Use of [18F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats

Abstract

BackgroundWe evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro-phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements.MethodsDifferent doses of 6-OHDA (0, 7, 14, and 28 μg) were unilaterally injected into the right striatum of male Sprague-Dawley rats. Dopaminergic functional activity in the striatum was assessed by [18F]FDOPA-PET, measurement of striatal dopamine (DA) and DA metabolite levels, tyrosine hydroxylase (TH) immunostaining, and methamphetamine-induced rotational testing.ResultsAccumulation of [18F]FDOPA in the bilateral striatum was observed in rats pretreated with both aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT) inhibitors. Unilateral intrastriatal injection of 6-OHDA produced a significant site-specific reduction in [18F]FDOPA accumulation. The topological distribution pattern of [18F]FDOPA accumulation in the ipsilateral striatum agreed well with the pattern in TH-stained corresponding sections. A significant positive relationship was found between Patlak plot Ki values and striatal levels of DA and its metabolites (r = 0.958). A significant negative correlation was found between both Ki values (r = -0.639) and levels of DA and its metabolites (r = -0.719) and the number of methamphetamine-induced rotations.ConclusionsKi values determined using [18F]FDOPA-PET correlated significantly with the severity of dopaminergic dysfunction. [18F]FDOPA-PET makes it possible to perform longitudinal evaluation of dopaminergic function in 6-OHDA-lesioned rats, which is useful in the development of new drugs and therapies for Parkinson's disease (PD).

High correlation between in vivo [123I]β-CIT SPECT/CT imaging and post-mortem immunohistochemical findings in the evaluation of lesions induced by 6-OHDA in rats

“…Common tracers are [ 18 F] l -3,4-dihydroxyphenylalanine (DOPA), that give an estimate of dopamine synthesis and radioligands with affinity for proteins important for the dopaminergic transmission (e.g., DAT, D 2 receptor, vesicular monoamine transporter type 2). In a recent study, Kyono et al [25] showed that PET detection of striatal uptake of [ 18 F]FDOPA, after inhibition of aromatic l -amino acid decarboxylase and catechol- O -methyltransferase, is significantly correlated to striatal dopamine levels in the partially 6-OHDA-lesioned rat brain. They did four-site striatal 6-OHDA lesions of a total of 7, 14, or 28 μg 6-OHDA.…”

In-vivo Measurement of LDOPA Uptake, Dopamine Reserve and Turnover in the Rat Brain Using [18F]FDOPA PET

“…4--6,8 Although an unchanged k ref in mild lesions is in keeping with predictions based on the characterization of the 6-OHDA model via non-PET methods, it disagrees with some PET-based reports of a reduced k ref (or K i ) in lesioned nonhuman primates 8 and 6-OHDA lesioned rats. 9 This discrepancy may be explained by the disease-dependent negative bias introduced into k ref when calculated by the traditional (nonextended) Patlak graphical analysis which neglects k loss . This bias depends on k loss , being most apparent in species where k loss is large (such as the rat), and/ or in the diseased state.…”

“…Such methodology has been successfully applied in humans 1--5 and nonhuman primates 6--8 but only limited studies have been reported in the rat. 9 Given that rodent models are critical in medical research, it is important to develop imaging methodology in these species, and for specific biological readouts to be verified. A number of diseases are associated with changes or dysfunction in the dopaminergic system, most notably Parkinson's disease (PD).…”

Measuring dopaminergic function in the 6-OHDA-lesioned rat: a comparison of PET and microdialysis

“…More recently, [ 18  F]FDOPA PET has been used in the study of mouse [7,8] and rat [9,10] models of Parkinson's disease (PD). The increasing availability of transgenic rodent models of PD which may recapitulate the cardinal features of the disease, including disease progression, has spurred new interest in imaging the dopaminergic system of rodents.…”