Journal
EXPERIMENTAL NEUROLOGY
Volume 226, Issue 2, Pages 265-273Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2010.08.024
Keywords
Parkinson's disease; Brain imaging; Transporter; Dopamine; Striatum; MPTP; Monkey; Primate; Substantia nigra; Midbrain; Animal model
Categories
Funding
- National Parkinson Foundation
- Yerkes Primate Center NIH/NCRR [RR00165]
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The positron emission tomography (PET) tracer 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)-nortropane (F-18-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 F-18-radiolabeled DAT ligands currently available. The goal of this study is to validate the use of F-18-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 F-18-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 F-18-FECNT test-retest specific uptake ratios were 0.99 (R-2) and 2.65%, respectively. The F-18-FECNT binding potential of the ventral midbrain and striatal regions was tightly correlated with postmortem stereological cell counts of nigral dopaminergic neurons (R-2=0.91), and striatal DAT (R-2=0.83) or TH (R-2=0.88) immunoreactivity intensity measurements. These findings demonstrate that F-18-FECNT is a highly sensitive PET imaging ligand to quantify both striatal dopamine denervation and midbrain dopaminergic cell loss associated with parkinsonism. (c) 2010 Elsevier Inc. All rights reserved.
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