PET Studies of Cerebral Levodopa Metabolism: A Review of Clinical Findings and Modeling Approaches

[18F]Fluoro-3,4-dihydroxyphenyl-l-alanine (FDOPA) was one of the
first successful tracers for molecular imaging by positron emission
tomography (PET), and has proven immensely valuable for studies of
Parkinson’s disease. Following intravenous FDOPA injection, the
decarboxylated metabolite [18F] fluorodopamine is formed and
trapped within terminals of the nigrostriatal dopamine neurons;
reduction in the simple ratio between striatum and cerebellum is
indicative of nigrostriatal degeneration. However, the kinetic
analysis of dynamic FDOPA-PET recordings is formidably complex due
to the entry into brain of the plasma metabolite O-methyl-FDOPA and
due to the eventual washout of decarboxylated metabolites. Linear
graphical analysis relative to a reference tissue input function is
popular and convenient for routine clinical studies in which serial
arterial blood samples are unavailable. This simplified approach
has facilitated longitudinal studies in large patient cohorts.
Linear graphical analysis relative to the metabolite-corrected
arterial FDOPA input yields a more physiological index of FDOPA
utilization, the net blood-brain clearance. Using a constrained
compartmental model, FDOPA-PET recordings can be used to calculate
the relative activity of the enzyme DOPA decarboxylase in living
brain. We have extended this approach so as to obtain an index of
steady-state trapping of [18F]fluorodopamine in synaptic vesicles.
Although simple methods of image analysis are sufficient for the
purposes of routine clinical studies, the more complex approaches
have revealed hidden aspects of brain dopamine in personality,
healthy aging, and in the pathophysiologies of Parkinson’s disease
and schizophrenia.