Synthesis and preliminary biological evaluations of [18F]-1-deoxy-1-fluoro-scyllo-inositol

Vasdev, Neil; Chio, Jason; Oosten, Erik M. van; Nitz, Mark; McLaurin, JoAnne; Vines, Douglass; Houle, Sylvain; Reilly, Raymond M.; Wilson, Alan A.

doi:10.1039/b913317h

Cited by 20 publications

(21 citation statements)

References 15 publications

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“…Scyllo-inositol labeled with fluorine-18 [ 18 F] gave promising results in specifically binding CAA in vitro but it did not penetrate blood-brain barrier in small animal models. 43 Resorufin (a phenoxazine derivative) and multidentate 18 F-polypegylated styrylpyridines showed preferential binding of cerebrovascular Aβ deposits over neuritic plaques in vitro but they have not been shown to cross blood-brain barrier in vivo. 44,45 More recently, 99m…”

Section: Challenges and Future Directionsmentioning

confidence: 99%

Molecular Neuroimaging in Vascular Cognitive Impairment

Gurol

2016

Stroke

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Section: Challenges and Future Directionsmentioning

confidence: 99%

Molecular Neuroimaging in Vascular Cognitive Impairment

Gurol

2016

Stroke

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“…Briefly, compounds 1 and 2 can be produced in a three-step procedure from myo-inositol. 24 The triflate is readily displaced with azide to give compound 14. Removal of the protecting groups from compound 14 with 95% TFA gave the azide derivative 16.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Aβ(1-42) Assembly in the Presence of scyllo-Inositol Derivatives: Identification of an Oxime Linkage as Important for the Development of Assembly Inhibitors

Shaw

Chio²,

Dasgupta³

et al. 2012

ACS Chem. Neurosci.

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To identify a lead skeleton structure for optimization of scyllo-inositol-based inhibitors of amyloid-beta peptide (Aβ) aggregation, we have synthesized aldoxime, hydroxamate, carbamate, and amide linked scyllo-inositol derivatives. These structures represent backbones that can be readily expanded into a wide array of derivatives. They also provide conservative modifications of the scyllo-inositol backbone, as they maintain the display of the equatorial polar atoms, preserving the stereochemical requirement necessary for maximum inhibition of Aβ(1-42) fiber formation. In addition, a reliable work plan for screening derivatives was developed in order to preferentially identify a backbone(s) structure that prevents fibrillogenesis and stabilizes nontoxic small molecular weight oligomers, as we have previously reported for scyllo-inositol. In the present studies, we have adapted a high throughput ELISA-based oligomerization assay followed by atomic force microscopy to validate the results screen compounds. The lead compounds were then tested for toxicity and ability to rescue Aβ(1-42) induced toxicity in vitro and the affinity of the compounds for Aβ(1-42) compared by mass spectrometry. The data to suggest that compounds must maintain a planar conformation to exhibit activity similar to scyllo-inositol and that the oxime derivative represents the lead backbone for future development. KEYWORDS: Amyloid-beta peptide, fibrillogenesis, medicinal chemistry, atomic force microscopy, mass spectrometry scyllo-Inositol, a potential therapeutic compound for Alzheimer's disease, has been shown to inhibit Aβ(1-42) fibrillogenesis in vitro, 1 stabilize cell-derived small molecular weight oligomers, 2 reduce amyloid plaque load and neuroinflammation, and ameliorate cognitive deficits in vivo. 2,3 These combined studies demonstrated that scyllo-inositol stabilizes low molecular weight oligomers of Aβ that are nontoxic and readily removed from and/or degraded within the central nervous system. scyllo-Inositol is the most potent inositol, with a single epimerization to form myo-inositol yielding a less active compound in vivo and in vitro, suggesting that efficacy is highly dependent on inhibitor stereochemistry. 3 scyllo-Inositolinduced changes to the peptide assembly of Aβ(1-42) are very sensitive to structural perturbations of scyllo-inositol such as the number and orientation of the hydroxyl groups. 2 These structure− function studies revealed that even the most conservative single hydroxyl substitution led to a decrease in compound potency with only 1-deoxy-1-fluoro-scyllo-inositol retaining properties similar to the parent scyllo-inositol. 4

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“…[74] However, cancer cells injected into the cranium are able to take up [ 18 F]-1-deoxy-1-fluoro-scyllo-inositol to a five-fold greater extent than the surrounding brain tissue. [75] In a human breast cancer model [ 18 F]-1-deoxy-1-fluoro-scyllo-inositol is taken up to a lesser extent than [ 18 F]-2-deoxy-2-fluoromyo-inositol.…”

Section: Scyllo-inositol and Diagnosticsmentioning

confidence: 99%

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

2015

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Cell signalling via inositol phosphates, eg the second messenger myo-inositol 1,4,5-trisphosphate, and phosphoinositides comprises a huge field of biology. Of nine 1,2,3,4,5,6-cyclohexanehexol isomers, myo-inositol is pre-eminent, with "other" inositols (cis-, epi-, allo-, muco-, neo-, L-chiro-, D-chiro-and scyllo-) and derivatives rarer or thought not to exist in nature. However, recently, neoand D-chiro-inositol hexakisphosphates were revealed in both terrestrial and aquatic ecosystems, highlighting the paucity of knowledge of the origins and potential biological functions of such stereoisomers, a prevalent group of environmental organic phosphates, and their parent inositols. Some "other" inositols are medically relevant, e.g. scyllo-inositol (neurodegenerative diseases), and D-chiro-inositol (diabetes). It is timely to consider exploration of roles and applications of "other" isomers and their derivatives, likely by exploiting techniques now well developed for the myo-series.

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Synthesis and preliminary biological evaluations of [18F]-1-deoxy-1-fluoro-scyllo-inositol

Abstract: A novel PET radiotracer, [18F]-1-deoxy-1-fluoro-scyllo-inositol, was synthesized via a one-pot reaction in 16 +/- 3% uncorrected radiochemical yield within 80 minutes; although this compound revealed low brain penetration it shows promise in rodent tumour models for breast cancer imaging.

Cited by 20 publications

References 15 publications

Molecular Neuroimaging in Vascular Cognitive Impairment

Molecular Neuroimaging in Vascular Cognitive Impairment

Aβ(1-42) Assembly in the Presence of scyllo-Inositol Derivatives: Identification of an Oxime Linkage as Important for the Development of Assembly Inhibitors

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

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