title: Synthesis and in vitro and in vivo evaluation of 18F-labeled positron emission tomography (PET) ligands for imaging the vesicular acetylcholine transporter.
abstract: A new class of vesicular acetylcholine transporter inhibitor that incorporates a carbonyl group into the benzovesamicol structure was synthesized, and analogues were evaluated in vitro. (+/-)-trans-2-Hydroxy-3-(4-(4-[(18)F]fluorobenzoyl)piperidino)tetralin (9e) has K(i) values of 2.70 nM for VAChT, 191 nM for sigma(1), and 251 nM for sigma(2). The racemic precursor (9d) was resolved via chiral HPLC, and (+/-)-[(18)F]9e, (-)-[(18)F]9e, and (+)-[(18)F]9e were respectively radiolabeled via microwave irradiation of the appropriate precursors with [(18)F]/F(-) and Kryptofix/K(2)CO(3) in DMSO with radiochemical yields of approximately 50-60% and specific activities of >2000 mCi/micromol. (-)-[(18)F]9e uptake in rat brain was consistent with in vivo selectivity for the VAChT with an initial uptake of 0.911 %ID/g in rat striatum and a striatum/cerebellum ratio of 1.88 at 30 min postinjection (p.i.). MicroPET imaging of macaques demonstrated a 2.1 ratio of (-)-[(18)F]9e in putamen versus cerebellum at 2 h p.i. (-)-[(18)F]9e has potential to be a PET tracer for clinical imaging of the VAChT.
authors.affiliation: Division of Radiological Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA. tuz@mir.wustl.edu
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.forename: Simon M N
authors.initials: SM
authors.lastname: Efange
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.forename: Shihong
authors.initials: S
authors.lastname: Li
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Jones
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Parsons
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D005462:Fluorine Radioisotopes; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014101:Torpedo; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism*
chemical_list: C550361:2-hydroxy-3-(4-(4-fluorobenzoyl)piperidino)tetralin; D005462:Fluorine Radioisotopes; D008024:Ligands; D010880:Piperidines; D019275:Radiopharmaceuticals; D013764:Tetrahydronaphthalenes; D050494:Vesicular Acetylcholine Transport Proteins