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In a recent PET study we demonstrated the ability to measure amphetamine-induced DA release in the human cortex with the relatively high affinity dopamine D 2/3 radioligand [ 11 C]FLB 457 (Narendran et al., 2009). The aim of this study was to evaluate the reproducibility and reliability of [ 11 C]FLB 457 in the same imaging paradigm we used to measure amphetamine-induced DA transmission. Six healthy human subjects (3 males/3 females) were studied twice with [ 11 C]FLB 457, once at baseline and again three-hours following the end of the baseline scan. D 2/3 receptor binding parameters were estimated using a two-tissue compartment kinetic analysis in the cortical regions of interest and cerebellum (reference region). The test-retest variability and intraclass correlation coefficient were assessed for distribution volume (V T ), binding potential relative to plasma concentration (BP P ), and binding potential relative to non-displaceable uptake (BP ND ) of [ 11 C]FLB 457. The test-retest variability of [ 11 C]FLB 457 V T , BP P and BP ND were ≤ 15%, consistent with the published test-retest variability for this ligand in other brain regions (Vilkman et al., 2000;Sudo et al., 2001). In addition, no significant decrease in [ 11 C]FLB 457 BP ND was observed in the second scan compared to the first one. This suggests that the contribution of carryover mass of [ 11 C]FLB 457 to the measured reduction in [ 11 C]FLB 457 BP ND following amphetamine was relatively low. These data support the further validation of [ 11 C]FLB 457 as a tool to measure amphetamine-induced dopamine release in the human cortex.

In a recent PET study we demonstrated the ability to measure amphetamine-induced DA release in the human cortex with the dopamine D 2/3 radioligand [ 11 C]FLB 457. As previous studies in animals have shown that a relatively high fraction of the [ 11 C]FLB 457 signal in the cerebellum represents specific binding to D 2/3 receptors, there was concern that the use of the cerebellum as a measure of nonspecific binding (i.e., reference region) to derive [ 11 C]FLB 457 binding potential (BP ND ) would bias cortical dopamine release measurements. Thus, we evaluated the fractional contribution of specific binding to D 2/3 receptors in the human cerebellum for [ 11 C]FLB 457.Six healthy human subjects (5M/1F) were studied twice with [ 11 C]FLB 457, once at baseline and again following a single oral dose of 15 mg of aripiprazole, a D 2/3 partial agonist. [ 11 C]FLB 457 distribution volume (V T ) was estimated using kinetic analysis in the cortical regions of interest and potential reference regions. The change in [ 11 C]FLB 457 V T following aripiprazole ranged from −33 to −42% in the cortical regions of interest (ROIs). The aripiprazole-induced change in [ 11 C]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 re-analysis of the published [ 11 C]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 [ 11 C]FLB 457 BP ND in dopamine release studies is unlikely to be successful because it leads to less reproducible outcome measures, which in turn diminishes the ability to measure dopamine release in the cortex. D 2/3 blocking studies with aripiprazole and [ 11 C]FLB 457 suggest specific binding to D 2/3 receptors in the cerebellum. These data also suggest that the contribution of specific binding to D 2/3 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 [ 11 C]FLB 457

Objective PET studies performed with [11C]raclopride have consistently reported lower binding to D2/3 receptors and lower amphetamine-induced dopamine release in cocaine abusers relative to healthy controls. A limitation of these studies that were performed with D2/3 antagonist radiotracers such as [11C]raclopride is the failure to provide information that is specific to D2/3 receptors configured in a state of high affinity for the agonists (i.e., D2/3 receptors coupled to G- proteins, D2/3 HIGH). As the endogenous agonist dopamine binds with preference to D2/3 HIGH relative to D2/3 LOW receptors (i.e., D2/3 receptors uncoupled to G-proteins) it is critical to understand the in vivo status of D2/3 HIGH receptors in cocaine dependence. Thus, we measured the available fraction of D2/3 HIGH receptors in 10 recently abstinent cocaine abusers (CD) and matched healthy controls (HC) with the D2/3 antagonist and agonist PET radiotracers [11C]raclopride and [11C]NPA Methods [11C]raclopride and [11C]NPA binding potential (BPND) in the striatum were measured with kinetic analysis using the arterial input function. The available fraction of D2/3 HIGH receptors, i.e., % RHIGH available=D2/3 HIGH/(D2/3 HIGH + D2/3 LOW) was then computed as the ratio of [11C]NPA BPND/[11C]raclopride BPND. Results No differences in striatal [11C]NPA BPND (HC = 1.00 ± 0.17; CD = 0.97 ± 0.17, p =0.67) or available % RHIGH (HC= 39% ± 5%; CD = 41% ± 5%, p = 0.50) was observed between cocaine abusers and matched controls Conclusions The results of this [11C]NPA PET study do not support alterations in D2/3 HIGH binding in the striatum in cocaine dependence.

Objective Positron emission tomography imaging studies in cocaine abusers have shown that decreased dopamine release in the striatum following an amphetamine challenge is associated with higher relapse rates. One possible mechanism that might lead to lower amphetamine-induced dopamine release is that fewer dopamine storage vesicles are available in the pre-synaptic terminals for release. Consistent with this hypothesis, postmortem studies have reported a reduction in the VMAT2, the membrane protein that regulates the size of the vesicular dopamine pool, in cocaine abusers relative to healthy subjects. In this study, we used PET and the VMAT2 radioligand [11C]-(+)-dihydrotetrabenazine (DTBZ) to assess the in vivo VMAT2 availability in a group of 12 recently abstinent cocaine abusers and matched healthy controls to confirm the postmortem findings. Methods [11C]DTBZ binding potential (BPND) was measured in subjects with kinetic analysis using the arterial input function and the simplified reference-tissue method if arterial input was unavailable. Results [11C]DTBZ BPND was significantly reduced by 10% in the limbic striatum, 16.3% in the associative striatum, and 13.4% in the sensori-motor striatum in cocaine abusers compared to controls. Conclusions The results of this in vivo PET study confirm previous in vitro reports of lower VMAT2 availability in the striatum of cocaine abusers. It also suggests a compensatory downregulation of the dopamine storage vesicles in response to chronic cocaine abuse and/or a loss of dopaminergic terminals. Further research is necessary to understand the clinical relevance of this observation as to whether it is related to relapse and outcome in abstinent cocaine abusers.