Microfluidic reactors have the ability to revolutionise radiopharmaceutical synthesis, according to Arkadij Elizarov from Siemens Molecular Imaging Biomarker Research, Los Angeles, US. He analyses the advantages and drawbacks of this potentially life-saving technology. 

Positron emission tomography (PET) is a powerful diagnostic tool used for assessing a wide range of disorders in areas such cancer, neurology, cardiology and inflammation. It relies on radiopharmaceuticals labelled with short-lived radioisotopes, such as fluorine-18 or carbon-11. The radiopharmaceutical is injected into the patient's body where it concentrates in the tissues of interest. Scientists then monitor its radioactive decay using an imaging scanner.

Raw isotope from the cyclotron (far left) must be quickly converted into a radiopharmaceutical before being injected into a patient

Radiopharmaceutical synthesis is a multi-step process that starts with the particle accelerator, known as the cyclotron, producing the raw isotope. The steps that follow include isotope concentration, solvent exchange, the radiolabelling reaction, other chemical transformations and purification. The radiopharmaceuticals must be produced rapidly and in high yield, immediately before being injected into the patient. The synthesis also has to be operated remotely to protect the user from radiation. Clearly, the synthetic chemist's traditional tools are insufficient. Scientists prepare radiopharmaceuticals using relatively large-scale automated synthesis modules. But these modules significantly dilute the labelling agents and reduce reaction rates.

Microfluidics could be the solution to radiosynthesis' deficiencies. Reactions in microfluidic devices are often rapid and high yielding and can be easily automated. Scientists have investigated multiple approaches but they can be classified into two main categories: continuous flow reactors and batch reactors. In flow reactors, reactions take place in running solutions. Their high surface-to-volume ratios and rapid heat and mass transfer increase the reaction rates while minimising the amount of radioactivity present at any given point in the system. (High concentration of radioactivity may decompose some species over time.) Batch reactors use fixed amounts of reagents in each synthetic step. They use higher concentrations of reagents, which improves reaction rates, but the high radioactivity concentration is a concern. This is lessened by minimising the time spent by reagents in a concentrated state.

Flow reactors are better understood and accepted - they have a massive amount of data from non-radioactive applications as a reference. Batch reactors explore new areas and frequently do not have non-radioactive analogues. Both technologies have improved the reaction times and yields of certain radiosynthesis steps. However, despite many published reports, microfluidic instruments have yet to make a revolutionary impact in the field of PET. None of the approaches contains a complete solution that can integrate the entire process, starting with raw radioisotope and yielding an injectable dose of radiopharmaceutical. The advantages of microfluidics in radiosynthesis have to be balanced against its drawbacks, such as material incompatibility or the inability to perform solvent exchange.

Many reports have concentrated on performing the radiolabelling reaction alone. While it is the most critical step of radiosynthesis, the steps before and after it have to occur without loss of reagent, product or time. Thus, the first system that draws on all reported advantages of microfluidics, addresses all the issues and enables total process integration should be a blockbuster. Several groups are pursuing this goal. When realised, it will not only open up a path for more efficiently producing known radiopharmaceuticals, but will enable scientists to develop and use new, more potent PET probes, which are being held back solely on the basis of their inefficient synthesis. Such technology, enabling earlier diagnosis of many diseases, will save hundreds of lives.

Read more in 'Microreactors for radiopharmaceutical synthesis' in issue 10 of  Lab on a Chip.

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