Intravenous ethanol increases dopamine release in the ventral striatum in humans: PET study using bolus-plus-infusion administration of [11C]raclopride

Ethanol increases the interstitial dopamine (DA) concentration in the nucleus accumbens (NAcc) of experimental animals, but positron emission tomography (PET) studies using the single-bolus protocol of the [¹¹C]-raclopride competition paradigm have yielded conflicting results in humans. To resolve disparate previous findings, we utilized the bolus-plus-infusion (B/I) method, allowing both baseline and intervention quantification of [¹¹C]raclopride binding during a single 105-minute PET scan, to investigate possible ethanol-induced DA release in nine healthy male subjects. A 25-minute intravenous ethanol (7.6%) infusion, resulting in a 1.3 g/L mean blood ethanol concentration, was administered using masked timing during the PET scan. Automated region-of-interest analysis testing the difference between baseline (40–50 minutes) and intervention (60–85 minutes) revealed an average 12.6% decrease in [¹¹C]raclopride binding in the ventral striatum (VST, P=0.003) including the NAcc. In addition, a shorter time interval from the start of ethanol infusion to the first subjective effect was associated with a greater binding potential decrease bilaterally in the VST (r=0.92, P=0.004), and the feeling of pleasure was associated with a decrease in binding potential values in both the caudate nucleus (r=−0.87, P=0.003) and putamen (r=−0.74; P=0.02). These results confirm that ethanol induces rapid DA release in the limbic striatum, which can be reliably estimated using the B/I method in one imaging session.     

The effect of nicotine on striatal dopamine release in man: A [11C]raclopride PET study

In common with many addictive substances and behaviors nicotine activates the mesolimbic dopaminergic system. Brain microdialysis studies in rodents have consistently shown increases in extrasynaptic DA levels in the striatum after administration of nicotine but PET experiments in primates have given contradicting results. A recent PET study assessing the effect of smoking in humans showed no change in [(11)C]raclopride binding in the brain, but did find that "hedonia" correlated with a reduction in [(11)C]raclopride binding suggesting that DA may mediate the positive reinforcing effects of nicotine. In this experiment we measured the effect of nicotine, administered via a nasal spray, on DA release using [(11)C]raclopride PET, in 10 regular smokers. There was no overall change in [(11)C]raclopride binding after nicotine administration in any of the striatal regions examined. However, the individual change in [(11)C]raclopride binding correlated with change in subjective measures of "amused" and "happiness" in the associative striatum (AST) and sensorimotor striatum (SMST). Nicotine concentration correlated negatively with change in BP in the limbic striatum. Nicotine had significant effects on cardiovascular measures including pulse rate, systolic blood pressure (BPr), and diastolic BPr. Baseline [(11)C]raclopride binding potential (BP) in the AST correlated negatively with the Fagerstr?m score, an index of nicotine dependence. These results support a role for the DA system in nicotine addiction, but reveal a more complex relationship than suggested by studies in animals.     

Effect of endogenous dopamine on endogenous dopamine on extrastriated [11C]FLB 457 binding measured by PET

Central dopaminergic systems are known to be implicated in the pathophysiology of schizophrenia and recent in vivo dopamine receptor imaging studies have focused on the measurement of extrastriatal dopamine receptor. However, there are only a limited number of ligands that can measure the low-density D2 receptor in extrastriatal regions and their sensitivity to endogenous dopamine in extrastriatal regions has not yet been fully examined. In this study, the effect of endogenous dopamine on the extrastriatal binding of [(11)C]FLB 457 was examined in the rhesus monkey after facilitation with 1 mg/kg of methamphetamine (MAP) and was compared with the effect on the striatal binding of [(11)C]raclopride. The indices of receptor binding were obtained by four methods using cerebellum as a reference region. The bindings of [(11)C]FLB 457 in the frontal cortex, temporal cortex, and thalamus were not significantly changed after MAP treatment, while the striatal binding of [(11)C]raclopride was decreased by more than 20%. These results suggest that [(11)C]FLB 457 is not sensitive to endogenous dopamine in the extrastriatal regions of rhesus monkeys, despite a sufficient dose of MAP to decrease the binding of [(11)C]raclopride in the striatum.     

