Automated radiosynthesis of [ 11 C]L-deprenyl-D 2 and [ 11 C]D-deprenyl using a commercial platform

Buccino, Pablo; Kreimerman, Ingrid; Zirbesegger, Kevin; Porcal, Williams; Savio, Eduardo; Engler, Henry

doi:10.1016/j.apradiso.2015.12.051

Cited by 12 publications

(12 citation statements)

References 15 publications

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“…The methylating agent [ 11 C]CH 3 I was produced in an automated module TRACERlab FX C Pro according to the method described. 32 Briefly (Figure 3A), the first step of the procedure was the production of [ 11 C]CO 2 in the cyclotron via the 14 N(p, α) 11 C nuclear reaction. [ 11 C]CO 2 was delivered from the target to the module where it was trapped for purification and further reduction to [ 11 C]CH 4 using a nickel catalyst at 400 °C.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer’s Disease: ¹¹C-Synthesis and In Vivo Proof of Concept

et al. 2021

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Herein we present the evaluation of 11C-labeled-maleimides as radiotracers for positron emission tomography imaging of GSK-3 associated with Alzheimer′s disease (AD). 3-Acetyl-4-(1-[11C]-methyl-1H-indol-3-yl)[1H]pyrrole-2,5-dione ([11C]-2) was obtained by direct methylation using [11C]-CH3I and Cs2CO3 in DMF with a 31 ± 4% radiochemical yield and a radiochemical purity of 97.7 ± 0.8%. [11C]-2 was stable both in its final formulation and in human plasma for 120 min and had a plasma protein binding of 70 ± 1% and a LogD7.4 value of 1.84 ± 0.04. [11C]-2 ex vivo biodistributions in healthy animals demonstrated significant brain uptake and retention, showing its ability to penetrate the intact blood–brain barrier. In vivo PET imaging in mice bearing AD showed, with respect to normal animals, significant differences in uptake in the hypothalamus, the striatum, and the amygdala and a significant increase in amygdala uptake in later stages of the pathology. These results are very promising, and further studies are being performed for a complete validation of this compound as novel tracer for AD.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer’s Disease: ¹¹C-Synthesis and In Vivo Proof of Concept

et al. 2021

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“…We have recently described the fully automated synthesis of [ 11 C]D-deprenyl tracer by one-step N -alkylation with [ 11 C]MeOTf using the commercially platform GE TRACERlab® FX C Pro (Scheme 4 ) (Buccino et al 2016 ). This methodology initially provided us great potential of [ 11 C]MeOTf for reducing the amount of precursor and synthesis time, as well as for increasing radiochemical yields and reproducibility.…”

Section: Resultsmentioning

confidence: 99%

“…Because of these results, in the present work we proposed the use of the precursor L-nordeprenyl-D 2 as free base for its labelling with [ 11 C]MeOTf. Using the commercially available hydrochloride salt of L-nordeprenyl-D 2 , (Buccino et al 2016 ), the overall radiochemical yield was 24 ± 9% ( n = 10) (end of synthesis, decay corrected from [ 11 C]MeI), but it increased to 44 ± 13% ( n = 12) with the employment of the L-nordeprenyl-D 2 free base (yields are referred to [ 11 C]MeI, even when [ 11 C]MeOTf is the radioactive precursor in the labelling reaction; TRACERlab®FX C Pro allows to measure activities of [ 11 C]MeI but not those of [ 11 C]MeOTf). The use of the aqueous NaOH to neutralize the hydrochloride salt is no longer necessary, and losses of radioactivity in the form of [ 11 C]MeOH (possible product of hydrolysis of the radioactive precursor [ 11 C]MeOTf) are diminished.…”

Section: Resultsmentioning

confidence: 99%

An efficient preparation of labelling precursor of [11C]L-deprenyl-D2 and automated radiosynthesis

Zirbesegger

Buccino

Kreimerman

et al. 2017

EJNMMI radiopharm. chem.

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BackgroundThe synthesis of [11C]L-deprenyl-D2 for imaging of astrocytosis with positron emission tomography (PET) in neurodegenerative diseases has been previously reported. [11C]L-deprenyl-D2 radiosynthesis requires a precursor, L-nordeprenyl-D2, which has been previously synthesized from L-amphetamine as starting material with low overall yields. Here, we present an efficient synthesis of L-nordeprenyl-D2 organic precursor as free base and automated radiosynthesis of [11C]L-deprenyl-D2 for PET imaging of astrocytosis. The L-nordeprenyl-D2 precursor was synthesized from the easily commercial available and cheap reagent L-phenylalanine in five steps. Next, N-alkylation of L-nordeprenyl-D2 free base with [11C]MeOTf was optimized using the automated commercial platform GE TRACERlab® FX C Pro.ResultsA simple and efficient synthesis of L-nordeprenyl-D2 precursor of [11C]L-deprenyl-D2 as free base has been developed in five synthetic steps with an overall yield of 33%. The precursor as free base has been stable for 9 months stored at low temperature (−20 °C). The labelled product was obtained with 44 ± 13% (n = 12) (end of synthesis, decay corrected) radiochemical yield from [11C]MeI after 35 min synthesis time. The radiochemical purity was over 99% in all cases and specific activity was (170 ± 116) GBq/μmol.ConclusionsA high-yield synthesis of [11C]L-deprenyl-D2 has been achieved with high purity and specific activity. L-nordeprenyl-D2 precursor as free amine was applicable for automated production in a commercial synthesis module for preclinical and clinical application.

