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

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.

Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant 18F-Labelled σ2 Receptor Ligand

“…The manual conditions were transferred to an automated synthesis module ( Figure S1, Supporting Information ). Particularly for copper-mediated radiofluorinations, this transfer is difficult due to the inert atmosphere in which those automated devices are operated, the usually higher basic environment employed for the elution of [ 18 F]fluoride, the order of addition of reagents, and other factors thoroughly explored elsewhere [ 34 , 42 ]. Starting with activities ranging from 2–13 GBq, [ 18 F] RM273 was successfully obtained with a radiochemical yield of 8.1 ± 1.6%, high radiochemical purity (≥99%), and molar activity of about 69–233 GBq/μmol in a total synthesis time of about 60 min ( n = 3).…”

Copper‐mediated nucleophilic radiofluorination of [18F]β‐CFT for positron emission tomography imaging of dopamine transporter

“…For reaction solvent, better conversion efficacies have been reported when dimethylacetamide (DMA) was used for replacement of DMF. 58,60,61 The reasons were proposed to be its higher boiling point and base resistant property. The importance of addition order of various reactants/reagents and dissolution of dried [ 18 F]KF were also demonstrated in previous study.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…Recently however, copper-mediated radiofluorination (CMRF) has greatly expanded the chemical space accessible for labeling with 18 F [65]. Reflecting on this, Elsinga recently employed CMRF to synthesize [ 18 F]atorvastatin from a pinacol boronate ester (BPin) precursor (Figure 9) [66]. As one of the most complex substrates labeled with CMRF to date, the work highlights important potentialities and limitations of CMRF going forward.…”

“…[ 18 F]atorvastatin from a pinacol boronate ester (BPin) precursor (Figure 9) [66]. As one of the most complex substrates labeled with CMRF to date, the work highlights important potentialities and limitations of CMRF going forward.…”