PET mapping of extrastriatal D2-like dopamine receptors in the human brain using an anatomic standardization technique and [11C]FLB 457

The Computerized Brain Atlas (CBA) transforms PET images of individual subjects into a standard brain anatomy. We have previously applied this to PET images with [(11)C]raclopride and confirmed that the D2 dopamine receptors in the striatum can be evaluated accurately with a standard brain anatomy. There is growing evidence that extrastriatal D2 receptors, in spite of their low density, have pathophysiological significance for schizophrenia. We used the CBA to explore the extrastriatal distribution of D2 receptors in 13 healthy subjects using [11C]FLB 457, a substituted benzamide with very high affinity for D2 and D3 receptors. There was good agreement between the specific binding ratios from CBA quantification of standardized images and those from region-of-interest analyses of original images. The highest levels of binding were observed in the putamen and caudate nucleus, followed by the globus pallidus and nucleus accumbens. Besides the basal ganglia, the hypothalamus and nucleus ruber also showed high levels of binding. Intermediate levels were found in the substantia nigra, nucleus subthalami, amygdala, and thalamus. Interestingly, there was very heterogeneous binding among the thalamic nuclei. The anterior and mediodorsal nuclei showed relatively high binding. The cerebral cortices showed lower levels with significant regional differences. Binding was highest in the temporal cortex and hippocampus followed by the anterior cingulate gyrus, and the parietal and frontal cortices, but was lowest in the occipital cortex. The use of CBA for analysis of [11C]FLB 457 binding makes it possible to build a normal database for the extrastriatal D2 receptors in the living human brain. The heterogeneous distribution of D2 receptors provides an attractive opportunity for new research on the pathophysiology and drug treatment of schizophrenia.     

Memory and frontal lobe functions; possible relations with dopamine D2 receptors in the hippocampus

Cerebral cortical regions are thought to be important for cognitive functions such as memory and executive function. Although the functional associations between dopamine D2 receptors and motor and cognitive functions have been extensively examined in the striatum using positron emission tomography (PET), the role of dopamine D2 receptors in extrastriatal regions has been unexplored. We aimed to investigate the relationship between dopamine D2 receptors in extrastriatal regions and the performance of a broad spectrum of cognitive functions including memory, language, attention, and executive function in healthy subjects. Extrastriatal dopamine D2 receptors were measured in 25 male subjects using PET with [(11)C]FLB457. After the PET scans, a battery of neuropsychological tests was administered to all subjects. We found that the binding potential (BP) of [(11)C]FLB457 in the hippocampus was positively correlated with memory function. Furthermore, BP of [(11)C]FLB457 in the hippocampus, but not in the prefrontal cortex, was associated with frontal lobe functions such as executive function and verbal fluency. Our findings suggest that dopamine D2 receptors in the hippocampus might affect the local hippocampal function, but also brain functions outside the hippocampus such as the prefrontal cortex.     

Error analysis for quantification of [(11)C]FLB 457 binding to extrastriatal D(2) dopamine receptors in the human brain

To estimate receptor binding of ligand by positron emission tomography (PET) without an arterial input function, several quantitative approaches based on the use of a reference region have been proposed. We compared three approaches for quantifying extrastriatal D(2) dopamine receptors using [(11)C]FLB 457. The PET measurements were performed on seven healthy men. Binding potential (BP) of [(11)C]FLB 457 was calculated by the reference tissue model method, transient equilibrium method, and late time method. The reference tissue model describes the time-activity curve in a brain region in terms of that in the reference region, assuming that the levels of nondisplaceable radioligand binding in both regions are the same. The transient equilibrium theoretically occurs when the derivative for specific binding is zero. With the late time method, BP is calculated by integrating a late part of the time-activity curve. BP values obtained by all methods were in good agreement with those obtained by the kinetic approach, and the highest coefficient of correlation was observed in the reference tissue model method. In the simulation study, the error of BP calculated by the reference tissue model method was smallest. Moreover, the effect of the difference in the influx rate constant K(1) between the brain and the reference regions on BP was nearly avoided as theoretically predicted. We concluded that the reference tissue model method is most suitable for calculating BP of extrastriatal D(2) dopamine receptors with [(11)C]FLB 457.     

