Evaluation of dopamine D₂/₃ specific binding in the cerebellum for the positron emission tomography radiotracer [¹¹C]FLB 457: implications for measuring cortical dopamine release.

In a recent positron emission tomography (PET) study, we demonstrated the ability to measure amphetamine-induced dopamine (DA) release in the human cortex with the DA D₂/₃ radioligand [¹¹C]FLB 457. As previous studies in animals have shown that a relatively high fraction of the [¹¹C]FLB 457 signal in the cerebellum represents specific binding to D₂/₃ receptors, there was concern that the use of the cerebellum as a measure of nonspecific binding (i.e., reference region) to derive [¹¹C]FLB 457 binding potential (BP) (BP(ND) ) would bias cortical DA release measurements. Thus, we evaluated the fractional contribution of specific binding to D₂/₃ receptors in the human cerebellum for [¹¹C]FLB 457. Six healthy human subjects (5M/1F) were studied twice with [¹¹C]FLB 457, once at baseline and again following a single oral dose of 15 mg of aripiprazole, a D₂/₃ partial agonist. [¹¹C]FLB 457 distribution volume (V(T) ) was estimated using kinetic analysis in the cortical regions of interest and potential reference regions. The change in [¹¹C]FLB 457 V(T) following aripiprazole ranged from -33 to -42% in the cortical regions of interest (ROIs). The aripiprazole-induced change in [¹¹C]FLB 457 V(T) in three potential reference regions suggests significant specific binding the cerebellum (CER, -17 ± 12%), but not pons (PON, -10 ± 10%) and centrum semiovale (CESVL, -3 ± 12%). Nevertheless, a reanalysis of the published [¹¹C]FLB 457 test-retest and amphetamine studies suggests that the use of the PON V(T) and CESVL V(T) as an estimate of nonspecific binding to derive [¹¹C]FLB 457 BP(ND) in DA release studies is unlikely to be successful because it leads to less reproducible outcome measures, which in turn diminishes the ability to measure DA release in the cortex. D₂/₃ blocking studies with aripiprazole and [¹¹C]FLB 457 suggest specific binding to D₂/₃ receptors in the cerebellum. These data also suggest that the contribution of specific binding to D₂/₃ receptors in the cerebellum is lower than that in the cortical ROIs and that CER V(T) is mostly representative of nonspecific binding. Nevertheless, caution is advised when using reference tissue methods that rely solely on the cerebellum signal as an input function to quantify [¹¹C]FLB 457 BP(ND).