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. H… Show more
“…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).…”
The σ2 receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ2 receptors in cancer cells and tissue in combination with the antiproliferative potency of σ2 receptor ligands motivates the research in the field of σ2 receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. RM273 (2-[4-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with 18F and evaluation regarding detection of σ2 receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [18F]RM273 in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ2 receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ2 receptor ligand [18F]RM273 has potential to assess by non-invasive molecular imaging the correlation between the availability of σ2 receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.
“…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).…”
The σ2 receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ2 receptors in cancer cells and tissue in combination with the antiproliferative potency of σ2 receptor ligands motivates the research in the field of σ2 receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. RM273 (2-[4-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with 18F and evaluation regarding detection of σ2 receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [18F]RM273 in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ2 receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ2 receptor ligand [18F]RM273 has potential to assess by non-invasive molecular imaging the correlation between the availability of σ2 receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.
“…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.…”
18 F]β-CFT is a positron emission tomography (PET) ligand for imaging of dopamine transporter. It was proved to be a sensitive PET marker to detect presynaptic dopaminergic hypofunction in Parkinson's disease. In recent years, copper-mediated 18 F-fluorination of aryl boronic esters has been successful in some molecules containing aromatic groups. In this study, we describe the novel synthetic strategy of [ 18 F]β-CFT by copper-mediated nucleophilic radiofluorination with pinacol-derived aryl boronic esters upon reaction with [ 18 F] KF/K 222 and Cu (OTf) 2 (py) 4 . The radiolabeling protocol was optimized with [ 18 F]fluoride elution method and amount of copper catalyst used. [ 18 F]β-CFT is obtained from boronic ester precursors in 2.2% to 10.6% non-isolated radiochemical yield (RCY). Purified [ 18 F]β-CFT with >99% radiochemical purity (RCP) and high molar activity was obtained in validation runs. The radiolabeling procedure is straightforward and can easily be adapted for clinical use.
“…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.…”
Section: Accessing New Pet Radiotracers With Copper-mediated Radioflumentioning
confidence: 99%
“…[ 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.…”
Section: Highlighted By Cristóbal De Los Ríosmentioning
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...]
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