title: Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter.
abstract: Nine fluorine-containing vesicular acetylcholine transporter (VAChT) inhibitors were synthesized and screened as potential PET tracers for imaging the VAChT. Compound 18a was one of the most promising carbonyl-containing benzovesamicol analogs; the minus enantiomer, (-)-18a displayed high potency (VAChT Ki=0.59 ± 0.06 nM) and high selectivity for VAChT versus σ receptors (>10,000-fold). The radiosynthesis of (-)-[(18)F]18a was accomplished by a two-step procedure with 30-40% radiochemical yield. Preliminary biodistribution studies of (-)-[(18)F]18a in adult male Sprague-Dawley rats at 5, 30, 60 and 120 min post-injection (p.i.) were promising. The total brain uptake of (-)-[(18)F]18a was 0.684%ID/g at 5 min p.i. and by 120 min p.i. slowly washed out to 0.409 %ID/g; evaluation of regional brain uptake showed stable levels of ∼0.800 %ID/g from 5 to 120 min p.i in the VAChT-enriched striatal tissue of rats, indicating the tracer had crossed the blood brain barrier and was retained in the striatum. Subsequent microPET brain imaging studies of (-)-[(18)F]18a in nonhuman primates (NHPs) showed high striatal accumulation in the NHP brain; the standardized uptake value (SUV) for striatum reached a maximum value of 5.1 at 15 min p.i. The time-activity curve for the target striatal region displayed a slow and gradual decreasing trend 15 min after injection, while clearance of the radioactivity from the cerebellar reference region was much more rapid. Pretreatment of NHPs with 0.25mg/kg of the VAChT inhibitor (-)-vesamicol resulted in a ∼90% decrease of striatal uptake compared to baseline studies. HPLC metabolite analysis of NHP plasma revealed that (-)-[(18)F]18a had a good in vivo stability. Together, these preliminary results suggest (-)-[(18)F]18a is a promising PET tracer candidate for imaging VAChT in the brain of living subjects.
authors.affiliation: Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA. Electronic address: tuz@mir.wustl.edu.
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
authors.forename: Xuyi
authors.initials: X
authors.lastname: Yue
authors.affiliation: Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
authors.forename: Prashanth K
authors.initials: PK
authors.lastname: Padakanti
authors.affiliation: Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
authors.forename: Lihai
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
authors.forename: Hubert P
authors.initials: HP
authors.lastname: Flores
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA.
authors.forename: Kota
authors.initials: K
authors.lastname: Kaneshige
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Parsons
authors.affiliation: Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
mesh_terms: D000818:Animals; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D008297:Male; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D050494:Vesicular Acetylcholine Transport Proteins
keywords: F-18; PET tracer; Striatum; VAChT; Vesamicol