In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride

(-)-N-Propyl-norapomorphine (NPA) is a full dopamine (DA) D2 receptor agonist and [11C]NPA is a suitable radiotracer to image D2 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic DA was assessed with PET in baboons and compared to that of the reference D2 receptor antagonist radiotracer [11C]raclopride. Three male baboons were studied with [11C]raclopride and [11C]NPA under baseline conditions and following administration of the potent DA releaser amphetamine (0.3, 0.5, and 1.0 mg kg(-1) i.v.). Kinetic modeling with an arterial input function was used to derive the striatal specific-to-nonspecific equilibrium partition coefficient (V3"). [11C]Raclopride V3" was reduced by 24 +/- 10%, 32 +/- 6%, and 44 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. [11C]NPA V3" was reduced by 32 +/- 2%, 45 +/- 3%, and 53 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. Thus, endogenous DA was more effective at competing with [11C]NPA binding compared to [11C]raclopride binding, a finding consistent with the pharmacology of these tracers (agonist vs. antagonist). These results also suggest that 71% of D2 receptors are configured in a state of high affinity for agonists in vivo. In conclusion, [11C]NPA might provide a superior radiotracer to probe presynaptic DA function with PET in health and disease.     

Differential effects of stress on [11C]raclopride and [11C]MNPA binding to striatal D2/D3 dopamine receptors: A PET study in conscious monkeys

It has been reported that stress and facilitation of dopamine neuronal system are closely related. In the present study, the effects of stress on the binding of antagonist‐based [¹¹C]raclopride and agonist‐based (R)‐2‐CH3O‐N‐n‐ propylnorapomorphine ([¹¹C]MNPA) to D₂/D₃ receptors were evaluated in the striatum of conscious monkey brain. The stress state assessed from plasma cortisol level was negatively correlated with [¹¹C]raclopride binding as expected. It was noteworthy that [¹¹C]MNPA binding exhibited a positive correlation with stress state; thus, the animals with higher cortisol levels showed higher binding to D₂/D₃ receptors. Synapse 65:84–89, 2011. © 2010 Wiley‐Liss, Inc.     

Characterization of in vivo pharmacokinetic properties of the dopamine D1 receptor agonist DAR-0100A in nonhuman primates using PET with [11C] NNC112 and [11C] raclopride

DAR-0100A, the active enantiomer of dihydrexidine, is a potent dopamine D1 agonist under investigation for treatment of cognitive impairment and negative symptoms of schizophrenia. We measured the dose–occupancy relationship for DAR-0100A at D1 receptors using positron emission tomography (PET) imaging in baboons with [¹¹C] NNC112 and its binding to D2 with [¹¹C] raclopride. Two baboons were scanned with [¹¹C] NNC112 at baseline and after three different doses of DAR-0100A. Two baboons were scanned with [¹¹C] raclopride at baseline and after one dose of DAR-0100A. Occupancy (ΔBP_ND) was computed in the striatum and cortex. A clear relationship was observed between plasma concentration of DAR-0100A and ΔBP_ND. ΔBP_ND was larger in the striatum than in the cortex, consistent with reports showing that 25% of [¹¹C] NNC112 BP_ND in the cortex is attributed to 5-HT_2A. Plasma EC₅₀ estimates ranged from 150 to 550 ng/mL according to the constraints on the model. There was no detectable effect of DAR-0100A on [¹¹C] raclopride BP_ND. These data suggest that at doses likely to be administered to patients, occupancy will not be detectable with [¹¹C] NNC112 PET and binding of DAR-0100A to D2 will be negligible. This is the first demonstration with PET of a significant occupancy by a full D1 agonist in vivo.     

Measurement of density and affinity for dopamine D2 receptors by a single positron emission tomography scan with multiple injections of [11C]raclopride

Positron emission tomography (PET) with [¹¹C]raclopride has been used to investigate the density (B_max) and affinity (K_d) of dopamine D₂ receptors related to several neurological and psychiatric disorders. However, in assessing the B_max and K_d, multiple PET scans are necessary under variable specific activities of administered [¹¹C]raclopride, resulting in a long study period and unexpected physiological variations. In this paper, we have developed a method of multiple-injection graphical analysis (MI-GA) that provides the B_max and K_d values from a single PET scan with three sequential injections of [¹¹C]raclopride, and we validated the proposed method by performing numerous simulations and PET studies on monkeys. In the simulations, the three-injection protocol was designed according to prior knowledge of the receptor kinetics, and the errors of B_max and K_d estimated by MI-GA were analyzed. Simulations showed that our method could support the calculation of B_max and K_d, despite a slight overestimation compared with the true magnitudes. In monkey studies, we could calculate the B_max and K_d of diseased or normal striatum in a 150 mins scan with the three-injection protocol of [¹¹C]raclopride. Estimated B_max and K_d values of D₂ receptors in normal or partially dopamine-depleted striatum were comparable to the previously reported values.     

Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand [11C]MNPA and antagonist [11C]raclopride

PET measurements of stimulant-induced dopamine (DA) release are typically performed with antagonist radioligands that bind to both the high- and low-affinity state of the receptor. In contrast, an agonist radioligand binds preferentially to the high-affinity state and is expected to have greater sensitivity to DA, which is the endogenous agonist. [(11)C]MNPA, (R)-2-CH(3)O-N-n-propylnorapomorphine (MNPA), is a D(2) agonist radioligand with subnanomolar affinity to the D(2) receptor. The aim of the present study is to assess and compare the sensitivity of the agonist radioligand [(11)C]MNPA and antagonist radioligand [(11)C]raclopride to synaptic DA levels. Four cynomolgus monkeys were examined with [(11)C]MNPA and [(11)C]raclopride (16 PET measurements with each tracer) at baseline and after pretreatment with various doses of amphetamine. The effect of amphetamine was calculated by the change in binding potential (BP) analyzed with the multilinear reference tissue model (MRTM2). Amphetamine caused a reduction in [(11)C]MNPA BP of 4% at 0.1, 23% at 0.2, 25% at 0.5, and 46% at 1.0 mg/kg. [(11)C]Raclopride BP was reduced to a lesser extent by 2% at 0.1, 16% at 0.2, 15% at 0.5, and 23% at 1.0 mg/kg. The data were used to estimate the in vivo percentage of high-affinity state receptors to be approximately 60%. These results demonstrate that [(11)C]MNPA is more sensitive than [(11)C]raclopride to displacement by endogenous DA, and that it may provide additional information about the functional state of the D(2) receptor in illnesses such as schizophrenia and Parkinson's disease.     

Imaging endogenous dopamine competition with [11C]raclopride in the human brain

This study images dopamine release in response to a neurochemically specific challenge with the psychostimulant drug methylphenidate. Changes in synaptic dopamine induced by methylphenidate were evaluated with positron emission tomography and [¹¹C]raclopride, a D₂ receptor radioligand that is sensitive to endogenous dopamine. Methylphenidate significantly decreased striatal [¹¹C]raclopride binding. The decrease was variable and was negatively correlated with age. Mood and anxiety at baseline, were also correlated with methylphenidate-induced DA changes. This strategy provides a tool to investigate the responsiveness of the dopamine system in the normal and diseased human brain and to investigate the neurochemical correlates of behavior. © 1994 Wiley-Liss, Inc.     

Difference in in vivo receptor binding between [3 H]N-methylspiperone and [3 H]raclopride in reserpine-treated mouse brain

Summary The in vivo binding of [³ H]N-methylspiperone (NMSP) and [³ H]raclopride was compared in mice treated with reserpine (5 mg/kg, 24 hr prior to the tracer injection). With both radioligands, selective accumulation of radioactivity in the striatum following intravenous injection was observed, whereas a relatively low accumulation and a rapid decline in radioactivity in the cerebellum was seen. Reserpine significantly decreased [³ H]NMSP binding in vivo, however it increased [³ H]raclopride binding. By compartment model analysis, it was found that the decrease in [³ H]NMSP binding was primarily due to the decrease in the association rate (K3) and the increase in [³ H]raclopride was due to the decrease in the dissociation rate (K4) in vivo. As both Kd and Bmax of dopamine D2 receptors have been reported to be unaltered by reserpine, these results suggested that some unknown factors except Kd and Bmax which influence on in vivo binding of receptors might be changed by reserpine. These results revealed that it is of importance to measure kinetics of ligand-receptor binding in vivo rather than static analysis. These two different types of radioligands can be combined to reveal functional roles of dopamine receptor in vivo, especially in the study of the human brain with positron emission tomography (PET).     

