Tina N. Grant

Nazarov reactions of vinyl cyclopropylamines: an approach to the imino-Nazarov problem.

Dichlorocyclopropanation of 2-amino-1,3-dienes affords 1-alkenyl-1-amino-2,2-dichlorocyclopropanes which undergo silver-assisted 2-π electrocyclic opening to furnish 3-aminopentadienyl cations. Nazarov-type cyclization of these intermediates leads to cyclopentenone iminium salts, which provide allylic amines upon reduction. This process, the imino version of the traditional Nazarov reaction, can also be combined with an interrupted Nazarov domino process to give polycyclic amines.

Radiopharmacological evaluation of 6-deoxy-6-[18F]fluoro-D-fructose as a radiotracer for PET imaging of GLUT5 in breast cancer.

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-[(18)F]fluoro-D-glucose ([(18)F]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-[(18)F]fluoro-D-fructose (6-[(18)F]FDF) as a potential PET radiotracer to image GLUT5 expression in breast cancers. METHODS Uptake of 6-[(18)F]FDF was studied in murine EMT-6 and human MCF-7 breast cancer cells over 60 min and compared to [(18)F]FDG. Biodistribution of 6-[(18)F]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 [(18)F]FDG. 6-[(18)F]FDF metabolism was investigated in mouse blood and urine. RESULTS 6-[(18)F]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-[(18)F]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-[(18)F]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, [(18)F]FDG uptake was significantly different in MCF-7 tumors (SUV(15 min) 0.74±0.12 to SUV(120 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-[(18)F]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-[(18)F]FDF may represent a novel radiotracer for PET imaging of GLUT5 and ketohexokinase-expressing tumors.

Synthesis and characterization of 6-deoxy-6-fluoro-d-fructose as a potential compound for imaging breast cancer with PET

FDG-based imaging with positron emission tomography (PET) has been widely used in the detection of cancer, but has not reached its full potential. In breast cancer, the glucose/fructose transporter GLUT2 and the fructose transporter GLUT5 are known to be overexpressed in transformed tissues, implicating that a fructose-based analogue would be a useful target for the improved imaging of breast cancer. We have successfully synthesized the fluorinated fructose compound, 6-deoxy-6-fluoro-D-fructose (6FDF) and examined its potential for transport and accumulation in breast cancer cells. Expression analysis of GLUT isoforms was performed on two GLUT5 expressing breast cancer cell lines using western blotting and immunocytochemistry. Uptake and inhibition studies were undertaken using [14C]-labelled hexoses. Transport inhibition studies showed dose dependent inhibition of fructose transport in both cell lines by the newly synthesized 6-deoxy-6-fluoro-D-fructose (6FDF). Also, near linear uptake over time of [14C]-labelled 6FDF was observed in both cell lines. It appears that 6FDF may have great promise for use in in vivo PET imaging of breast cancer. Ongoing work will confirm the efficacy of this compound in imaging in mouse models.

Ring expansion of lactones and lactams via propiolate 1-carbon intercalation.

Readily available five- and six-membered lactones and N-sulfonyllactams undergo efficient addition of t-butyl propiolate, and the resulting adducts undergo cycloisomerization to six- and seven-membered cyclic ethers or amines in the presence of pyridinium acetate. The ring expansion process occurs in generally good yields and is proposed to involve a nucleophilic catalysis mechanism.