Over the last few years, several groups demonstrated that PET and SPECT neuroreceptor imaging techniques can be used, not only to measure receptor parameters, but also to detect acute fluctuations in the concentration of endogenous transmitters in the vicinity of the receptors (for review, see Laruelle, 2000). Using this approach, we and others have reported an abnormal regulation of DA transmission following amphetamine in several neuropsychiatric disorders such as schizophrenia (Breier et al., 1997; Laruelle et al., 1996), attention-deficit hyperactivity disorder (Volkow et al., 2007) and addiction (Malison et al., 1999; Martinez et al., 2007; Volkow et al., 1997). An important limitation of these studies is the fact that measurements of D2 receptors and amphetamine-induced DA release were restricted mostly to the striatum because the ligands used did not provide enough signal to noise ratio to quantify D2 receptors in extrastriatal regions. Given that fMRI/metabolic imaging data suggests a correlation between impairments in executive function and pathological activation of the prefrontal cortex in several neuropsychiatric disroders such as schizophrenia, ADHD and addiction, it is of extreme interest to understand the regulatory role of DA in this particular region (Bush et al., 2008; Callicott et al., 1999; Volkow and Fowler, 2000). We recently demonstrated that the high affinity D2 receptor PET radiotracer [11C]FLB 457 can be used to measure amphetamine-induced DA release in the cortical regions of interest that include the dorsolateral prefrontal cortex, medial prefrontal cortex, anterior cingulate cortex, medial temporal lobe (which includes the amygdala and hippocampus) and parietal cortex. In this application, we propose to further validate the use of [11C]FLB 457 to detect changes in endogenous DA in the cortical regions in non human primates (specific aim 1) and healthy controls (specific aim 2-4). The proposed validation of [11C]FLB 457 to study amphetamine-induced DA release as outlined in this application will provide the research community with a new tool to study cortical dopamine transmission in both health and disease. PUBLIC HEALTH RELEVANCE: In this application we propose to further validate the use of [11C]FLB 457 to measure amphetamine- induced dopamine (DA) transmission in the human cortex.