title: Synthesis and biological evaluation of 3-alkyl-dihydrotetrabenazine derivatives as vesicular monoamine transporter-2 (VMAT2) ligands.
abstract: In the search of new probes for in vivo brain imaging of vesicular monoamine transporter type 2 (VMAT2), we have developed an efficient synthesis of a novel series of 3-alkyl-dihydrotetrabenazine (DTBZ) derivatives. The affinity of VMAT2 was evaluated by an in vitro inhibitory binding assay using [(125)I]-iodovinyl-TBZ or [(18)F](+)-FP-DTBZ as radioligands in rat striatal tissue homogenates. New DTBZ derivatives exhibited moderate to good binding affinity to VMAT2. Among these new ligands, compound 4b showed the best affinity for VMAT2 (K(i)=5.98 nM) and may be a useful lead compound for future structure-activity studies.
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Pinguan
authors.initials: P
authors.lastname: Zheng
authors.forename: Brian P
authors.initials: BP
authors.lastname: Lieberman
authors.forename: Seok Rye
authors.initials: SR
authors.lastname: Choi
authors.forename: Karl
authors.initials: K
authors.lastname: Plöessl
authors.forename: Hank F
authors.initials: HF
authors.lastname: Kung
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D003952:Diagnostic Imaging; D005462:Fluorine Radioisotopes; D008024:Ligands; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D051381:Rats; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D050493:Vesicular Monoamine Transport Proteins / Q000737:chemistry*
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D013747:Tetrabenazine