18F-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 (18F-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 18F-radiolabeled DAT ligands currently available. The goal of this study is to validate the use of 18F-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 18F-FECNT PET at baseline (twice; ten 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 18F-FECNT test-retest specific uptake ratios were 0.99 (R2) and 2.65%, respectively. The 18F-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 18F-FECNT is a highly sensitive PET imaging ligand to quantify both striatal dopamine denervation and midbrain dopaminergic cell loss associated with parkinsonism.

Synthesis of novel halo and tosyloxy nortropane derivatives as efficient precursors for the one-step synthesis of the dopamine transporter PET ligand [18F]FECNT

“…The solution was then washed with water (30 mL), aqueous saturated NaHCO 3 (30 mL), water again (30 mL), and finally dried over anhydrous Na 2 SO 4 for 12 h followed by evaporation to dryness. The crude product (0.70 g) was purified by crystallization from petroleum ether to afford 0.58 g of compound 6 (1.78 mmol, 89%) as colorless needles and with a purity >99% (HPLC, UV, 220 nm) (2-Fluoroethyl)-4-bromobenzenesulfonate (7). A mixture of 2-fluoroethanol (2.5 g, 39 mmol), anhydrous pyridine (15 mL), and anhydrous THF (30 mL) under an argon atmosphere was cooled to 5°C using an ice/water bath.…”

“…1,5,6 Moreover, high degree of testretest reproducibility and extremely high sensitivity of [ 18 F] FECNT for imaging the DAT in PET studies were recently demonstrated. 7 However, the use of this radioligand as a clinical marker for the state of the DAT system is highly dependent on the robustness of the radiochemical process used for its preparation, and this in particular in terms of efficiency and speed. To date, 1,8 [ 18 F]FECNT has been synthesized in a two-step chemical process, involving the preparation of 2-[…”

Alpha-1 Adrenergic Receptors are Localized on Presynaptic Elements in the Nucleus Accumbens and Regulate Mesolimbic Dopamine Transmission

“…Table 1 describes all primary antibodies and peptides and their concentrations used in this study. The specificity of each of these antibodies has been characterized previously (Dallvechia-Adams et al, 2002;Montana et al, 2004;Nakadate et al, 2006;Masilamoni et al, 2010), and preadsorption of the a1AR antibody with the synthetic a1AR peptide eliminated all labeling (data not shown).…”

Clinical features of drug-induced parkinsonism based on [18F] FP-CIT positron emission tomography

“…This study was approved by the Institutional Review Board (IRB) of Asan Medical Center. The diagnostic criteria of DIP were: (1) the presence of parkinsonism, (2) no history of parkinsonism or extrapyramidal disorders before use of the offending drug, and (3) onset of parkinsonism symptoms during use of the offending drug [9]. Data obtained from 20 patients with ischemic changes in the basal ganglia on brain MRI scans were excluded.…”

“…The availability of presynaptic DAT can be evaluated by positron emission tomography (PET) scanning [9,10]. PET is superior to single photon emission tomography (SPECT) in that it has a higher imaging resolution, making it possible to detect subtle changes in the integrity of the presynaptic dopaminergic system.…”