Similar striatal D2/D3 dopamine receptor availability in adults with Tourette syndrome compared with healthy controls: A [11C]‐(+)‐PHNO and [11C]raclopride positron emission tomography imaging study

Pharmacological and anatomical evidence implicates striatal dopamine receptors in Tourette syndrome (TS). Nevertheless, results of positron emission tomography (PET) studies of the dopamine system in TS have been inconsistent. We investigated striatal D2/3 dopamine receptors in TS using the radioligands [¹¹C]raclopride and [¹¹C]‐(+)‐PHNO, an agonist that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state. Eleven adults with TS and 11 matched healthy control (HC) participants underwent [¹¹C]raclopride and [¹¹C]‐(+)‐PHNO PET scans. General linear model was used for voxelwise contrasts of striatal binding potentials (BP_ND) between TS and HC participants. Analysis of variance was performed to investigate main effect of radioligand. In addition, BP_ND values were extracted for ventral, motor, and associative striatum. Finally, we examined the relationship between BP_ND measures and symptom severity in TS participants. Main effects analyses showed that [¹¹C]‐(+)‐PHNO BP_ND was higher in ventral striatum, whereas [¹¹C]raclopride BP_ND was higher in motor and associative striatum. There were no significant group differences between TS and HC. Furthermore, TS and HC participants had similar [¹¹C]‐(+)‐PHNO and [¹¹C]raclopride BP_ND in the three striatal subregions. Moreover, there was no significant correlation between BP_ND and symptom severity. TS and HC participants had similar striatal D2/3 receptor availability measures. These results challenge the assumption that striatal dopamine receptors have a major role in the pathophysiology of TS. Consistent with previous findings, [¹¹C]‐(+)‐PHNO localized preferentially to ventral striatal, D3 receptor‐rich regions, in contrast to [¹¹C]raclopride, which localized preferentially in the dorsal striatum. Hum Brain Mapp 36:2592–2601, 2015. © 2015 Wiley Periodicals, Inc .     

Dopamine (D2/3) receptor agonist positron emission tomography radiotracer [11C]-(+)-PHNO is a D3 receptor preferring agonist in vivo

[11C]PHNO is a recently introduced agonist to image DA D2-like receptors with Positron Emission Tomography (PET). In cats and humans, [11C]PHNO revealed an atypical distribution compared to radiolabeled D2-like antagonists (such as [11C]raclopride) or other D2-like agonists (such as [11C]NPA), as it displayed unusual high binding in the globus pallidus (GP). The goal of this study was to assess the pharmacological nature of the binding of [11C]PHNO in the GP in nonhuman primates. As previously reported in humans, [11C]PHNO equilibrium specific to nonspecific equilibrium partition coefficients (V3') in baboons was much higher in GP (3.88 +/- 1.15) than in the dorsal striatum (DST, 2.07 +/- 0.43), whereas the reverse was true for [11C]raclopride (1.48 +/- 0.41 in GP, 2.56 +/- 0.91 in DST) and [11C]NPA (0.87 +/- 0.19 in GP, 1.02 +/- 0.13 in DST). Administration of unlabeled raclopride resulted in similar reductions of [11C] PHNO V3' and [11C]raclopride V3' in both the GP and the DST. This observation demonstrated that the [11C]PHNO binding in the GP was specific to D2-like receptors. To evaluate the respective contribution of D3 and D2 receptors to the binding potential (BP) of [11C]PHNO and [11C]raclopride, experiments were carried out with the selective D3 partial agonist 1-(4(2-Napthoylamino)butyl)-4-(2-methoxyphenyl)-1A-piperazine HCL (BP897). BP897 reduced [11C]raclopride V3' by 29% +/- 9%, 19% +/- 8%, and 10% +/- 7% in GP, VST, and DST, respectively, a result consistent with expectation from postmortem studies (D3/D2 ratio in GP > VST > DST). BP897 reduced [11C]PHNO V3' by 57% +/- 11%, 30% +/- 11%, and 13% +/- 8% in GP, VST, and DST, respectively, indicating that the D3 receptor contribution to [11C]PHNO signal is higher than that of [11C]raclopride. From these experiments we conclude that [11C]PHNO is a D3 preferring agonist, and that this property explains the high GP signal not observed with [11C]raclopride or [11C]NPA. This property might contribute to its higher vulnerability to endogenous DA compared to [11C]raclopride and [11C]NPA.     

