Pyrrolovesamicols—Synthesis, structure and VAChT binding of two 4-fluorobenzoyl regioisomers

Wenzel, Barbara; Li, Yan; Kraus, Werner; Sorger, Dietlind; Sabri, Osama; Brust, Peter; Steinbach, Jörg

Pyrrolovesamicols—Synthesis, structure and VAChT binding of two 4-fluorobenzoyl regioisomers

2012

This Letter describes the synthesis of two regioisomers of a new class of vesamicol analogs as possible ligands for imaging the vesicular acetylcholine transporter in future PET studies. The two pyrrolovesamicols (±)-6a and (±)-6b were synthesized by nucleophilic ring opening reaction of a tetrahydroindole epoxide precursor with 4-phenylpiperidine. The reaction mechanism of the synthesis was studied by HPLC and the molecular structures were determined by X-ray structure analysis. Unexpected low binding affinities to VAChT (Kᵢ=312±73nM for (±)-6a and Kᵢ=7320±1840nM for (±)-6b) were determined by competitive binding analysis using a cell line stably transfected with ratVAChT and (−)-[³H]vesamicol.

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