title: Synthesis of novel 4- and 5-substituted benzyl ether derivatives of vesamicol and in vitro evaluation of their binding properties to the vesicular acetylcholine transporter site.
abstract: Detection of the central cholinergic deficits, a consistent feature of Alzheimer's disease, is essential to allow preventive measures and/or symptomatic treatment already at a very early stage of the disease. The vesicular acetylcholine transporter (VAChT) represents an appropriate target to establish PET radiotracer that are adequate for brain imaging the loss of cholinergic terminals. Here we describe the synthesis and binding characteristics of novel derivatives of vesamicol, known to represent a specific antagonist of VAChT sites. Novel benzyl ether derivatives of vesamicol either 4- or 5-substituted at the cyclohexylring have been synthesized by different regioselective ring opening reactions of a same epoxide precursor. The affinity and selectivity of the novel compounds to VAChT sites were analyzed by competitive radioligand binding studies in rat brain and liver membrane preparations using tritium labeled radioligands. The 4-substituted fluorobenzylether of vesamicol 10b was shown to exhibit a high affinity to VAChT sites (K(i)-value(10b)=10.7+/-1.7 nM), but demonstrated also binding capacities to sigma receptors (K(i-)value(10b)=18.5+/-6.9 nM, [(3)H]DTG; K(i)-value(10b)=30.6+/-9.6 nM, [(3)H]haloperidol). The data suggest the potential of vesamicol derivatives to design appropriate radiotracer for PET imaging of central cholinergic deficits.
authors.affiliation: Institut für Interdisziplinäre Isotopenforschung, Permoserstr. 15, 04318 Leipzig, Germany. scheunemann@iif-leipzig.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.forename: Dietlind
authors.initials: D
authors.lastname: Sorger
authors.forename: Barbara
authors.initials: B
authors.lastname: Wenzel
authors.forename: Katrin
authors.initials: K
authors.lastname: Heinitz
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schliebs
authors.forename: Margrit
authors.initials: M
authors.lastname: Klingner
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004986:Ether; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D026901:Membrane Transport Proteins; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D026901:Membrane Transport Proteins; D010880:Piperidines; D017480:Receptors, sigma; C493461:Slc18a3 protein, rat; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D004986:Ether; C006189:vesamicol