Opportunities in Low-Level Radiocarbon Microtracing: Applications and New Technology

Abstract

¹⁴C-radiolabeled (radiocarbon) drug studies are central to defining the disposition of therapeutics in clinical development. Concerns over radiation, however, have dissuaded investigators from conducting these studies as often as their utility may merit. Accelerator mass spectrometry (AMS), originally designed for carbon dating and geochronology, has changed the outlook for in-human radiolabeled testing. The high sensitivity of AMS affords human clinical testing with vastly reduced radiative (microtracing) and chemical exposures (microdosing). Early iterations of AMS were unsuitable for routine biomedical use due to the instruments’ large size and associated per sample costs. The situation is changing with advances in the core and peripheral instrumentation. We review the important milestones in applied AMS research and recent advances in the core technology platform. We also look ahead to an entirely new class of ¹⁴C detection systems that use lasers to measure carbon dioxide in small gas cells.

Lay Abstract: Radiocarbon (¹⁴C) is produced continuously in the upper atmosphere and incorporated into biological systems through photosynthesis. Incorporation of ¹⁴C ceases at death, hence by measuring natural levels of radiocarbon in deceased organic materials the age of the objects (e.g. vegetation, wood and historical artifact, among others) can be determined. Early carbon dating determinations (starting in the late 1940s) relied on monitoring the small levels of radioactivity decay energy emerging from the sample. In the late 1970s nuclear physicists in collaboration with archeologists developed a far more sensitive and efficient measuring technique known as accelerator mass spectrometry (AMS), which can identify individual carbon atoms. The technology was extended to biomedical research in the early 1990s. Here it had an immediate impact on in vivo human research across diverse areas such as carcinogenesis and human nutrition. The same carbon dating technology now supports human ¹⁴C-tracer metabolism studies conducted as part of early drug development. The high sensitivity of AMS enables scientists to explore new drug candidates safely in any human subpopulation at very low chemical (microdosing) and radioactive doses (microtracing). A ‘big physics’ tool originally developed for dating archeological artifacts is now benefiting modern drug development in unanticipated ways. The full benefits of the sensitive measurement technology were impeded by the scale and operational complexity of the early instruments, but this situation has changed significantly over the last decade after the emergence of purpose-built biomedical instruments. The evolving relationship between radiocarbon, AMS, and modern drug development is discussed in this review.

Keywords::

• accelerator mass spectrometry
• AMS
• cavity ring-down spectroscopy
• microdosing
• microtracing
• pediatrics
• radiocarbon

Acknowledgements

The authors appreciate the comments of the anonymous reviewers who forced a clearer presentation of bioanalytical accelerator mass spectrometry and the overall quality of the manuscript. The authors would also like to thank J Vogel for preparation of some of the figures and for pioneering the bio AMS field with his colleagues at Lawrence Livermore National Laboratory.

Author contributions

LT Vuong was the coprincipal author and specifically prepared the pediatric section. Q Song assisted in the preparation and review of the manuscript and assisted specifically with the sections on mass balance. HJ Lee assisted in the preparation and review of the manuscript. YG Shin assisted specifically with the sections on mass balance. A Roffel assisted in the review of the manuscript and provided assistance on the CRO perspective for the dose formulation section. S-H Shin assisted in the review and proof reading of the manuscript in collaboration with YG Shin of ChungNam. YG Shin was the primary author of the mass balance and metabolite profiling section. SR Dueker was the coprincipal author of all sections and to whom correspondence is addressed.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.