BACR10
Development of [18F]Fluoro-[1,2-2H4]choline as a new PET imaging probe
Graham Smith1, Yongjun Zhao1, Julius Leyton1, Bo Shan1, Quang-de Nguyen1, Meg Perumal1, David Turton2, Erik Årstad2, Sajinder K Luthra2, Edward G Robins2, Eric O Aboagye2
1Comprehensive Cancer Imaging Centre, Faculty of Medicine, Imperial College London, London, UK, 2MDx Discovery (part of GE Healthcare) at Hammersmith Imanet Ltd, Hammersmith Hospital, London, UK
Background
Choline is a quaternary ammonium salt and essential nutrient that is phosphorylated by choline kinase and then incorporated into the cell membrane via the Kennedy pathway. Alteration in choline uptake and choline kinase activity, and hence phosphoryl choline levels, are associated with malignant cell transformation and, as a result, choline kinase activity represents a potential biomarker for diagnostic use in oncology. The PET analogue of endogenous choline, [11C]choline, was examined as a putative radiotracer for PET imaging, demonstrating utility as a tumour imaging marker for use in tissues such as brain and prostate, for which [18F]FDG imaging is less attractive due to high background uptake. The short half-life of carbon-11 (t½ = 20.1 min.) limits [11C]choline utilisation to centres with an on-site cyclotron. Therefore, fluorine-18 radiolabelled choline analogues have found recent interest. In order to further develop the choline scaffold we reasoned that isotopic substitution (deuterium for hydrogen) on the ethyl alcohol portion of choline would yield a radiotracer with increased metabolic stability.
Method
18F]Fluorocholine and [18F]fluoro-[1,2-2H4]choline were synthesized by alkylation of the relevant precursor with [18F]fluorobromomethane or [18F]fluoromethyl tosylate. Radiosynthesis of [18F]fluoromethyl tosylate required extensive modification of the existing method. The two radiotracers were then subjected to comparison in both in vitro and in vivo stability models. Finally, [18F]fluoro-[1,2-2H4]choline was evaluated in a time course biodistribution study in RIF-1 tumour bearing mice.
Results
Alkylation with [18F]fluoromethyltosylate proved to be the most reliable radiosynthetic route. Stability models indicated that [18F]fluoro-[1,2-2H4]choline possesses increased oxidative stability relative to [18F]fluorocholine. With the exception of reduced kidney and lung radioactivity levels, the biodistribution of [18F]fluoro-[1,2-2H4]choline in tumour bearing mice showed a comparable distribution profile to that previously reported for [18F]fluorocholine.
Conclusion
Stability analysis and biodistribution suggest that [18F]fluoro-[1,2-2H4]choline warrants further in vivo investigation as a PET probe of choline kinase activity.
