Towards synthesis and characterisation of [18F]DPA-714 for positron emission tomography imaging of the 18-kDa translocator protein (TSPO) in the brain

Abstract

The imaging and tracing processes for a series of particular diseases are highly required for unmet need in clinical research. Positron emission tomography (PET) has been used as a non invasive imaging modality to measure biochemical processes in vivo. To achieve this goal, the active compounds are labelled with radioisotopes and incorporate with the small molecule of interest. Among all the radionuclides, fluorine-18 is a preferred PET nuclide for radiopharmaceutical chemistry. The translocator protein (TSPO, 18 kDa) is a five transmembrane domain protein which is expressed in the variety of tissues throughout the body but increasing expression has been reported which coincides with the process of microglia activation, therefore, TSPO has been identified as a valuable biomarker in neuroinflammation studies. As a pyrazolopyrimidine ligand, [ 18F]DPA-714 shows high specific activity to evaluate the expression of TSPO in neuroinflammatory processes. This thesis describes the synthesis of cold reaction of DPA-714, in the meantime, the derivates of DPA-714 which are prepared for radiolabelling are also achieved. Moreover, the development of radiolabelling protocols of [ 18F]DPA-714 by using Neptis Perform™ has also been completed for the further research. Finally, the direct fluorination method has been explored to avoid the need for an activated precursor. The drug-likeness of fluorination on benzylic position of DPA-713 has been evaluated by SeeSAR and SwissADME. Meanwhile, we found that manganese catalysts, such as Mn(salen)Cl and Mn(salen)OTs give the improved possibility to achieve the benzylic fluorination. N N R NEt2 O Me N Me R = OCH3, DPA-713 R = OCH2CH2 F, DPA-714 benzylic position IV Declaration The work described in this thesis was carried out under the supervi