Novel PET/SPECT Probes for Imaging of Tau in Alzheimer’s Disease

Watanabe, Hiroyuki; Ono, Masahiro; Saji, Hideo

doi:10.1155/2015/124192

Cited by 18 publications

(16 citation statements)

References 44 publications

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“…The radiosynthesis included three stages: 1) labeling reaction; 2) purification; and 3) formulation. We employed more reactive [ 11 C]CH 3 OTf, instead of commonly used [ 11 C]methyl iodide ([ 11 C]CH 3 I), 31 3 I confirmed this result. The labeling reaction was conducted using a V-vial method.…”

supporting

confidence: 60%

“…Alzheimer's disease (AD) is the most common form of dementia and affects over 30 million people worldwide, and there are no reliable disease-modifying therapies at present. [1][2][3][4] Currently, the cause of AD remains unclear and no any effective strategy is approved for preventing, curing and slowing the progress of AD. [5][6][7] To discover more effective treatments, a reliable diagnostic tool is really needed.…”

mentioning

confidence: 99%

“…39 In summary, synthetic routes with moderate to high yields have been developed to produce isonicotinamide precursors and reference standards, and carbon-11labeled isonicotinamides. The radiosynthesis employed [ 11 C]CH 3 OTf for O-[ 11 C]methylation at the pyridinyl hydroxyl or phenyl hydroxyl position of the desmethyl precursor, followed by product purification and isolation using a semi-preparative RP HPLC combined with SPE. The carbon-11-labeled isonicotinamides were obtained in high radiochemical yield, radiochemical purity and chemical purity, with a reasonably short overall synthesis time, and high specific activity.…”

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confidence: 99%

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Synthesis of carbon-11-labeled isonicotinamides as new potential PET agents for imaging of GSK-3 enzyme in Alzheimer’s disease

Gao

Wang

Zheng

2017

Bioorganic & Medicinal Chemistry Letters

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The authentic standards 2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide (4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide (7a), and their corresponding precursors 2-(cyclopropanecarboxamido)-N-(4-hydroxypyridin-3-yl)isonicotinamide (4b) and 2-(cyclopropanecarboxamido)-N-(4-(4-hydroxyphenyl)pyridin-3-yl)isonicotinamide (7b) were synthesized from methyl 2-aminoisonicotinate and cyclopropanecarbonyl chloride with overall chemical yield 47% in three steps, 22% in four steps, 40% in three steps, and 17% in four steps, respectively. The target tracers 2-(cyclopropanecarboxamido)-N-(4-[C]methoxypyridin-3-yl)isonicotinamide ([C]4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-[C]methoxyphenyl)pyridin-3-yl)isonicotinamide ([C]7a) were prepared from the precursors (4b and 7b) with [C]CHOTf through O-[C]methylation and isolated by HPLC combined with SPE in 40-50% radiochemical yield, based on [C]CO and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370-1110GBq/μmol with a total synthesis time of ∼40-min from EOB.

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confidence: 60%

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confidence: 99%

mentioning

confidence: 99%

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Synthesis of carbon-11-labeled isonicotinamides as new potential PET agents for imaging of GSK-3 enzyme in Alzheimer’s disease

Gao

Wang

Zheng

2017

Bioorganic & Medicinal Chemistry Letters

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“…Synthesis of N-desmethyl-PBB3 (7) and TBS-protected Ndesmethyl-PBB3 (8). 2 . This is a 1-pot-2-step radiosynthesis.…”

Section: The Synthesis Of Precursorsmentioning

confidence: 99%

Synthesis of a PET tau tracer [11C]PBB3 for imaging of Alzheimer’s disease

Wang

Gao

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Abstract-The authentic standard PBB3 and its precursor N-desmethyl-PBB3 as well as TBS-protected N-desmethyl-PBB3 precursor for radiolabeling were synthesized from 5-bromo-2-nitropyridine, acrolein diethyl acetal, 6-methoxy-2-methylbenzothiazole, and diethylchlorophosphate with overall chemical yield 1% in six steps, 2% in five steps, and 1% in six steps, respectively. [11 C]PBB3 was prepared from either desmethyl-PBB3 or TBS-protected desmethyl-PBB3 with [11 C]CH 3 OTf through N-[ 11 C]methylation and isolated by HPLC combined with SPE in 20-25% and 15-20% radiochemical yield, respectively, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/mol with a total synthesis time of ~40-minutes from EOB.

