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\begin{document}

\title{Exploring Radiochemical Spaces: Optimizing Copper~ Mediated
Radiofluorinations using the Design of Experiments (DoE)
Approach~~~~~~~~}



\author[1]{SRSTT Radiopharmaconnect}%
\affil[1]{Radiopharmaconnect}%


\vspace{-1em}



  
  \date{April 20, 2024}


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\textbf{\href{https://www.srsweb.org/cafachem2020}{CAFACHEM~2020}}
organizers are grateful for the support of
\textbf{\href{www.gehealthcare.co.uk/products/molecular-imaging/pet-radiopharmacy/chemistry--systems}{}\href{https://www.gehealthcare.co.uk/products/molecular-imaging/pet-radiopharmacy/chemistry--systems}{GE
Healthcare}}\selectlanguage{english}
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\textbf{Authors:} \textbf{Gregory D.
Bowden}\textsuperscript{\textbf{1}}, Nantanat
Chailanggar\textsuperscript{1}, Bernd J. Pichler\textsuperscript{1,2},
Andreas Maurer\textsuperscript{1,2}

\textsuperscript{1}Werner Siemens Imaging Center, Department of
Preclinical Imaging and Radiopharmacy, Eberhard Karls University,
T\selectlanguage{ngerman}übingen, Germany

\textsuperscript{2}iFIT-Cluster of Excellence, Eberhard Karls
University, Tübingen, Germany

\par\null

\textbf{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).\textsuperscript{1} ~

\textbf{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.\textsuperscript{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.

\par\null

\textbf{Methods}

\emph{Experimental matrices for each DoE study were designed and
analyzed using MODDE Go 12 (Umetrics) software.} \textsuperscript{18}F
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.

\par\null

\textbf{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.

\par\null

\textbf{References}

\textbf{1.} \emph{Bowden, G. D., Pichler, B. J. \& Maurer, A. A Design
of Experiments (DoE) Approach Accelerates the Optimization of
Copper-Mediated} \textsuperscript{\emph{18}}\emph{F-Fluorination
Reactions of Arylstannanes. Sci. Rep. \textbf{9}, 11370 (2019)}

\textbf{2.} \emph{Makaravage, K. J., Brooks, A. F., Mossine, A. V.,
Sanford, M. S. \& Scott, P. J. H. H. Copper-Mediated Radiofluorination
of Arylstannanes with {[}}\textsuperscript{\emph{18}}\emph{F{]}KF. Org.
Lett. \textbf{18}, 5440--5443 (2016)}

\textbf{3.} \emph{Mossine, A. V et al. Synthesis of
{[}}\textsuperscript{\emph{18}}\emph{F{]}Arenes via the Copper-Mediated
{[}}\textsuperscript{\emph{18}}\emph{F{]}Fluorination of Boronic Acids.
Org. Lett. \textbf{17}, 5780--5783 (2015).}

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