Authors: Gregory D. Bowden1, Nantanat Chailanggar1, Bernd J. Pichler1,2, Andreas Maurer1,2
1Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
2iFIT-Cluster of Excellence, Eberhard Karls University, Tübingen, Germany
Background
Reaction optimization is an important part of the radiosynthesis process. A good understanding of which factors are essential to optimal reaction performance can help expedite tracer development, particularly when designing an automated synthesis route. Design of Experiments (DoE) is a statistical approach to process optimization that is able to model the effects of multiple experimental parameters simultaneously with high experimental efficiency (fewer experiments).1
Aims
Using DoE, we studied the copper mediated radiofluorinations of several compounds with the aim of modelling the effects of important experimental factors (e.g: copper loading, pyridine loading, reaction atmosphere, solvent composition etc) that should be considered when using either arylstannane or arylboronate precursors.2,3 Moreover, we aimed to develop a robust testing framework that would allow for multiple experiments from one delivery of activity while still being scalable and automatable.
Methods
Experimental matrices for each DoE study were designed and analyzed using MODDE Go 12 (Umetrics) software. 18F was trapped on a QMA conditioned with KOTf. After washing the QMA with MeOH, the activity was eluted using TBAOTf (10 mg in 1 ml MeOH). Reaction mixtures containing the necessary reagents were added and left to stir under the required conditions for 20 min before quenching. Radiochemical conversions were assessed using radioTLC and the acquired data was fitted using multiple linear regression.
Results and Conclusion
Several DoE studies were conducted using different arylstannane and arylboronate precursors. These studies showed that each precursor type has a different set of experimental requirements for optimal reaction performance. Arylstannanes require high copper loads and can be labelled under inert gas. Arylboronates benefit from low copper loads and require an oxidative atmosphere. Adjusting the pyridine concentration can be used to tune the synthesis performance for different precursors.
References
1. Bowden, G. D., Pichler, B. J. & Maurer, A. A Design of Experiments (DoE) Approach Accelerates the Optimization of Copper-Mediated 18F-Fluorination Reactions of Arylstannanes. Sci. Rep. 9, 11370 (2019)
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. Mossine, A. V et al. Synthesis of [18F]Arenes via the Copper-Mediated [18F]Fluorination of Boronic Acids. Org. Lett. 17, 5780–5783 (2015).