Selective serotonin reuptake inhibitor (SSRI) modulation of striatal dopamine measured with [11C]-raclopride and positron emission tomography

The effect of a pharmacologic increase in serotonin concentrations on striatal dopamine (D2) receptor availability has been measured in several studies using positron emission tomography (PET) and the radiotracer [11C]-raclopride as a method for the in vivo imaging of serotonin modulation of striatal dopamine in human subjects. These studies have shown that an acute increase in serotonin concentrations produced a decrease in striatal D2 receptor availability. The current study was undertaken to measure the effects of a more pharmacologically selective serotonergic agent compared to previous studies, the serotonin reuptake inhibitor, citalopram, on striatal D2 receptor availability. Twelve healthy control subjects underwent two PET scans performed on the same day following i.v. administration of saline (Scan 1) and citalopram (Scan 2, 40 mg, i.v.). The [11C]-raclopride data were analyzed with a graphical analysis method using the cerebellum as the input function. Plasma levels of citalopram, cortisol, and prolactin were measured. The citalopram concentrations peaked at the end of infusion (EOI) and remained relatively consistent from 30 min to 3 h postinfusion. An increase in cortisol and prolactin concentrations was observed from the EOI until 60 min after the EOI. A significant decrease in striatal D2 receptor availability was observed after citalopram infusion (-5%), presumably due to an increase in endogenous dopamine concentrations. In summary, i.v. administration of the selective serotonin reuptake inhibitor, citalopram, produced modest reductions in striatal D2 receptor availability, consistent with other human [11C]-raclopride studies using less pharmacologically selective serotonergic agents.     

Comparative effects of methamphetamine and nicotine on the striatal [(11)C]raclopride binding in unanesthetized monkeys

Although a very large literature exists on the in vitro, ex vivo, and in vivo effects of nicotine on dopamine release in rodents, similar data in primates are scant. This study was initiated to compare methamphetamine to nicotine given i.v. to normal unanesthetized monkeys using positron emission tomography (PET) techniques. Release of dopamine in the striatum using [¹¹C]raclopride was determined indirectly in four nicotine‐naïve adult Macaca mulatta monkeys under conscious and isoflurane‐anesthetized conditions using high‐resolution PET. [¹¹C]Raclopride was given i.v. as a bolus injection followed by continuous infusion with steady state over 30–45 min. Nicotine bitartrate was then given as a bolus plus infusion for 30 min in doses of 32 μg/kg + 0.8 μg/kg/min or 100 μg/kg + 2.53 μg/kg/min as base. The larger doses of nicotine caused significant cardiovascular effects; these doses did not displace [¹¹C]raclopride binding in either dorsal or ventral striatum under the anesthetized conscious condition. In contrast, isoflurane‐anesthesia induced a slight but significant dose‐dependent reduction of [¹¹C]raclopride binding by nicotine even at the same doses used in the anesthetized condition. Methamphetamine in bolus doses of 0.1, 0.3, and 1.0 mg/kg i.v. under conscious condition caused a significant displacement of [¹¹C]raclopride and isoflurane‐anesthesia facilitated the displacement induced by nicotine. These results indicate that nicotine, in high tobacco‐smoking‐related doses, does not release sufficient brain dopamine to displace [¹¹C]raclopride in the striatum in the awake and fully conscious state, in contrast to small doses of methamphetamine. Synapse 45:207–212, 2002. © 2002 Wiley‐Liss, Inc.     

Positron emission tomography imaging of amphetamine‐induced dopamine release in the human cortex: A comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride

The use of PET and SPECT endogenous competition binding techniques has contributed to the understanding of the role of dopamine in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of acute changes in synaptic dopamine have been restricted to the striatum. The ligands previously used, such as [¹¹C]raclopride and [¹²³I]IBZM, do not provide sufficient signal to noise ratio to quantify D₂ receptors in extrastriatal areas, such as cortex, where the concentration of D₂ receptors is much lower than in the striatum. Given the importance of cortical DA function in cognition, a method to measure cortical dopamine function in humans would be highly desirable. The goal of this study was to compare the ability of two high affinity DA D₂ radioligands [¹¹C]FLB 457 and [¹¹C]fallypride to measure amphetamine‐induced changes in DA transmission in the human cortex. D₂ receptor availability was measured in the cortical regions of interest with PET in 12 healthy volunteers under control and postamphetamine conditions (0.5 mg kg^?1, oral), using both [¹¹C]FLB 457 and [¹¹C]fallypride (four scans per subjects). Kinetic modeling with an arterial input function was used to derive the binding potential (BP_ND) in eight cortical regions. Under controlled conditions, [¹¹C]FLB 457 BP_ND was 30–70% higher compared with [¹¹C]fallypride BP_ND in cortical regions. Amphetamine induced DA release led to a significant decrease in [¹¹C]FLB 457 BP_ND in five out the eight cortical regions evaluated. In contrast, no significant decrease in [¹¹C]fallypride BP_ND was detected in cortex following amphetamine. The difference between [¹¹C]FLB 457 and [¹¹C]fallypride ability to detect changes in the cortical D₂ receptor availability following amphetamine is related to the higher signal to noise ratio provided by [¹¹C]FLB 457. These findings suggest that [¹¹C]FLB 457 is superior to [¹¹C]fallypride for measurement of changes in cortical synaptic dopamine. Synapse 63:447–461, 2009. © 2009 Wiley‐Liss, Inc.     

