Bansal Aditya, Shuyan Wang, Hara Toshiko, Harris Robert A, Degrado Timothy R
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Eur J Nucl Med Mol Imaging. 2008 Jun;35(6):1192-203. doi: 10.1007/s00259-008-0736-y. Epub 2008 Feb 9.
[(18)F]Fluorocholine ([(18)F]FCH) was developed as an analog of [(11)C]choline for tumor imaging; however, its metabolic handling remains ill defined. In this study, the metabolism of [(18)F]FCH is evaluated in cultured 9L glioma cells and Fisher 344 rats bearing 9L glioma tumors.
9L glioma cells were incubated with [(18)F]FCH and [(14)C]choline under normoxic and hypoxic (1% O(2)) conditions and analyzed for metabolic fate. [(18)F]FCH and [(14)C]choline kinetics and metabolism were studied in Fisher 344 rats bearing subcutaneous 9L tumors.
[(18)F]FCH and [(14)C]choline were similarly metabolized in 9L cells in both normoxic and hypoxic conditions over a 2-h incubation period. In normoxia, radioactivity was predominantly in phosphorylated form for both tracers after 5-min incubation. In hypoxia, the tracers remained mainly in nonmetabolized form at early timepoints (<20 min). Slow dephosphorylation of intracellular [(18)F]phosphofluorocholine (0.043-0.060 min(-1)) and [(14)C]phosphocholine (0.072-0.088 min(-1)) was evidenced via efflux measurements. In rat, both [(18)F]FCH and [(14)C]choline showed high renal and hepatic uptake. Blood clearance of both tracers was rapid with oxidative metabolites, [(18)F]fluorobetaine and [(14)C]betaine, representing the majority of radiolabel in plasma after 5 min postinjection. Oxidation (in liver) and lipid incorporation (in lung) were somewhat slower for [(18)F]FCH relative to [(14)C]choline. The majority of radiolabel in hypoxic subcutaneous tumor, as in hypoxic cultured 9L cells, was found as nonmetabolized [(18)F]FCH and [(14)C]choline.
[(18)F]FCH mimics choline uptake and metabolism by 9L glioma cells and tumors. However, subtle changes in biodistribution, oxidative metabolism, dephosphorylation, lipid incorporation, and renal excretion show moderate effects of the presence of the radiofluorine atom in [(18)F]FCH. The decrease in phosphorylation of exogenous choline by cancer cells should be considered in interpretation of positron emission tomography images in characteristically hypoxic tumors.
[（18）F]氟胆碱（[（18）F]FCH）作为[（11）C]胆碱的类似物被开发用于肿瘤成像；然而，其代谢过程仍不明确。在本研究中，对[（18）F]FCH在培养的9L胶质瘤细胞和荷9L胶质瘤肿瘤的Fisher 344大鼠中的代谢进行了评估。
将9L胶质瘤细胞在常氧和低氧（1% O₂）条件下与[（18）F]FCH和[（14）C]胆碱一起孵育，并分析其代谢去向。在荷皮下9L肿瘤的Fisher 344大鼠中研究了[（18）F]FCH和[（14）C]胆碱的动力学及代谢情况。
在2小时的孵育期内，[（18）F]FCH和[（14）C]胆碱在常氧和低氧条件下于9L细胞中的代谢情况相似。在常氧条件下，孵育5分钟后两种示踪剂的放射性主要以磷酸化形式存在。在低氧条件下，示踪剂在早期时间点（<20分钟）主要以未代谢形式存在。通过流出测量证明细胞内[（18）F]氟磷酸胆碱（0.043 - 0.060分钟⁻¹）和[（14）C]磷酸胆碱（0.072 - 0.088分钟⁻¹）的去磷酸化缓慢。在大鼠中，[（18）F]FCH和[（14）C]胆碱均显示出高肾摄取和肝摄取。两种示踪剂的血液清除迅速，氧化代谢产物[（18）F]氟甜菜碱和[（14）C]甜菜碱在注射后5分钟时占血浆中放射性标记的大部分。相对于[（14）C]胆碱，[（18）F]FCH在肝脏中的氧化和在肺中的脂质掺入稍慢。与低氧培养的9L细胞一样，低氧皮下肿瘤中的大部分放射性标记物为未代谢的[（18）F]FCH和[（14）C]胆碱。
[（18）F]FCH模拟9L胶质瘤细胞和肿瘤对胆碱的摄取和代谢。然而，生物分布、氧化代谢、去磷酸化、脂质掺入和肾脏排泄的细微变化表明[（18）F]FCH中放射性氟原子的存在有中度影响。在解释典型低氧肿瘤的正电子发射断层扫描图像时，应考虑癌细胞对外源胆碱磷酸化的降低。
