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

Abstract

Recent advancements in 18 F 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 18 F PET tracer synthesis.

High-field superconductivity in C-doped MgB2 bulk samples prepared by a rapid synthesis route

“…The Design of Experiment (DoE) is a statistical tool used to determine the effects of experimental factors on a desired output in a system. It offers a set of advantages over the traditional one-variable-at-a-time approach since it can help to resolve parameter interactions and provide detailed maps of the system behavior 30 . We used two types of DoE in this work.…”

“…The main properties of the samples prepared in the frame of the screening DoE are reported in Table 1 . Based on this preliminary investigation, we performed a Response-Surface-Methodology (RSM) DoE, which is used to produce a detailed mathematical model of the process behavior as a function of the input variables 30 , 31 . The RSM DoE required the preparation of 26 samples, which were all investigated at the University of Geneva.…”

“…Samples SCR_1, SCR_6 and SCR_11 are three replicas of the DoE “center point”. Replicating the center point in a DoE provides a measure of process stability and reproducibility 30 . We found variations by ~ 1% for T C , ~ 40% for ΔT c. , ~ 2% for H Irr and ~ 4% for H C2 .…”

Late-Stage Copper-Catalyzed Radiofluorination of an Arylboronic Ester Derivative of Atorvastatin

“…From a review of the literature, it seems undeniable that the nature of the (hetero)arene labeling precursor plays a major role in the efficiency of 18 F-fluorination. The wise approach still seems to be to perform an individual “one variable at a time” optimization for each scaffold to be radiolabeled, despite the fact that this might ignore the influence of multifactorial interactions [46]. Thus, the search for more robust late-stage radiofluorination procedures compatible with suitable heteroaromatic pharmacophores remains a very stimulating topic that, ultimately, can lead not only to refined radiopharmaceutical drug discovery but also to aid the pharmaceutical industry to evaluate pharmacokinetics/dynamics and better understand certain mechanisms of action.…”

Guest Edited Collection: Radioisotopes and radiochemistry in health science

“…For instance, a new route to [ 18 F]fluoroform has been demonstrated 19 , where the trifluoromethyl synthon is formed in the gas phase by passing [ 18 F]fluoromethane over heated CoF 3 , one of the few binary phases that release elemental fluorine (F 2 ) upon heating. The introduction of new 18 F-labelled triazolyl-linked argininamides to target neuropeptides for the imaging of mammary carcinoma 20 serves as an apt example of click chemistry-based 18 F-labelling, and a Design of Experiments (DoE) approach has been reported to optimize copper-mediated radiofluorination 21 . The evaluation of new 18 F-labelled melanoma xenograft targeting peptides is the subject of an imaging study 22 that is also published as part of this Collection.…”