Advantages of Radiochemistry in Microliter Volumes

Abstract

Positron emission tomography (PET) provides quantitative 3D visualization of physiological parameters (e.g., metabolic rate, receptor density, gene expression, blood flow) in real time in the living body. By enabling measurement of differences in such characteristics between normal and diseased tissues, PET serves as vital tool for basic research as well as for clinical diagnosis and patient management. Prior to a PET scan, the patient is injected with a short-lived tracer labeled with a positron-emitting isotope. Safe preparation of the tracer is an expensive process, requiring specially trained personnel and high-cost equipment operated within hot cells. The current centralized manufacturing strategy, in which large batches are prepared and divided among many patients, enables the most commonly used tracer (i.e., [ 18 F]FDG) to be obtained at an affordable price. However, as the diversity of tracers increases, other strategies for cost reduction will become necessary. This challenge is being addressed by the development of miniaturized radiochemistry instrumentation based on microfluidics. These compact systems have the potential to significantly reduce equipment cost and shielding while increasing diversity of tracers produced in a given facility. The most common approach uses "flow-through" microreactors, which leverage the ability to precisely control reaction conditions to improve synthesis times and yields. Several groups have also developed "batch" microreactors which offer significant additional advantages such as reduced reagent consumption, simpler purifications, and exceptionally high specific activity, by reducing operating volumes by orders of magnitude. In this chapter, we review these "batch" approaches and the advantages of using small volumes, with special emphasis on digital microfluidics, in which reactions have been performed with volumes as low as~1 μL.

Rapid, efficient, and economical synthesis of PET tracers in a droplet microreactor: application to O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET)

“…Of the several different microfluidic approaches reported in the last decade (Elizarov 2009;Keng and van Dam 2015;Miller et al 2010;Pascali and Matesic 2016;Rensch et al 2013), microvolume reaction approaches offer the greatest potential for reagent and instrument reductions (Dooraghi et al 2013;Elizarov et al 2010;Iwata et al 2018;Keng et al 2016;Lebedev et al 2012;Wang et al 2017). A particular configuration we are exploring is performing reactions in microliter-sized droplets on simple Teflon-coated silicon microfluidic chips, which has advantages of simple operation, low-cost disposable chips, and a compact system size, which reduces the necessary shielding.…”

Performing multi-step chemical reactions in microliter-sized droplets by leveraging a simple passive transport mechanism

“…In recent years there has been significant development of microfluidic devices to perform radiochemical synthesis of PET tracers 8,9 . Among the various approaches that have been explored, droplet-based systems have perhaps the most potential for cost reductions 10,11 . By performing reactions at the microliter scale, amounts of expensive reagents such as precursor can be reduced by 2–3 orders of magnitude compared to conventional approaches.…”

Recent Progress toward Microfluidic Quality Control Testing of Radiopharmaceuticals

“…If realized, integration of microscale QC tests on an automated platform would allow for unified QC system validation, eliminate operator-induced variation, significantly reduce radiation exposure to personnel, and streamline the overall workflow. As increasing numbers of the thousands of known tracers [ 126 , 127 ] move into the clinic, and as new technologies such as microfluidic systems enable more widespread production of tracers on demand [ 24 , 128 , 129 , 130 ], it will become increasingly important to have an integrate QC testing platform that simplifies and reduces the cost of QC testing.…”