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“…Novel probes with the ability to reveal early tau tangles or Aβ-aggregates are being developed for positron emission tomography, these probes and the characterization of CSF biomarkers are the main tools currently available for making an early diagnosis (de Souza et al 2014, Watanabe, Ono, andSaji 2015).…”

Section: Therapeutic Strategies In Clinical Trialsmentioning

confidence: 99%

Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems

Domert¹

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Every year is getting shorter, never seem to find the time Plans that either come to naught or half a page of scribbled lines Hanging on in quiet desperation is the research wayThe time is gone, the thesis over, thought I'd something more to say The general aim of this thesis was to investigate mechanisms associated with neurotoxic peptide activity by Aβ, tau and α-syn in relation to cellular degradation and transfer with a cell-to-cell transfer model system.We found that intercellular transfer of oligomeric Aβ occurs independently of isoform. However, the amount of transfer correlates with each isoforms ability to resist degradation or cellular clearance. The Aβ1-42 isoform showed particular resistance to clearance, which resulted in higher levels of cell-to-cell transfer of the isoform and lysosomal stress caused by accumulation.As Aβ accumulations can inhibit the proteasomal degradation we investigated how reduced proteasomal degradation affected neuron-like cells. We found increased levels of phosphorylated tau protein, disturbed microtubule stability and impaired neuritic transport after reduced proteasomal activity. These changes was partly linked to c-Jun and ERK 1/2 kinase activity.We could also show that α-syn transferred from cell-to-cell in our model system, with a higher degree of transfer for the larger oligomer and fibrillar species. Similar to Aβ, α-syn mainly colocalized with lysosomes, before and after transfer.Lastly, we have developed our cell-to-cell transfer system into a model suitable for high throughput screening (HTS). The type of cells have been upgraded from SH-SY5Y cells to induced pluripotent stem cells (iPSCs), with a differentiation profile more similar to mature neurons. The next step will be screening a small molecular library for substances with inhibitory effect on cell-to-cell transfer of Aβ peptides.The importance of the degradative systems in maintaining protein homeostasis and prevent toxic accumulations in general is well known. Our findings shows the importance of these systems for neurodegenerative diseases and also highlight the link between degradation and cell-to-cell transfer. To restore or enhance the degradative systems would be an interesting avenue to treat neurodegenerative diseases. Another way would be to inhibit the transfer of misfolded protein aggregates. By using the HTS model we developed, a candidate substance with good inhibitory effect on transfer can hopefully be found. Om det går att stoppa överföringen av skadliga proteinansamlingar mellan nervcellerna, är det förmodligen möjligt att bromsa upp sjukdomsutvecklingen av t.ex. Alzheimers sjukdom. Genom att utveckla vårt cellulära modellsystem och anpassa det till ett högkapacitets-screening format, har vi möjliggjort för att testa tiotusentals substanser för att hitta molekyler vilka kan bromsa eller stoppa den cellulära överföringen av beta-amyloid-ansamlingar.

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Novel PET/SPECT Probes for Imaging of Tau in Alzheimer’s Disease

Cited by 18 publications

References 44 publications

Synthesis of carbon-11-labeled isonicotinamides as new potential PET agents for imaging of GSK-3 enzyme in Alzheimer’s disease

Synthesis of carbon-11-labeled isonicotinamides as new potential PET agents for imaging of GSK-3 enzyme in Alzheimer’s disease

Synthesis of a PET tau tracer [11C]PBB3 for imaging of Alzheimer’s disease

Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems

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