Radiosynthesis and pre-clinical evaluation of [18F]fluoro-[1,2-2H4]choline

Introduction: Choline radiotracers are widely used for clinical PET diagnosis in oncology. [C-11]Choline finds particular utility in the imaging of brain and prostate tumor metabolic status, where 2-[F-18]fluoro-2-deoxy-D-glucose ('FDG') shows high background uptake. More recently we have extended the clinical utility of [C-11]choline to breast cancer where radiotracer uptake correlates with tumor aggressiveness (grade). In the present study, a new choline analog, [F-18]fluoro-[1,2-H-2(4)]choline, was synthesized and evaluated as a potential PET imaging probe. Methods: [F-18]Fluorocholine, [F-18]fluoro-[1-H-2(2)]choline and [F-18]fluoro-[1,2-H-2(4)]choline were synthesized by alkylation of the relevant precursor with [F-18]fluorobromomethane or [F-18]fluoromethyl tosylate. Radiosynthesis of [F-18]fluoromethyl tosylate required extensive modification of the existing method. [F-18]Fluorocholine and [F-18]fluoro-[1,2-H-2(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, [F-18]fluoro-[1-H-2(2)]choline, were then evaluated in vivo in a time-course biodistribution study in HCT-116 tumor-bearing mice. Results: Alkylation with [F-18]fluoromethyl tosylate proved to be the most reliable radiosynthetic route. Stability models indicate that [F-18] fluoro-[1,2-H-2(4)]choline possesses increased chemical and enzymatic (choline oxidase) oxidative stability relative to [F-18]fluorocholine. The distribution of the three radiotracers, [F-18]fluorocholine, [F-18]fluoro-[1-H-2(2)]choline and [F-18]fluoro-[1,2-H-2(4)]choline, showed a similar uptake profile in most organs. Crucially, tumor uptake of [F-18]fluoro-[1,2-H-2(4)]choline was significantly increased at late time points compared to [F-18]fluorocholine and [F-18]fluoro-[1-H-2(2)]choline. Conclusions: Stability analysis and biodistribution suggest that [F-18]fluoro-[1,2-H-2(4)]choline warrants further in vivo investigation as a PET probe of choline metabolism. (C) 2011 Elsevier Inc. All rights reserved.