Pushing the Development of Novel Radiopharmaceuticals Forward Through the Use of a Design of Experiments (DoE) Approach
A "Design of Experiments" (DoE) Approach can help accelerate the synthesis optimization of novel radiotracers, an important step in the radiotracer development pipeline.
There is a lack of a clear pipeline and defined workflows for the development of new radiotracers for positron emission tomography (PET) which has been previously pointed out by Campbell et al. in their 2016 commentary in Nature Chemistry.1 They specifically discussed the important need to bring new radiochemical methodologies into clinical relevancy through their application to novel challenges in tracer synthesis. The recent years have seen a boom in the number of new methods available for the incorporation of 18F into novel tracer compounds, which has allowed applied radiochemists more creativity and flexibility when it comes to the synthesis of chemically diverse radiopharmaceuticals. An important part of bringing a new radiotracer concept from the bench to the bedside is the efficient production and automation of the synthesis process. This a universally challenging endeavor as each new tracer compound is chemically distinct and requires a different set of optimal reaction conditions for its efficient production and is, in itself, a unique and complex optimization problem.
Within our own group, we struggled to establish and understand the nuanced experimental factors involved in the copper-mediated radiofluorination reactions o aryl stannane2 and aryl boronic acid pinacol ester precursors.3,4 Our attempts to optimize our syntheses through the traditional “one variable at a time” (OVAT) approach proved unsuccessful, giving often confusing results despite the accumulation of a large number of individual experimental data points. We also noticed, through our interactions with other radiochemists in community, that the optimization of complex radiochemical synthesis problems was not unique to us and thus we began to work to develop more streamlined optimization workflows that could help us rapidly optimize problematic syntheses and help accelerate our delivery of novel PET tracers to our collaborating preclinical imaging scientists and biologists.
A key part of this work is the use of the “Design of Experiments” (DoE) approach to process optimization, which has long been used by chemical engineers and process chemists to optimize industrial processes in a time and cost-efficient manner. The DoE approach allows for the statistical analysis and optimization of multiple complex and interacting experimental factors through the systematic adjustment of multiple experimental parameters simultaneouslyThis thus gives a more detailed understanding of which experimental factors are important and which are not, how each parameter affects the outcome of the process, and how these parameters can be manipulated to achieve the best possible outcome. DoE is used to plan which experiments should be run so that only experimental points that contribute the formation of a valid and useful model of the behavior of the process, across all of the investigated experimental parameters, are performed. In the context of radiochemistry, fewer experimental points mean less use of expensive reactants, reagents, SPE cartridges; reduced cyclotron and lead hot-cell time; and a lower dose of harmful ionizing radiation to those performing the experiments.
The work we described in our paper “A Design of Experiments (DoE) Approach Accelerates the Optimization of Copper-Mediated 18F-Fluorination Reactions of Arylstannanes” allowed us to not only optimize the synthesis of a number of 18F labelled synthons and novel tracers, but also gave us new insights into the behavior of the chemistry itself and what needs to be considered when using this reaction for the development of novel compounds. We believe that appropriate application of DoE could do so much more than just accelerate the optimization of tracer productions, but that it could also be a valuable tool to expand our understanding of new radiochemistry and expedite the translation of these methodologies into routine use for clinical tracer production.
1. Campbell, M. G. et al. Bridging the gaps in 18F PET tracer development. Nat. Chem. 9, 1–3 (2016).
2. Makaravage, K. J., Brooks, A. F., Mossine, A. V., Sanford, M. S. & Scott, P. J. H. H. Copper-Mediated Radiofluorination of Arylstannanes with [18F]KF. Org. Lett. 18, 5440–5443 (2016).
3. Tredwell, M. et al. A General Copper-Mediated Nucleophilic 18 F Fluorination of Arenes. Angew. Chemie Int. Ed. 53, 7751–7755 (2014).
4. Mossine, A. V et al. Synthesis of [18F]Arenes via the Copper-Mediated [18F]Fluorination of Boronic Acids. Org. Lett. 17, 5780–5783 (2015).