6-[18F]fluoro-L-DOPA PET studies of the turnover of dopamine in MPTP-induced parkinsonism in monkeys

Abstract

This report describes a method to assess, in vivo, the turnover of dopamine (DA) and describes its application to the evaluation of DA function in normal monkeys and monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lesions of the DA nigro-striatal pathway. Using positron emission tomography with the tracer of presynaptic DA function, 6-[18F]fluoro-L-DOPA (FDOPA), and an extension of the graphical method of analysis, we measured the striatal FDOPA uptake rate constant, Ki, and the rate of reversibility of FDOPA trapping k(loss) in normal and MPTP-treated monkeys, either neurologically normal or displaying a parkinsonian symptomatology. An index of effective DA turnover was defined as the ratio of k(loss)/Ki. Compared to normal controls, Ki was decreased and k(loss) was increased in the MPTP-lesioned monkeys. The index of DA turnover was significantly increased in the monkeys displaying a parkinsonian symptomatology as compared to the controls and the neurologically normal MPTP-treated monkeys. The DA turnover index was also significantly increased in the neurologically normal MPTP-lesioned animals compared to normals. This suggests that an increase in DA turnover develops early in the disease process and may be one of the compensatory mechanisms partly responsible for the delay in the development of the clinical manifestations in Parkinson's disease.

Effect of Dopamine Loss and the Metabolite 3-O-Methyl-[18F]Fluoro-dopa on the Relation between the 18F-Fluorodopa Tissue Input Uptake Rate Constant Kocc and the [18F]Fluorodopa Plasma Input Uptake Rate Constant Ki

“…The fact that both K i and K occ are sensitive to k loss implies that to some extent they are also measures of storage capacity or turnover time, especially in advanced stages of disease, when the loss rate is higher (Doudet et al, 1998). In these extreme cases, when a clear curvature is apparent even in the K i Patlak plots (data not shown), it becomes questionable whether the Patlak analysis can still be applied, because a deviation from a straight-line relation is itself indicative of a certain degree of reversibility.…”

Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model

“…PET imaging of presynaptic targeting reagents such as fluoro-dopa, fluoro-metatyrosine, or 2β-carbomethoxy-3β-4-fluorophenyltropane (CFT) determines whether cells implanted in vivo have the molecular machinery necessary for dopamine synthesis and/or storage (28)(29)(30). In this study, we examined the uptake of fluoro-dopa at 14 weeks after transplantation.…”

PET Studies of Net Blood—Brain Clearance of FDOPA to Human Brain: Age-Dependent Decline of [18F]Fluorodopamine Storage Capacity

“…The magnitude of K in app is reduced by the eventual catabolism of [ 18 F]fluorodopamine to metabolites that diffuse from the brain (k loss ), especially when calculated from dynamic emission recordings of long duration Doudet et al, 1998;Cumming et al, 2001;Sossi et al, 2001Sossi et al, , 2002Sossi et al, , 2003. The effective distribution volume, an index of the specific binding capacity for FDOPA metabolites in the brain, has been defined as the ratio K in app /k loss (EDV 1 ; Sossi et al, 2001Sossi et al, , 2002, and in the present study as the ratio K/k loss (EDV 2 ).…”