Department of Oncology, University of Alberta-Cross Cancer Institute, Edmonton, AB-T6G 1Z2, Canada.
Nucl Med Biol. 2011 May;38(4):461-75. doi: 10.1016/j.nucmedbio.2010.11.004. Epub 2011 Feb 4.
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.
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.
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.
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.
几项临床研究表明，乳腺癌患者 GLUT1 的表达水平较低或为阴性，这可能导致 2-脱氧-2-[(18)F]氟-D-葡萄糖 ([(18)F]FDG) 在正电子发射断层扫描 (PET) 中的临床特异性和敏感性较低。因此，有人提出，其他肿瘤特征，如许多乳腺癌中 GLUT2 和 GLUT5 的高表达，可以用来开发替代策略来检测乳腺癌。在这里，我们研究了 6-脱氧-6-[(18)F]氟-D-果糖 (6-[(18)F]FDF) 作为潜在的 PET 放射性示踪剂，用于检测 GLUT5 在乳腺癌中的表达。
在 60 分钟内研究了 [(18)F]FDG 在鼠 EMT-6 和人 MCF-7 乳腺癌细胞中的摄取情况，并与 [(18)F]FDG 进行了比较。在 BALB/c 小鼠中测定了 6-[(18)F]FDF 的生物分布。在 EMT-6 荷瘤 BALB/c 小鼠和人异种 MCF-7 荷瘤 NIH-III 小鼠中，通过小动物 PET 动态研究了肿瘤摄取情况，并与 [(18)F]FDG 进行了比较。研究了 6-[(18)F]FDF 在小鼠血液和尿液中的代谢情况。
6-[(18)F]FDF 可被 EMT-6 和 MCF-7 乳腺癌细胞摄取，与细胞外葡萄糖水平无关，但依赖于细胞外果糖浓度。60 分钟后，在 EMT-6 和 MCF-7 细胞中分别发现 30±4% (n=9)和 12±1% (n=7) ID/mg 蛋白的 6-[(18)F]FDF。6-脱氧-6-氟-D-果糖对 EMT-6 细胞摄取 6-[(18)F]FDF 的抑制作用比果糖强 10 倍。正常小鼠的生物分布显示骨骼和大脑有放射性摄取。放射性在 EMT-6 肿瘤中积累，在注射后 5 分钟达到 3.65±0.30% ID/g (n=3)，在注射后 120 分钟降至 1.75±0.03% ID/g (n=3)。小动物 PET 显示，在注射后 15 分钟，MCF-7 肿瘤中的放射性摄取明显低于 EMT-6 肿瘤[标准摄取值 (SUV)=0.76±0.05；n=3]。有趣的是，与 EMT-6 肿瘤 (SUV(15 min)=0.74±0.12 至 SUV(120 min)=0.80±0.15；n=3)相比，MCF-7 肿瘤中的 [(18)F]FDG 摄取差异显著 (SUV(15 min)=0.74±0.12 至 SUV(120 min)=0.80±0.15；n=3)。6-[(18)F]FDF 被证明是重组人酮己糖激酶的底物，在体内代谢迅速。
基于 GLUT5 的特异性转运和酮己糖激酶的磷酸化，6-[(18)F]FDF 可能代表一种用于检测 GLUT5 和酮己糖激酶表达肿瘤的新型 PET 放射性示踪剂。