Decreased dopamine D receptor binding in essential blepharospasm

Objectives – The purpose of this study was to investigate whether dopamine D₂ receptor binding was altered in the striatum of essential blepharospasm patients. Methods – Striatal dopamine D₂ receptor binding was measured with positron emission tomography and [¹¹C]raclopride. We studied eight drug‐naive patients with bilateral blepharospasm and eight age‐matched normal controls. Results – The uptake indices in the blepharospasm group were significantly reduced by 11.7% in the caudate (P < 0.005), 11.6% in the anterior putamen (P < 0.0001), and 10.3% in the posterior putamen (P < 0.005) relative to the control group. Conclusions – This study indicates decreased dopamine D₂ receptor binding in the entire striatal region of blepharospasm patients. The findings suggest that decreased dopamine D₂ receptor binding might be one of the predisposing factors that leads to the dysfunction of the motor circuit, resulting in the loss of broad inhibition of unwanted movements during an intended movement in blepharospasm patients.     

Reproducibility of striatal and thalamic dopamine D2 receptor binding using [11C]raclopride with high-resolution positron emission tomography

Positron emission tomography (PET) imaging of small striatal brain structures such as the ventral striatum (VST) has been hampered by low spatial resolution causing partial-volume effects. The high-resolution research tomograph (HRRT) is a brain-dedicated PET scanner that has considerably better spatial resolution than its predecessors. However, its superior spatial resolution is associated with a lower signal-to-noise ratio. We evaluated the test–retest reliability of the striatal and thalamic dopamine D₂ receptor binding using the HRRT scanner. Seven healthy male volunteers underwent two [¹¹C]raclopride PET scans with a 2.5-hour interval. Dopamine D₂ receptor availability was quantified as binding potential (BP_ND) using the simplified reference tissue model. To evaluate the reproducibility of repeated BP_ND estimations, absolute variability (VAR) and intraclass correlation coefficients (ICCs) were calculated. VAR values indicated fairly good reproducibility and were 3.6% to 4.5% for the caudate nucleus and putamen and 4.5% to 6.4% for the lateral and medial part of the thalamus. In the VST, the VAR value was 5.8% when the definition was made in the coronal plane. However, the ICC values were only moderate, in the range of 0.34 to 0.66, for all regions except the putamen (0.87). Experimental signal processing methods improved neither ICC nor VAR values significantly.     

Oral D-amphetamine causes prolonged displacement of [11C]raclopride as measured by PET

Parenterally administered D-amphetamine has been used as a challenge drug to release dopamine, which in turns inhibits [11C]raclopride binding to dopaminergic D2 receptors as measured using positron emission tomography (PET) techniques. The primary objective of this study was to determine whether orally administered D-amphetamine would inhibit [11C]raclopride binding in a manner similar to that produced by intravenously administered D-amphetamine. The secondary objective was to assess the timeline of these effects. Twelve healthy human volunteers participated in this study. Subjects were scanned at baseline and 2 h after D-amphetamine administration (n = 5); at baseline, 2 and 6 h postdrug (n = 4); or at baseline, 2 and 24 h postdrug (n = 3). Orally administered D-amphetamine caused a significant decrease in [11C]raclopride binding at 2 h (13% +/- 5%). Receptor availability was still decreased at 6 h (18% +/- 6%), even though physiological effects had completely returned to baseline. [11C]Raclopride binding returned to baseline at 24 h. The percentage of [11C]raclopride displacement was not correlated with plasma D-amphetamine concentrations. In conclusion, orally administered D-amphetamine caused a reliable and prolonged [11C]raclopride displacement, the magnitude of which is similar to that observed after intravenous administration. Possible mechanisms for the observed prolonged displacement may include persistence of intrasynaptic dopamine and/or receptor internalization.