Nucleophilic Substitution Reactions for Positron Emission Tomography; Factors Influencing the Reactivity of [18F]Fluoride

Abstract

Clinical use of positron emission tomography (PET) is expanding from use of [18F]FDG to a wider spectrum of PET-tracers and proprietary PET radiopharmaceuticals. The development of new PET-tracers is however far from trivial and the radiochemistry is a major limiting factor. Nucleophilic substitution reactions with [18F]fluoride generally suffer from inconsistent labeling yields. There is a need to investigate the generic impurities causing such inconsistency in order to build more robust syntheses that also are in line with regulatory demands for approval of new PET radiopharmaceuticals. The aim of this thesis was to investigate how pharmaceutical-chemical impurities from a typical synthesis setup may influence labeling yields in nucleophilic substitution reactions with [18F]fluoride. Following areas were studied: Borosilicate glassware, Kryptofix based eluent solutions, anion-exchange cartridges, and irradiated [18O]water. Materials and methods The new commercial synthesizer, GE FASTlab™, was used as an investigational platform using three different benchmark reactions: [18F]FACBC, [18F]FDG and [18F]Flutemetamol. The importance of identified impurities was investigated with radiochemical yield as the measured response. Eluent solutions of K222, K2CO3 in aqueous acetonitrile extracted ppm levels of silicon, boron and aluminum if stored in borosilicate glass at room temperature (days). It was revealed that relevant levels of aluminum present in the eluent solution (0.4–2 ppm) could pass a polymer-based anion-exchange cartridge and cause detrimental effects on the RCY. Calcium, magnesium, zinc and aluminum were identified as potential impurities in irradiated [18O]water. Aluminum, if present in the [18O]water, was fully adsorbed on the anion-exchange cartridge and to a variable degree co-eluted with [18F]fluoride, causing detrimental effect on the RCY. Type of anion-exchange cartridge was a major determining factor for the amount of eluted aluminum. Eluent solutions containing K222 and K2CO3 in aqueous acetonitrile degraded relatively quickly when stored at room temperature or above. Acetate, one of the degradation products would negatively affect RCY if generated at sufficient levels (hundreds of ppm). A methanol-based eluent solution was successfully developed, showing no degradation after 6 months of storage at 50 oC.