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The reactions of (trans-2-phenylcyclopropyl) ethyne, (trans,trans-2-methoxy-3-phenylcyclopropyl) ethyne, and (trans,trans-2-methoxy-1-methyl-3-phenylcyclopropyl) ethyne, with either aqueous sulfuric acid or tris (trimethylsilyl) silane or AIBN are investigated. Protonation and addition of the silyl radical occurred at the terminal position of the alkyne giving an alpha-cyclopropyl-substituted vinyl cation or radical, respectively.

A novel Nazarov reaction is described in which 2-chloro-3-silyloxypentadienyl cations capable of electrocyclization are generated from easily available dichlorocyclopropane precursors, as an alternative method for generation of Nazarov-type pentadienyl systems which may permit novel trapping pathways or greater functional group compatibility. Examples are presented of an apparent sequential 2pi electrocyclic opening/4pi electrocyclic closure using alkenyldichlorocyclopropanes as pentadienyl cation precursors.

Abstract: Introduction: Several clinical studies have shown low or no expression of GLUT1 in breast cancer patients, which may account for the low clinical specificity and sensitivity of 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) used in positron emission tomography (PET). Therefore, it has been proposed that other tumor characteristics such as the high expression of GLUT2 and GLUT5 in many breast tumors could be used to develop alternative strategies to detect breast cancer. Here we have studied the in vitro and in vivo radiopharmacological profile of 6-deoxy-6-[18F]fluoro-d-fructose (6-[18F]FDF) as a potential PET radiotracer to image GLUT5 expression in breast cancers. Methods: Uptake of 6-[18F]FDF was studied in murine EMT-6 and human MCF-7 breast cancer cells over 60 min and compared to [18F]FDG. Biodistribution of 6-[18F]FDF was determined in BALB/c mice. Tumor uptake was studied with dynamic small animal PET in EMT-6 tumor-bearing BALB/c mice and human xenograft MCF-7 tumor-bearing NIH-III mice in comparison to [18F]FDG. 6-[18F]FDF metabolism was investigated in mouse blood and urine. Results: 6-[18F]FDF is taken up by EMT-6 and MCF-7 breast tumor cells independent of extracellular glucose levels but dependent on the extracellular concentration of fructose. After 60 min, 30±4% (n=9) and 12±1% (n=7) ID/mg protein 6-[18F]FDF was found in EMT-6 and MCF-7 cells, respectively. 6-deoxy-6-fluoro-d-fructose had a 10-fold higher potency than fructose to inhibit 6-[18F]FDF uptake into EMT-6 cells. Biodistribution in normal mice revealed radioactivity uptake in bone and brain. Radioactivity was accumulated in EMT-6 tumors reaching 3.65±0.30% ID/g (n=3) at 5 min post injection and decreasing to 1.75±0.03% ID/g (n=3) at 120 min post injection. Dynamic small animal PET showed significantly lower radioactivity uptake after 15 min post injection in MCF-7 tumors [standard uptake value (SUV)=0.76±0.05; n=3] compared to EMT-6 tumors (SUV=1.23±0.09; n=3). Interestingly, [18F]FDG uptake was significantly different in MCF-7 tumors (SUV15 min 0.74±0.12 to SUV120 min 0.80±0.15; n=3) versus EMT-6 tumors (SUV 15 min 1.01±0.33 to SUV 120 min 1.80±0.25; n=3). 6-[18F]FDF was shown to be a substrate for recombinant human ketohexokinase, and it was metabolized rapidly in vivo. Conclusion: Based on the GLUT5 specific transport and phosphorylation by ketohexokinase, 6-[18F]FDF may represent a novel radiotracer for PET imaging of GLUT5 and ketohexokinase-expressing tumors. [Copyright &y& Elsevier]