Radiochemistry refers to chemistry involving radioisotopes.
Radiochemistry has many applications, including: assays in biological research, diagnostic medical imaging (i.e. emitted radiation is detected to measure biological processes or structures), radiotherapeutics (i.e., targeted molecules or particles accumulate at the disease site and emit radiation that causes local tissue damage), environmental and ecosystem research, nuclear reactor fuel and waste research, etc.
In our research, we are mainly concerned with the chemistry of incorporating a positron-emitting isotope into an organic molecule for positron emission tomography (PET).
While simply a subset of organic chemistry, radiosynthesis poses some very unique challenges:
- The synthesis and purification must be completed quickly (generally within 1-2 half lives of the radioisotope). This often restricts the types of possible reactions, requires high temperatures, and requires careful design of the synthetic approach such that the radioisotope is incorporated late in the process.
- The synthesis must be carried out behind radiation shielding (generally requires automation)
- Prior to injection, it is necessary to perform quality control tests to assess the safety of the batch
- Repetitive production is necessary due to the short half-life
- Success of production is critical as patients are generally already waiting
Radiochemistry Production Process
The production of PET tracers involves numerous steps:
- Production of the radioisotope (e.g. proton bombardment of [O-18]water in a cyclotron to produce [F-18]fluoride)
- Preparation of the radioisotope (e.g. separation of [F-18]fluoride from [O-18]water to increase its reactivity)
- Chemical incorporation of the radioisotope into the precursor molecule
- Purification of the tracer
- Formulation of the tracer (e.g. into saline)
- Quality control testing
- Dispensing of individual doses and delivery to the imaging site
The overall process is complex and expensive, involving numerous pieces of expensive equipment and highly trained personnel. Currently, production of PET tracers such as [18F]FDG are produced in a ”satellite” manner. Radiopharmacies manufacture large batches that can be subdivided among many patients within a local area to leverage economies of scale and offer the compounds at an affordable price. A modest number of radiopharmacies can supply compounds for a wide area such as the United States.
While this model is effective for supplying 1 or 2 tracers, as the diversity of PET tracers increases in medical care and research, it becomes more challenging to coordinate needs for tracers among imaging centers. Each radiopharmacy would need to produce a great number of batches, but each batch would be subdivided among fewer patients, increasing the cost for each patient. To increase the diversity of tracers available at low cost will require a fundamental reduction in the production cost, and this requires innovative new technologies.
Several trends in radiosynthesizer technology have emerged toward achieving the goal of affordable "batch-on-demand" or "dose-on-demand". "Kit-based" synthesizers, that can be configured to make different probes on the same or subsequent days merely by installing different disposable “cassettes”, lower cost by reducing the need for having a dedicated synthesizer (and associated equipment) for every probe. Another important direction is in miniaturized radiosynthesizers based on microfluidics. These have the potential to dramatically reduce the cost of equipment as well as the amount of shielding infrastructure (e.g. hot cells) that are needed for operation.
Numerous radioisotopes are used for PET imaging, with particular choices depending in part on the particular biology being investigated, on the timescale of the biological process being monitored, on the availability of the isotope, and on the complexity of the synthesis and purification process.
The most commonly used isotope in PET imaging is fluorine-18, in large part due to its many favorable physical characteristics. A radioactive half life of 110 min allows sufficient time for uptake and distribution in the subject, yet is short enough not to cause prolonged radiation exposure after the PET scan procedure is complete. Furthermore, the half-life is long enough to prepare the tracer (synthesis and purification) and even transport it from a production facility to imaging facilities up to a travel distance of 2-3 half-lives. The decay of fluorine-18 yields a high percentage of positrons (97%), and the positron energy is lower than many other isotopes, limiting the distance between the decay and when the gamma rays are produced (thus improving resolution). Chemically, fluorine forms strong bonds and results in tracers that have good metabolic stability in vivo.
The widespread use of fluorine-18 in PET has led to networks of radiopharmacies around the world for production of fluorine-18 (via proton bombardment of oxygen-18 water in a cyclotron) , leading to excellent availability of [18F]fluoride and a couple of 18F-labeled tracers (mainly [18F]FDG and [18F]NaF).
The following book chapter describes emerging technologies to address bottlenecks in PET tracer production:
- Pei Yuin Keng, Melissa Esterby, R. Michael van Dam. Emerging Technologies for Decentralized Production of PET Tracers. In Positron Emission Tomography – Current Clinical and Research Aspects. Ed. Hsieh C-H. pg 153-182. ISBN 978-953-307-824-3, InTech, 2012. (PDF Link)
The following papers provide excellent reviews of fluorine-18 radiochemistry, especially modern techniques:
- O. Jacobson, D. O. Kiesewetter, and X. Chen, “Fluorine-18 Radiochemistry, Labeling Strategies and Synthetic Routes,” Bioconjugate Chem 26(1): 1-18, 2015 (Journal Link)
- Cai, L. S.; Lu, S. Y.; Pike, V. W. Chemistry with [18F]Fluoride ion. Eur. J. Org. Chem. 2008, 2853−2873 (Journal Link)
- Cole EL, Stewart MN, Littich R, Hoareau R, Scott PJH. Radiosyntheses using Fluorine-18: the Art and Science of Late Stage Fluorination. Current topics in medicinal chemistry 14(7):875-900 (2014). (PMC Link)
- A.F. Brooks, J.J. Topczewski, N. Ichiishi, M.S. Sanford, P.J.H. Scott. Late-stage [18F]fluorination: new solutions to old problems. Chemical Science 5: 4545-4553, 2014. (Journal Link)
Lecture slides from Pei Yuin Keng's lecture from the START program are also very informative:
The following papers review developments in microfluidics for radiochemistry:
- Rensch C, Jackson A, Lindner S, et al. (2013) Microfluidics: A Groundbreaking Technology for PET Tracer Production? Molecules 18:7930–7956. doi: 10.3390/molecules18077930
- Miller PW, deMello AJ, Gee AD (2010) Application of Microfluidics to the Ultra-Rapid Preparation of Fluorine-18 Labelled Compounds. Current Radiopharmaceuticals 3:254–262.
- Elizarov AM (2009) Microreactors for radiopharmaceutical synthesis. Lab Chip 9:1326–1333.
- Lu S, Giamis AM, Pike VW (2009) Synthesis of [18F]fallypride in a micro-reactor: rapid optimization and multiple-production in small doses for micro-PET studies. Curr Radiopharm 2:1–13.
- Watts P, Pascali G, Salvadori PA (2012) Positron Emission Tomography Radiosynthesis in Microreactors. Journal of Flow Chemistry 2:37–42. doi: 10.1556/JFC-D-12-00010
- Lebedev A (2013) Microfluidic devices for radio chemical synthesis. In: Microfluidic Devices for Biomedical Applications. Elsevier, pp 594–633
- Pascali G, Watts P, Salvadori PA Microfluidics in radiopharmaceutical chemistry. Nuclear Medicine and Biology. doi: 10.1016/j.nucmedbio.2013.04.004