Comprehensive Cancer Imaging Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
Nucl Med Biol. 2011 Jan;38(1):39-51. doi: 10.1016/j.nucmedbio.2010.06.012. Epub 2010 Sep 1.
Choline radiotracers are widely used for clinical PET diagnosis in oncology. [(11)C]Choline finds particular utility in the imaging of brain and prostate tumor metabolic status, where 2-[(18)F]fluoro-2-deoxy-D-glucose ('FDG') shows high background uptake. More recently we have extended the clinical utility of [(11)C]choline to breast cancer where radiotracer uptake correlates with tumor aggressiveness (grade). In the present study, a new choline analog, [(18)F]fluoro-[1,2-(2)H(4)]choline, was synthesized and evaluated as a potential PET imaging probe.
[(18)F]Fluorocholine, [(18)F]fluoro-[1-(2)H(2)]choline and [(18)F]fluoro-[1,2-(2)H(4)]choline were synthesized by alkylation of the relevant precursor with [(18)F]fluorobromomethane or [(18)F]fluoromethyl tosylate. Radiosynthesis of [(18)F]fluoromethyl tosylate required extensive modification of the existing method. [(18)F]Fluorocholine and [(18)F]fluoro-[1,2-(2)H(4)]choline were then subjected to in vitro oxidative stability analysis in a chemical oxidation model using potassium permanganate and an enzymatic model using choline oxidase. The two radiotracers, together with the corresponding di-deuterated compound, [(18)F]fluoro-[1-(2)H(2)]choline, were then evaluated in vivo in a time-course biodistribution study in HCT-116 tumor-bearing mice.
Alkylation with [(18)F]fluoromethyl tosylate proved to be the most reliable radiosynthetic route. Stability models indicate that [(18)F]fluoro-[1,2-(2)H(4)]choline possesses increased chemical and enzymatic (choline oxidase) oxidative stability relative to [(18)F]fluorocholine. The distribution of the three radiotracers, [(18)F]fluorocholine, [(18)F]fluoro-[1-(2)H(2)]choline and [(18)F]fluoro-[1,2-(2)H(4)]choline, showed a similar uptake profile in most organs. Crucially, tumor uptake of [(18)F]fluoro-[1,2-(2)H(4)]choline was significantly increased at late time points compared to [(18)F]fluorocholine and [(18)F]fluoro-[1-(2)H(2)]choline.
Stability analysis and biodistribution suggest that [(18)F]fluoro-[1,2-(2)H(4)]choline warrants further in vivo investigation as a PET probe of choline metabolism.
胆碱放射性示踪剂在肿瘤临床 PET 诊断中被广泛应用。[(11)C]胆碱在脑和前列腺肿瘤代谢状态的成像中具有特殊的作用，而 2-[(18)F]氟-2-脱氧-D-葡萄糖（'FDG'）显示出较高的背景摄取。最近，我们将[(11)C]胆碱的临床应用扩展到乳腺癌，其中放射性示踪剂的摄取与肿瘤侵袭性（分级）相关。在本研究中，我们合成了一种新的胆碱类似物[(18)F]氟-[1,2-(2)H(4)]胆碱，并将其评估为一种潜在的 PET 成像探针。
[(18)F]氟代胆碱、[(18)F]氟代-[1-(2)H(2)]胆碱和[(18)F]氟代-[1,2-(2)H(4)]胆碱是通过[(18)F]氟溴甲烷或[(18)F]氟甲基对甲苯磺酸与相应的前体物烷基化合成的。[(18)F]氟甲基对甲苯磺酸的放射性合成需要对现有的方法进行广泛的修改。然后，将[(18)F]氟代-[1,2-(2)H(4)]胆碱和[(18)F]氟代-[1-(2)H(2)]胆碱进行体外氧化稳定性分析，在化学氧化模型中使用高锰酸钾，在酶模型中使用胆碱氧化酶。然后，在 HCT-116 荷瘤小鼠的时间过程生物分布研究中，对这两种放射性示踪剂及其相应的双氘代化合物[(18)F]氟代-[1-(2)H(2)]胆碱进行了体内评价。
[(18)F]氟甲基对甲苯磺酸的烷基化被证明是最可靠的放射性合成途径。稳定性模型表明，[(18)F]氟代-[1,2-(2)H(4)]胆碱相对于[(18)F]氟代胆碱具有更高的化学和酶（胆碱氧化酶）氧化稳定性。三种放射性示踪剂[(18)F]氟代胆碱、[(18)F]氟代-[1-(2)H(2)]胆碱和[(18)F]氟代-[1,2-(2)H(4)]胆碱在大多数器官中的摄取模式相似。至关重要的是，与[(18)F]氟代胆碱和[(18)F]氟代-[1-(2)H(2)]胆碱相比，[(18)F]氟代-[1,2-(2)H(4)]胆碱在晚期时间点的肿瘤摄取显著增加。
稳定性分析和生物分布表明，[(18)F]氟代-[1,2-(2)H(4)]胆碱值得进一步进行体内研究，作为胆碱代谢的 PET 探针。
