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. 2019 Aug 6;9(1):11370.
doi: 10.1038/s41598-019-47846-6.

A Design of Experiments (DoE) Approach Accelerates the Optimization of Copper-Mediated 18F-Fluorination Reactions of Arylstannanes

Gregory D Bowden  1 , Bernd J Pichler  1   2 , Andreas Maurer  3   4
Affiliations

A Design of Experiments (DoE) Approach Accelerates the Optimization of Copper-Mediated 18F-Fluorination Reactions of Arylstannanes

Gregory D Bowden et al. Sci Rep. .

Abstract

Recent advancements in 18F radiochemistry, such as the advent of copper-mediated radiofluorination (CMRF) chemistry, have provided unprecedented access to novel chemically diverse PET probes; however, these multicomponent reactions have come with a new set of complex optimization problems. Design of experiments (DoE) is a statistical approach to process optimization that is used across a variety of industries. It possesses a number of advantages over the traditionally employed "one variable at a time" (OVAT) approach, such as increased experimental efficiency as well as an ability to resolve factor interactions and provide detailed maps of a process's behavior. Here we demonstrate the utility of DoE to the development and optimization of new radiochemical methodologies and novel PET tracer synthesis. Using DoE to construct experimentally efficient factor screening and optimization studies, we were able to identify critical factors and model their behavior with more than two-fold greater experimental efficiency than the traditional OVAT approach. Additionally, the use of DoE allowed us to glean new insights into the behavior of the CMRF of a number of arylstannane precursors. This information has guided our decision-making efforts while developing efficient reaction conditions that suit the unique process requirements of 18F PET tracer synthesis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Recent copper-mediated nucleophilic radiofluorinations of electron-rich and electron-neutral (a) arylboronic esters by Tredwell et al., (b) arylboronic acids by Mossine et al., and (c) arylstannane precursors by Makaravage et al.–.
Figure 2
Figure 2
(a) The OVAT approach resolves reaction space one dimension at a time. The DoE approach builds a matrix of experimental runs to model a response surface across all reaction space. Different design types allow for (b) efficient factor screening studies or (c) more focused and detailed response surface optimization studies. The color grading represents the value of the true response (blue low, red high.) This figure has been recreated and modified with permission from the catalysisconsulting.co.uk website.
Figure 3
Figure 3
The investigated factors and their ranges for the fractional factorial factor screening of the model synthesis 4-[18F]fluorobiphenyl ([18F]2) from 4-tributyltinbiphenyl (1). In a fractional factorial design, experimental points are arranged at the corner of a K-dimensional hypercube. p is the total number of generators used to form the array (1/Kp is the fraction of the total number of runs from the full factorial experiment (all vertices of a hypercube). Center points (CP, shown in Green) are repeated experiments carried out at the center of the hypercube to estimate reproducibility and measure curvature in the response surface.
Figure 4
Figure 4
The scaled and centered regression factors calculated from the results of fractional factorial factor screening DoE. Large regression coefficients represent factors with large contributions to the response (%RCC). A positive number denoted a positive influence on the response. A negative number denotes a diminishing effect on the response. To fit an accurate model, non-significant terms would need to be eliminated, but for the purposes of factor screening, these non-significant terms are shown here. If a factor’s regression coefficient is smaller than the associated errors bars it is probable (at the 95% confidence interval) that that factor is not significant.
Figure 5
Figure 5
The investigated factors and their ranges for the orthogonal central composite design RSO of [18F]pFBC ([18F]4). Starpoint distance a is scaled in order to ensure orthogonality throughout the experimental matrix. An orthogonal central composite design (CCO) has a distance “a” scaled so as to ensure orthogonality in the experimental matrix.
Figure 6
Figure 6
(a) The scaled and centered regression factors calculated from the results of the RSO (CCO) (a) 4D plot output from Modde Go 12. Pyridine (ligand) and catalyst loadings are plotted on the vertical and horizontal axis respectively. The three windows, from right to left, represent an increasing amount of substrate (10–30 µmol). (c) Reaction conditions and radiochemical conversions of the optimized CMRF synthesis of [18F]pFBC.
Figure 7
Figure 7
The investigated factors and their ranges of the Box Behnken response surface optimization design for the synthesis of [18F]pFBnOH ([18F]6) from p-tributyltin-benzyl alcohol (5). The BBD arranges the experimental points on the edges of the reaction space cube and can be thought of as a combination of three 2D full factorial designs (performed at 90° to each other) with shared center points.
Figure 8
Figure 8
The response surface output from the Box Behnken response surface optimization of [18F]6.
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References

    1. van der Born D, et al. Fluorine-18 labelled building blocks for PET tracer synthesis. Chem. Soc. Rev. 2017;46:4709–4773. doi: 10.1039/C6CS00492J. - DOI - PubMed
    1. Brooks AF, Topczewski JJ, Ichiishi N, Sanford MS, Scott PJH. Late-stage [18F]fluorination: New solutions to old problems. Chem. Sci. 2014;5:4545–4553. doi: 10.1039/C4SC02099E. - DOI - PMC - PubMed
    1. Campbell MG, et al. Bridging the gaps in 18F PET tracer development. Nat. Chem. 2016;9:1–3. doi: 10.1038/nchem.2693. - DOI - PubMed
    1. Miller PW, Long NJ, Vilar R, Gee AD. Synthesis of 11 C, 18 F, 15 O, and 13 N Radiolabels for Positron Emission Tomography. Angew. Chemie Int. Ed. 2008;47:8998–9033. doi: 10.1002/anie.200800222. - DOI - PubMed
    1. Campbell MG, Ritter T. Modern carbon-fluorine bond forming reactions for aryl fluoride synthesis. Chem. Rev. 2015;115:612–633. doi: 10.1021/cr500366b. - DOI - PubMed

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