society was transformative, ultimately yielding substantial improvements in living conditions and lifespan in many parts of the world. During the same time period, the first manual syntheses of organic molecules was achieved. Now, two centuries later, we are poised for an analogous transition from highly customized crafting of specific molecular targets by hand to the increasingly general and automated assembly of many different types of molecules with the push of a button. Automation of customized small molecule synthesis pathways is already enabling safer, more reproducible, and readily scalable production of specific targets, and general machines now exist for the synthesis of a wide range of different peptides, oligonucleotides, and oligosaccharides. Creating general machines that are similarly capable of making many different types of small molecules on-demand, akin to that which has been achieved on the macroscopic scale with 3D printers, has proven to be substantially more challenging. Yet important progress is being made toward this potentially transformative objective with two complementary approaches: (1) automation of customized synthesis routes to different targets via machines that enable use of many different reactions and starting materials, and (2) automation of generalized platforms that make many different targets using common coupling chemistry and building blocks. Continued progress in these exciting directions has the potential to shift the bottleneck in molecular innovation from synthesis to imagination, and thereby help drive a new industrial revolution on the molecular scale.

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“…Zumindest die teilweise Automatisierung von optimierten Synthesen ist im industriellen Maßstab bereits weit verbreitet, und als wichtiger Grund dafürk ann der positive Einfluss der automatischen Herstellung auf die Skalierbarkeit gesehen werden. [27] [32] In Schema 3i st die automatische Synthese des 18 [33] Weitere Beispiele fürd ie automatisierte Synthese von radiomarkierten Verbindungen sind Pittsburgh compound-B ( 11 C-markiertes Derivat), [34] Paclitaxel ( 18 F-markiertes Derivat) [35] sowie andere 18 Fund 68 Ga-markierte Verbindungen. [36] Zusätzlich zu Sicherheitsrisiken, die mit bestimmten Chemikalien einhergehen, kçnnen auch extreme Bedingungen und exotherme Reaktionen speziell im großen Maßstab eine nicht zu unterschätzende Gefahrenquelle sein.…”

Section: Skalierbarkeitunclassified

Die molekulare industrielle Revolution: zur automatisierten Synthese organischer Verbindungen

Trobe

Burke

2018

Angewandte Chemie

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Derzeitkündigt sichein Wandel von der manuellen Synthese spezifischer Moleküle,die über individuell angepasste Routen verläuft, hin zu automatisch zusammenfügten Verbindungen unterschiedlichster Klassen mit nur einem Knopfdruckan. Die Entwicklung einer Maschine fürdie Herstellung unterschiedlichsterorganischer Moleküle je nachBedarf ist eine komplexe Aufgabe,e ss ind aber bereits bedeutende Fortschritte auf Basis von zwei komplementären Ansätzen zu verzeichnen:1 )Automatisierung individueller Routen fürdie Synthese diverser Verbindungen, wobei viele unterschiedliche Reaktionstypen und spezifische Reagentien genutzt werden kçnnen, und 2) Automatisierung einer generellen Plattform, die die Herstellung unterschiedlicher Verbindungen ausgehend von diversen Bausteinen, die mit derselben Kupplungsreaktion verknüpft werden, ermçglicht. Fortschritte in diesen Bereichen bieten die Mçglichkeit, Synthese-Engpässe zu vermeiden und den Fokus molekularer Innovation auf die Entwicklung neuer Methoden zu lenken und so eine "molekulare industrielle Revolution" zu beschleunigen.

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A “dose on demand” Biomarker Generator for automated production of [18F]F− and [18F]FDG

Cited by 30 publications

References 9 publications

Toward miniaturized analysis of chemical identity and purity of radiopharmaceuticals via microchip electrophoresis

Toward miniaturized analysis of chemical identity and purity of radiopharmaceuticals via microchip electrophoresis

The Molecular Industrial Revolution: Automated Synthesis of Small Molecules

Die molekulare industrielle Revolution: zur automatisierten Synthese organischer Verbindungen

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