Abstract
There is an unmet need for late-stage 18F-fluorination strategies to label molecules with a wide range of relevant functionalities to medicinal chemistry, in particular (hetero)arenes, aiming to obtain unique in vivo information on the pharmacokinetics/pharmacodynamics (PK/PD) using positron emission tomography (PET). In the last few years, Cu-mediated oxidative radiofluorination of arylboronic esters/acids arose and has been successful in small molecules containing relatively simple (hetero)aromatic groups. However, this technique is sparsely used in the radiosynthesis of clinically significant molecules containing more complex backbones with several aromatic motifs. In this work, we add a new entry to this very limited database by presenting our recent results on the 18F-fluorination of an arylboronic ester derivative of atorvastatin. The moderate average conversion of [18F]F− (12%), in line with what has been reported for similarly complex molecules, stressed an overview through the literature to understand the radiolabeling variables and limitations preventing consistently higher yields. Nevertheless, the current disparity of procedures reported still hampers a consensual and conclusive output.
Highlights
Being already a clinically established molecular imaging modality, positron emission tomography (PET) increasingly broadened its application field by becoming an essential partner of the pharmaceutical industry [1,2]
Cu‐catalyzed strategy when compared of this radiolabeling strategy, we present and discuss one of the most complex labeling precursor previous simple drug‐like molecules or even to the majority of the molecules reported in the scaffolds that have been submitted to Cu-catalyzed radiofluorination
This late-stage Cu-mediated radiofluorination strategy has already shown to be very dependent of the type and complexity of the labeling precursor used, and very sensitive to all the processes associated with the method–from the additives used to enable
Summary
Being already a clinically established molecular imaging modality, positron emission tomography (PET) increasingly broadened its application field by becoming an essential partner of the pharmaceutical industry [1,2]. The radionuclide should be added to the desired molecular structure causing as little disturbance as possible, especially in the vicinity of the active site(s), and at the latest possible stage in the process to avoid radiation loss and exposure. Radiochemistry found an unparalleled ally in nucleophilic substitution reactions with [18 F]F− [3,4]. This became more challenging when the focus fell on the labeling of (hetero)arenes that are not reactive to aromatic nucleophilic substitutions. The ubiquitous role of heteroaromatic pharmacophores in drug development and medicinal chemistry stressed out the need for improved radiofluorination techniques to overcome the typically far-from-ideal electrophilic fluorination with carrier-added [18 F]F2. Several methods have been published aiming for a practical, transversal, and straightforward 18 F-fluorination of electron-rich, -poor, and –neutral
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