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“…[ 11 C]DED was synthesized according to the method previously reported by our group (Buccino et al, 2016). [ 11 C]CH 3 OTf was bubbled into the organic precursor solution to react with 1 mg of the precursor nor-DED.HCl in 350 μL butanone (MEK) for 1 min at 80°C.…”

Section: Methodsmentioning

confidence: 99%

Biological Assessment of a 18F-Labeled Sulforhodamine 101 in a Mouse Model of Alzheimer’s Disease as a Potential Astrocytosis Marker

et al. 2019

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Neurodegenerative diseases have mainly been associated with neuronal death. Recent investigations have shown that astroglia may modulate neuroinflammation in the early and late stages of the disease. [ 11 C]Deuterodeprenyl ([ 11 C]DED) is a tracer that has been used for reactive astrocyte detection in Alzheimer’s disease, Creutzfeldt–Jakob disease and amyotrophic lateral sclerosis, among others, with some limitations. To develop a new radiotracer for detecting astrocytosis and overcoming associated difficulties, we recently reported the synthesis of a sulfonamide derivative of Sulforhodamine 101 (SR101), labeled with 18 F, namely SR101 N -(3-[ 18 F]Fluoropropyl) sulfonamide ([ 18 F]2B-SRF101). The red fluorescent dye SR101 has been used as a specific marker of astroglia in the neocortex of rodents using in vivo models. In the present work we performed a biological characterisation of the new tracer including biodistribution and micro-PET/computed tomography (CT) images. PET/CT studies with [ 11 C]DED were also done to compare with [ 18 F]2B-SRF101 in order to assess its potential as an astrocyte marker. Biodistribution studies with [ 18 F]2B-SRF101 were carried out in C57BL6J black and transgenic (3xTg) mice. A hepatointestinal metabolization as well as the pharmacokinetic profile were determined, showing appropriate characteristics to become a PET diagnostic agent. Dynamic PET/CT studies were carried out with [ 18 F]2B-SRF101 and [ 11 C]DED to evaluate the distribution of both tracers in the brain. A significant difference in [ 18 F]2B-SRF101 uptake was especially observed in the cortex and hippocampus, and it was higher in 3xTg mice than it was in the control group. These results suggested that [ 18 F]2B-SRF101 is a promising candidate for more extensive evaluation as an astrocyte tracer. The difference observed for [ 18 F]2B-SRF101 was not found in the case of [ 11 C]DED. The comparative studies between [ 18 F]2B-SRF101 and [ 11 C]DED suggest that both tracers have different roles as astrocytosis markers in this animal model, and could provide different and complementary information at the same time. In this way, by means of a multitracer approach, useful information could be obtained for the staging of the disease.

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Automated radiosynthesis of [ 11 C]L-deprenyl-D 2 and [ 11 C]D-deprenyl using a commercial platform

Cited by 12 publications

References 15 publications

Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer’s Disease: ¹¹C-Synthesis and In Vivo Proof of Concept

Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer’s Disease: ¹¹C-Synthesis and In Vivo Proof of Concept

An efficient preparation of labelling precursor of [11C]L-deprenyl-D2 and automated radiosynthesis

Biological Assessment of a 18F-Labeled Sulforhodamine 101 in a Mouse Model of Alzheimer’s Disease as a Potential Astrocytosis Marker

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Automated radiosynthesis of [ 11 C]L-deprenyl-D 2 and [ 11 C]D-deprenyl using a commercial platform

Cited by 12 publications

References 15 publications

Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer’s Disease: 11C-Synthesis and In Vivo Proof of Concept

Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer’s Disease: 11C-Synthesis and In Vivo Proof of Concept

An efficient preparation of labelling precursor of [11C]L-deprenyl-D2 and automated radiosynthesis

Biological Assessment of a 18F-Labeled Sulforhodamine 101 in a Mouse Model of Alzheimer’s Disease as a Potential Astrocytosis Marker

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Product

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Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer’s Disease: ¹¹C-Synthesis and In Vivo Proof of Concept

Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer’s Disease: ¹¹C-Synthesis and In Vivo Proof of Concept