[18F]Fluoroform - a versatile building block for PET tracer synthesis

Fluorine-18 (half-life: 110 min) is a popular radionuclide for positron emission tomography (PET), a functional imaging technique that non-invasively visualizes biochemical processes in vivo. It can be introduced into tracer molecules via fluorine-18 labelled building blocks. [18F]Fluoroform is a building block that has received much interest in recent years and is used to introduce radioactive CF3 groups into the tracer molecules. However, shortcomings of [18F]fluoroform, such as the low molar activities typically obtained and the limited 18F-trifluoromethylation strategies available, hampered its use in PET tracer synthesis so far. The aim of this thesis was therefore to address these shortcomings and develop [18F]fluoroform into a useful building block for PET tracer synthesis. In Chapter 1 a general introduction into the topic is provided, discussing the basic concepts of positron emission tomography, different radionuclides and radiofluorination strategies. Furthermore, the building block [18F]fluoroform is introduced. Chapter 2 gives a comprehensive overview of the fluorine-18 labelled building blocks used in PET tracer synthesis from 2010-2016. The overview comprises aromatic and aliphatic building blocks, including [18F]fluoroform. Chapter 3 reports the development of a new method to obtain reactive [18F]fluoride omitting the commonly used azeotropic drying procedures. For this method, hydrated [18F]fluoride was reacted with a bistriflate precursor to form gaseous [18F]triflyl fluoride. The [18F]triflyl fluoride was distilled into a dry organic solvent containing base and cryptand, where it was converted to free [18F]fluoride. Besides being fast, reliable, and high-yielding, this novel method offers high flexibility in the subsequent radiofluorination reaction, particularly enabling the reduction of base and cryptand amounts. Chapter 4 describes the optimization of the [18F]fluoroform synthesis towards a high molar activity procedure. Stability studies with the labelling precursor difluoroiodomethane showed that difluoroiodomethane was unstable under the basic radiofluorination conditions, probably causing the low molar activity typically observed with [18F]fluoroform. By reducing the amount of base and cryptand 100-fold compared to standard radiofluorination conditions the stability of difluoroiodomethane and the molar activity of [18F]fluoroform could be drastically improved. Radiochemical yields of around 40% and molar activities close to 100 GBq/µmol were obtained. The optimized synthesis procedure was automated on a commercially available synthesizer to enhance applicability and facilitate the use in other PET centres. In chapter 5 a novel precursor for the synthesis of [18F]fluoroform is presented, 1-(difluoromethyl)-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium triflate. It was investigated whether this precursor could provide [18F]fluoroform with even higher molar activities than difluoroiodomethane. It was found that also for this precursor reduction of base and cryptand amounts led to increased precursor stability and high molar activities of [18F]fluoroform. Especially in the automated synthesis the triazolium precursor provided [18F]fluoroform with some of the highest molar activities observed so far (~150 GBq/µmol). Chapter 6 reports the first synthesis and application of fluorine-18 labelled Ruppert-Prakash reagent ([18F]Me3SiCF3) as 18F-trifluoromethylation agent. [18F]Me3SiCF3 was synthesized by reaction of [18F]fluoroform with trimethylsilyl chloride and obtained with radiochemical yields of 85-95% and radiochemical purities of >95%. It was reacted in a simple model reaction with a range of aromatic aldehydes and ketones and proved good reactivity as well as a complementary substrate scope to previously reported methods. Chapter 7 describes the development and evaluation of the new tracer [18F]cinacalcet for the localization of overactive parathyroid glands for surgery. [18F]Cinacalcet was synthesized using the optimized [18F]fluoroform procedure described in chapter 4, followed by aromatic 18F-trifluoromethylation of a boronic acid precursor. [18F]Cinacalcet was obtained with an overall radiochemical yield of 8±4% and a molar activity of 40±11 GBq/µmol within 1 hour (n=7,dc). A biodistribution and metabolite study was performed in healthy rats, showing decent uptake in the parathyroid glands and fast blood metabolism. Chapter 8 gives a short summary and outlook.