New systematically modified vesamicol analogs and their affinity and selectivity for the vesicular acetylcholine transporter – A critical examination of the lead structure

• Synthesis of four series of vesamicol analogs modified in ring A, B, and C.
• Determination of their in vitro binding affinity toward VAChT as well as σ1 and σ2 receptors.
• Comparison and discussion of different methods for determination of VAChT affinity.
• SAR study with regard to both affinity and selectivity as basis for the development of PET radioligands for VAChT.

To verify vesamicol as lead structure in the development of radioligands for imaging of VAChT in the brain by PET, we systematically modified this molecule and investigated four different groups of derivatives. Structural changes were conducted in all three ring systems A, B, and C resulting in a library of different vesamicol analogs. Based on their in vitro binding affinity toward VAChT as well as σ1 and σ2 receptors, we performed a structure-affinity relationship (SAR) study regarding both affinity and selectivity. The compounds possessed VAChT affinities in the range of 1.32 nM (benzovesamicol) to >10 μM and selectivity factors from 0.1 to 73 regarding σ1 and σ2 receptors, respectively. We could confirm the exceptional position of benzovesamicols as most affine VAChT ligands. However, we also observed that most of the compounds with high VAChT affinity demonstrated considerable affinity in particular to the σ1 receptor. Finally, none of the various vesamicol analogs in all four groups showed an in vitro binding profile suitable for specific VAChT imaging in the brain.

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