Synthesis of a series of VAChT ligands as basis for the development of ¹⁸F-labelled radiotracers for imaging in brain

The department of Neuroradiopharmaceuticals is part of the Helmholtz-Zentrum Dresden-Rossendorf and deals with the development of radiotracers for brain research using positron emission tomography (PET).
Those tracers are ligands labelled with radioactive isotopes which bind to selected biomolecules in brain. Due to this specific binding it is possible to visualise neurotransmission processes in living organisms. For the development of such ligands it is necessary to synthesise various organic compounds and to determine their in-vitro binding affinity to the desired biological target. Afterwards, a promising candidate is selected for labelling with a short-lived radioactive nuclide such as fluorine-18.
The vesicular acetylcholine transporter (VAChT) is located in cholinergic areas in brain and is an interesting target for the in-vivo imaging of neuronal deficits as observed in Alzheimer’s disease. It is known that vesamicol (2-(4-phenylpiperidin-1-yl)cyclohexanol) acts as a high-potential inhibitor for this transporter and thus represents the chemical lead for the development of VAChT-radioligands. The aim of our studies is to develop a selective ligand by varying the vesamicol-skeleton in a systematic manner at its’ three ring structures and determining the binding profile of the resulting derivatives. These in-vitro data are correlated with the various chemical structures leading to a three dimensional computational model, a so-called quantitative structure affinity relationship (QSAR). Based on those results, we will be able to find a promising candidate for radiolabelling studies and further investigations.