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.

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

Introduction-Organic Anion Transporting Polypeptides (OATP) are a family of membrane associated transporters that facilitate estrone-3-sulphate (E3S) uptake by hormone dependent, post-menopausal breast cancers. We have established E3S as a potential ligand for targeting hormone dependent breast cancer cells, and in this study sought to prepare and investigate radioiodinated E3S as a tool to study the OATP system. Methods-2-and 4-Iodoestrone-3-sulfates were prepared from estrone via aromatic iodination followed by a rapid and high yielding sulfation procedure. The resulting isomers were separated by preparative HPLC and verified by 1 H NMR and analytical HPLC. Transport studies of 2-and 4-[ 125 I]-E3S were conducted in hormone dependent (i.e. MCF-7) and hormone independent (i.e. MDA-MB-231) breast cancer cells in the presence or absence of the specific transport inhibitor, bromosulfophthalein (BSP). Cellular localization of OATP1A2, OATP2B1, OATP3A1 and OATP4A1 were determined by immunofluorescence analysis using anti-Na + /K + ATPase-α (1:100 dilution) and DAPI as plasma membrane and nuclear markers, respectively. Results-Significantly

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