title: (18)F-FECNT: validation as PET dopamine transporter ligand in parkinsonism.
abstract: The positron emission tomography (PET) tracer 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)-nortropane ((18)F-FECNT) is a highly specific ligand for dopamine transporter (DAT) that yields higher peak striatum-to-cerebellum ratios and offers more favorable kinetics than most (18)F-radiolabeled DAT ligands currently available. The goal of this study is to validate the use of (18)F-FECNT as a PET radiotracer to assess the degree of striatal dopamine terminals denervation and midbrain dopaminergic cell loss in MPTP-treated parkinsonian monkeys. Three rhesus monkeys received weekly injections of MPTP (0.2-0.5 mg/kg) for 21 weeks, which resulted in the progressive development of a moderate level of parkinsonism. We carried out (18)F-FECNT PET at baseline (twice; 10 weeks apart) and at week 21 post-MPTP injections. Postmortem stereological cell counts of dopaminergic neurons in the ventral midbrain, and intensity measurements of DAT and tyrosine hydroxylase (TH) immunoreactivity in the striatum were performed and correlated with striatal and ventral midbrain PET data. Three additional monkeys were used as controls for midbrain dopaminergic cell counts, and striatal DAT or TH immunoreactivity measurements. The correlation and coefficient of variance between (18)F-FECNT test-retest specific uptake ratios were 0.99 (R²) and 2.65%, respectively. The (18)F-FECNT binding potential of the ventral midbrain and striatal regions was tightly correlated with postmortem stereological cell counts of nigral dopaminergic neurons (R²=0.91), and striatal DAT (R²=0.83) or TH (R²=0.88) immunoreactivity intensity measurements. These findings demonstrate that (18)F-FECNT is a highly sensitive PET imaging ligand to quantify both striatal dopamine denervation and midbrain dopaminergic cell loss associated with parkinsonism.
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
authors.forename: Gunasingh
authors.initials: G
authors.lastname: Masilamoni
authors.forename: John
authors.initials: J
authors.lastname: Votaw
authors.forename: Leonard
authors.initials: L
authors.lastname: Howell
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Villalba
authors.forename: Mark
authors.initials: M
authors.lastname: Goodman
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Voll
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Stehouwer
authors.forename: Thomas
authors.initials: T
authors.lastname: Wichmann
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
mesh_terms: D000818:Animals; D001345:Autoradiography; D001526:Behavioral Symptoms / Q000209:etiology; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D064026:Calbindins; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes; D008024:Ligands; D020267:MPTP Poisoning / Q000150:complications / Q000175:diagnosis / Q000000981:diagnostic imaging*; D008253:Macaca mulatta; D009662:Nortropanes; D049268:Positron-Emission Tomography / Q000379:methods; D015203:Reproducibility of Results; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C410211:2-carbomethoxy-3-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane; D064026:Calbindins; D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D008024:Ligands; D009662:Nortropanes; D064030:S100 Calcium Binding Protein G; D014446:Tyrosine 3-Monooxygenase