Measurement of methylphenidate-induced change in extrastriatal dopamine concentration using [11C]FLB 457 PET.

[(11)C]FLB 457 is a very high-affinity radiotracer that allows the measurement of dopamine D(2/3) receptor availability in regions of the brain where densities are very low, such as the cerebral cortex. It is not known if [(11)C]FLB 457 binding is sensitive to the concentration of endogenous dopamine in humans in a manner analogous to [(11)C]raclopride and [(123)I]IBZM in the striatum. To test this possibility, extrastriatal [(11)C]FLB 457 binding was measured at baseline and after the oral administration of 40 to 60 mg of the psychostimulant methylphenidate (MP) in 12 healthy volunteers using positron emission tomography (PET) in a balanced-order, double-blind design. The dynamic PET data were quantified using a two-tissue compartment model with a metabolite-corrected arterial plasma input function. Two volunteers were excluded because of excessive head movement. In the remainder, MP caused significant reductions in the volume of distribution (VD) in temporal and frontal cortical regions and thalamus, suggesting that [(11)C]FLB 457 binding is sensitive to endogenous dopamine concentration. Moreover, the change in [(11)C]FLB 457 binding after MP correlated with the dose of MP (in mg/kg body weight) in all regions assessed. We conclude that MP in doses within the therapeutic range for the treatment of attention deficit hyperactivity disorder causes increases in dopamine concentrations in extrastriatal regions and that [(11)C]FLB 457 PET may be a useful tool for the assessment of change in dopamine concentration in these areas in humans.