Small-volume reactions offer big advantages for the radiosynthesis of imaging biomarkers

Performing the synthesis of radiolabeled imaging biomarkers (“tracers”) in microliter volumes instead of conventional milliliter volumes offers many advantages. One in particular is improved isotopic purity (“molar activity”) of the produced tracers, a property that can affect image quality, logistics of tracer distribution and use, and the potential for pharmacologic effects in the subject.
Published in Chemistry
Small-volume reactions offer big advantages for the radiosynthesis of imaging biomarkers

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The paper in Communications Chemistry is here:

Positron-emission tomography (PET) is a whole-body imaging technique widely used in the clinic to diagnose disease (e.g. neurological disorders or cancer) and monitor response to therapy. It is also a crucial tool in drug development. Just prior to imaging, the subject is injected with a tiny amount of a short-lived radiolabeled “tracer”. The tracer molecules circulate, accumulate in certain regions, and are detected by a PET scanner when the radionuclides undergo radioactive decay (Figure 1A). Depending on the type of radiotracer injected, PET can visualize the distribution of biological structures or metabolic activity.

For safety reasons, PET radiotracers are prepared by automated “radiosynthesizers” operated inside “hot cells” that shield the operator from radiation. During the last decade there has been tremendous interest in exploring compact microfluidic devices as alternatives to current approaches for tracer preparation. Microfluidics offers the advantages of reduced reagent amounts and costs, reduced preparation times, increased reaction yields, and dramatically reduced equipment size and shielding requirements.

During characterization of a droplet-based microfluidic radiochemistry platform that we developed, we stumbled upon an interesting observation: the “molar activity” (AM) of the tracers was significantly higher when produced in our microfluidic platform compared to a conventional system. Typically reported as radioactivity per number of moles, AM is a measure of the isotopic purity of the synthesized tracer, i.e. the proportion of molecules labeled with the radioactive isotope (e.g. fluorine-18) versus those containing the non-radioactive form (e.g. fluorine-19; invisible to the PET scanner). In general, AM should be high: it avoids pharmacologic effects by minimizing occupancy when imaging low tissue density targets (e.g. neuroreceptors), facilitates PET “microdosing” studies to evaluate the pharmacokinetics of potential new drug compounds, extends the distance/time over which tracers can be transported from the preparation site to the imaging site, and is critical in preclinical research, where much higher concentrations of the tracer per mass of the animal must be injected (compared to humans) to achieve sufficient signal-to-noise ratio. In fact, as an example, we show in our paper that AM of the tracer [18F]Fallypride can have a significant influence on the ability to visualize the target (dopamine D2/D3 neuroreceptors) (Figure 1B).

With the goal of learning how to maximize AM, we conducted a systematic study to determine the origin of this difference between microscale and conventional synthesis of PET tracers by studying the influence of several variables on AM of tracers produced by the two approaches. Our study concluded that reagents are the dominant source of fluorine-19 contamination. Thus microfluidic reactors, with 100-1000x lower reagent amounts (microliters vs milliliters), were able to produce radiotracers with high AM over a wide range of conditions (Figure 1C), providing a convenient means to routinely produce tracers with high molar activity. With conventional techniques, it is necessary to use very high amounts of starting radioactivity to achieve similar values. Microscale radiochemistry thus may provide a safer platform for production of tracers when high molar activity is important. This new technology would be particularly advantageous when only a small amount of the tracer is needed (e.g. in small preclinical research studies), by avoiding the need for a large-scale production, most of which would be wasted, when using conventional technologies.

Figure 1: (A) Overview of positron emission tomography (PET). (B) In many cases, it is critical that the tracer produced with high “molar activity”. As shown in this series of PET/CT images of mouse brain, the molar activity of the tracer [18F]Fallypride can have a dramatic impact on the ability visualize the striata (brain regions rich in dopamine D2/D3 neuroreceptors targeted by this tracer). (C) The molar activity depends on the synthesis method and the batch size (amount of radioactivity used). In particular, synthesis in microliter volumes results in very high specific activity compared to conventional approaches over a wide range of conditions, providing a convenient and safe means to obtain high molar-activity radiotracers.

R. Michael van Dam, Maxim Sergeev, Pei Yuin Keng

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