Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter

Zhude Tu, Xiang Zhang, Hongjun Jin, Xuyi Yue, Prashanth K. Padakanti, Lihai Yu, Hui Liu, Hubert P. Flores, Kota Kaneshige, Stanley M. Parsons, Joel S. Perlmutter

Research output: Contribution to journalArticle

18 Scopus citations

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 (-)-[18F]18a was accomplished by a two-step procedure with 30-40% radiochemical yield. Preliminary biodistribution studies of (-)-[18F]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 (-)-[18F]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 (-)-[18F]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 0.25 mg/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 (-)-[18F]18a had a good in vivo stability. Together, these preliminary results suggest (-)-[18F]18a is a promising PET tracer candidate for imaging VAChT in the brain of living subjects.

Original languageEnglish
Pages (from-to)4699-4709
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number15
DOIs
StatePublished - Jul 23 2015

Keywords

  • F-18
  • PET tracer
  • Striatum
  • VAChT
  • Vesamicol

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