Synthesis of fluorine-18 labelled radiotracers and their pre-clinical and clinical characterization

Abstract

Positron emission tomography (PET) is one of the most sensitive in vivo imaging techniques available to clinicians and researchers. It helps in understanding the biological interactions and mechanism of various diseases through use of radiolabelled compounds called radiotracers. Herein is described the development of facile radiolabelling approaches for straightforward access to 18F-labelled trifluoromethyl radiotracers. Direct nucleophilic radiofluorination of difluorovinyl precursors was achieved for 18F-trifluoromethylation of aliphatic compounds, and applied to the radiosynthesis of [18F]lansoprazole and N-methyl[18F]lansoprazole. The compounds were used to analyze the blood-brain barrier penetration in healthy persons and for the detection of tau-neurofibrillary tangles in Alzheimer’s patients. For 18F-trifluoromethylation of aromatic compounds, in situ synthesis of Cu[18F]CF3 was achieved and used in 18F-trifluoromethylation of iodo-arenes using a single vial one-step method. The procedure was applied for radiosynthesis of a derivative of AH7921, which is a sub-type selective mu-opioid receptor agonist. The developed procedures are applicable to available radiosynthesis hardware, and provide access to desired compounds within 40 minutes in high radiochemical yields. In addition, a series of new compounds were synthesized with aim to discover the new radioligands based on modifications to the lead compounds i.e. lansoprazole and AH7921. Several interesting candidates with good combination of affinity and selectivity were identified from each series, and radiolabelled with fluorine-18. The newly developed 18F-labelled compounds have good potential to provide the in vivo characterization of tau-neurofibrillary tangles and quantification of the opioid receptors using the PET imaging.