Emerging Technologies for Decentralized Production of PET Tracers

Keng, Pei Yuin; Esterby, Melissa; Dam, R. Michael van

doi:10.5772/31390

Cited by 7 publications

(6 citation statements)

References 83 publications

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“…To ensure that PET was reasonably affordable, it was logical to design equipment to synthesize large batches of the dominant radiotracer. 26 The pipeline was also effective in supporting increasing [ 18 F]FDG demand as PET usage continued to grow. Production facilities could easily increase their [ 18 F]FDG throughput by increasing the amount of bombardment time in the cyclotron to produce more 18 F. Now, however, with so many novel radiotracers developed, this economic strategy is no longer optimal.…”

Section: Commercial Production Of [18f]fdg and Other Tracersmentioning

confidence: 99%

“…To change this, microfluidic approaches have been touted as the ideal solution. 15,22,26 Microfluidic approaches require far smaller working volumes, resulting in several significant improvements. Reduced volumes lead to more controllable fluid manipulation and higher surface to volume ratios, improving heat transfer.…”

Section: Microfluidic Radiotracer Productionmentioning

confidence: 99%

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Microfluidic synthesis of radiotracers: recent developments and commercialization prospects

Mc Veigh,

Bellan

2024

Lab Chip

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Section: Commercial Production Of [18f]fdg and Other Tracersmentioning

confidence: 99%

Section: Microfluidic Radiotracer Productionmentioning

confidence: 99%

Microfluidic synthesis of radiotracers: recent developments and commercialization prospects

Mc Veigh,

Bellan

2024

Lab Chip

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“…Positron emission tomography (PET) medical imaging 1 may soon be revolutionised via the introduction of dose-ondemand radiopharmaceutical production. [2][3][4][5][6][7][8][9] In the current "centralised" methodology, large batches of a single type of radiotracer, usually [ 18 F]2-fluoro-2-deoxy-D-glucose ([ 18 F]FDG), are synthesised at a production facility before being transported to an imaging centre for administration to patients prior to their PET scan. However, dose-on-demand or "decentralised" production would allow single doses of specific tracers to be generated at the imaging centre, requiring only transport of the radioisotope (if local generation is unavailable), e.g.…”

Section: Introductionmentioning

confidence: 99%

On-chip electrochemical detection of glucose towards the miniaturised quality control of carbohydrate-based radiotracers

Patinglag

Esfahani

Ragunathan

et al. 2020

Analyst

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“…However, effective new chemical matter may prove necessary if existing 2-NI hypoxia imaging agents cannot be successfully repurposed for effective vector imaging. The development pathway for novel radiobiological compounds may also become more simple with time, due to a push for development of PET imaging agents for more varied applications (Coenen et al, 2010) and progress in technologies for miniaturized automated production of varied PET probes (Li and Conti, 2010;Yuin et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Development of bacterial nitroreductase enzymes for noninvasive imaging in cancer gene therapy

Williams¹

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<p>There is strong interest in developing novel targeted cancer therapies. It has been known for over a century that certain viruses and bacteria can preferentially infect and lyse cancerous cells. Clinical utility has lagged behind the initial promise of the idea; however three therapeutic agents from the oncolytic virus field are currently in Phase IIB/Phase III clinical trials. The development path of such therapies would be substantially smoothed by an ability to nonin vasively monitor the ir location in the patient’s body post-administration. This would allay fears that viral/bacterial distribution may not be confined to the tumour and provide real time information on vector localisation and replication. This could be achieved by positron emission tomography (PET) scanning if the vector expressed a reporter protein which could activate a PET suitable imaging agent. Furthermore the potency of such therapies could be increased by if this reporter protein could also act therapeutically by converting a systemically delivered benign prodrug into a potent chemotherapeutic – thus targeting the toxicity of the prodrug specifically to cancerous cells. A promising enzyme/prodrug combination is the use of bacterial nitroreductase (NTR) enzymes to activate DNA damaging prodrugs, such as the dinitrobenzamides CB1954 and PR-104A. This thesis presents work aimed at developing the ability to noninvasively image bacterial NTR expression so that these enzymes can act as both therapeutic and reporter proteins. The primary focus of this study was to achieve this by repurposing pre-existing 2-nitroimidazole (NI) PET imaging agents, originally developed for imaging tumour hypoxia. Microplate based screening strategies were developed to enable detection of 2-NI bioreductive activation by different bacterial NTRs over-expressed heterologously in Escherichia coli, and these technologies were used to screen a 58-membered library of nitroreductase candidates. Although the most widely studied NTR for enzyme/prodrug therapy - NfsB from E. coli - was found to lack activity with 2-NI substrates, numerous NTRs from the NfsA family were able to metabolise these molecules to the cell entrapped form required for PET imaging. Following this discovery, a directed evolution study was conducted to improve the native activity of the enzyme NfsA from E. coli. In this study targeted mutagenesis of active site residues was carried out, resulting in identification of several NfsA multi-site mutants that were substantially improved in their ability to activate a range of 2-NI imaging agents. In addition to repurposing existing PET probes, this work sought to identify and engineer NTRs for efficient activation of a next - generation PET probe that is designed to be substantially less responsive to hypoxia and hence give a cleaner signal for NTR imaging (i.e. low to no background resulting from tumour hypoxia). SN 33623, a novel 5-NI analogue of the existing 2-NI PET probe EF5, was designed and synthesised by our University of Auckland collaborators. It was found that this novel probe was not only activated by NfsA enzymes, but also by a subset of NfsB enzymes. Although this subset did not include E. coli NfsB, sequence alignment and site-directed mutagenesis were used to identify two key mutations that can be introduced into E. coli NfsB (as well as engineered variants thereof) to confer high levels of SN 33623 activity. Finally work was carried out, as part of a wider collaborative project, to generate NfsA mutants that retained the ability to metabolise 2-NI imaging agents while also showing increased activation of the nitroaromatic prodrug PR-104A. Ongoing evaluation of these enzymes will include assessment of their therapeutic effect in preclinical models and their ability to be noninvasively imaged (by microPET) when expressed from the tumour targeting bacterial strain Clostridium sporogenes.</p>

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Emerging Technologies for Decentralized Production of PET Tracers

Cited by 7 publications

References 83 publications

Microfluidic synthesis of radiotracers: recent developments and commercialization prospects

Microfluidic synthesis of radiotracers: recent developments and commercialization prospects

On-chip electrochemical detection of glucose towards the miniaturised quality control of carbohydrate-based radiotracers

Development of bacterial nitroreductase enzymes for noninvasive imaging in cancer gene therapy

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