Normal database of dopaminergic neurotransmission system in human brain measured by positron emission tomography

The central dopaminergic system is of interest in the pathophysiology of schizophrenia and other neuropsychiatric disorders. Both pre- and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET) with different radiotracers. However, an integrated database of both pre- and postsynaptic dopaminergic neurotransmission components including receptors, transporter, and endogenous neurotransmitter synthesis has not yet been reported. In the present study, we constructed a normal database for the pre- and postsynaptic dopaminergic functions in the living human brain using PET. To measure striatal and extrastriatal dopamine D(1) and D(2) receptor bindings, dopamine transporter binding, and endogenous dopamine synthesis rate, PET scans were performed on healthy men after intravenous injection of [(11)C]SCH23390, [(11)C]raclopride, [(11)C]FLB457, [(11)C]PE2I, or L-[beta-(11)C]DOPA. All PET images were anatomically standardized using SPM2, and a database was built for each radiotracer. Gray matter images were segmented and extracted from all anatomically standardized magnetic resonance images using SPM2, and they were used for partial volume correction. These databases allow the comparison of regional distributions of striatal and extrastriatal dopamine D(1) and D(2) receptors, dopamine transporter, and endogenous dopamine synthesis capability. These distributions were in good agreement with those from human postmortem studies. This database can be used in various researches to understand the physiology of dopaminergic functions in the living human brain. This database could also be used to investigate regional abnormalities of dopaminergic neurotransmission in neuropsychiatric disorders.     

Dopamine D2 receptors in the insular cortex and the personality trait of novelty seeking

Human personality has been considered to have a neurochemical background. We examined the relation between extrastriatal dopamine D2 receptor binding in living human brain and the personality trait of novelty seeking that has been proposed to be related to dopaminergic function in the brain. We measured extrastriatal dopamine D2 receptors of 24 healthy young male subjects using [(11)C]FLB 457 positron emission tomography. The personality trait of each subject was assessed by the Temperament and Character Inventory (TCI). Correlation of dopamine D2 receptor binding with novelty seeking was calculated using region-of-interest analysis and statistical parametric mapping based on the binding potential images generated using a reference tissue model. A significant negative correlation was observed between binding potential values and the novelty seeking scores on TCI in the right insular cortex. No significant correlation was observed in any other region. Our result indicates that there is a significant association between dopamine D2 receptor binding and the human novelty seeking trait in the right insular cortex.     

Error analysis for PET measurement of dopamine D2 receptor occupancy by antipsychotics with [11C]raclopride and [11C]FLB 457

Dopamine D₂ receptor occupancy by antipsychotic drugs has been measured with positron emission tomography (PET) by comparing the binding potential (BP) values before and after drug administration. This occupancy has been found to be related to clinical effects and side effects. In this study, we evaluated the uncertainty of the quantitative analysis for estimating the dopamine D₂ receptor occupancy by antipsychotics in simulation and human studies of [¹¹C]raclopride and for the high affinity ligand [¹¹C]FLB 457. Time–activity curves of [¹¹C]raclopride and [¹¹C]FLB 457 were simulated, and the reliability of BP estimated by a simplified reference tissue model and the calculated occupancy were investigated for various noise levels, BP values, and scan durations. Then, in the human PET study with and without antipsychotics, the uncertainty of BP and occupancy estimates and the scan duration required for a reliable estimation were investigated by a bootstrap approach. Reliable and unbiased estimates of [¹¹C]raclopride BP_ND could be obtained with recording as short as 32 min, with the relative standard deviation (SD) of the striatal occupancy remaining less than 10%. Conversely, in [¹¹C]FLB 457 studies, the mean value increased and SD of the temporal cortex and thalamus exceeded 10% when the scan duration was shorter than 60 min. These results demonstrated that dopamine D₂ receptor occupancy by antipsychotics can be estimated precisely with an optimal scan duration with [¹¹C]raclopride and [¹¹C]FLB 457.     

Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET

Dopaminergic neurotransmission in extrastriatal regions may play a crucial role in the pathophysiology and treatment of neuropsychiatric disorders. The high-affinity radioligands [(11)C]FLB 457, [(123)I]epidepride, and [(18)F]fallypride are now used in clinical studies to measure these low-density receptor populations in vivo. However, a single determination of the regional binding potential (BP) does not differentiate receptor density (B(max)) from the apparent affinity (K(D)). In this positron emission tomography (PET) study, we measured extrastriatal dopamine D2 receptor density (B(max)) and apparent affinity (K(D)) in 10 healthy subjects using an in vivo saturation approach. Each subject participated in two to three PET measurements with different specific radioactivity of [(11)C]FLB 457. The commonly used simplified reference tissue model (SRTM) was used in a comparison of BP values with the B(max) values obtained from the saturation analysis. The calculated regional receptor density values were of the same magnitude (0.33-1.68 nM) and showed the same rank order as reported from postmortem studies, that is, in descending order thalamus, lateral temporal cortex, anterior cinguli, and frontal cortex. The affinity ranged from 0.27 to 0.43 nM, that is, approximately 10-20 times the value found in vitro (20 pM). The area under the cerebellar time activity curve (TAC) was slightly lower (11 +/- 8%, mean +/- SD, P = 0.004, n = 10) after injection of low as compared with high specific radioactivity, indicating sensitivity to the minute density of dopamine D2 receptors in the this region. The results of the present study support that dopamine D2 receptor density and affinity can be differentiated in low-density regions using a saturation approach. There was a significant (P < 0.001) correlation between the binding potential calculated with SRTM and the receptor density (B(max)), which supports the use of BP in clinical studies where differentiation of B(max) and K(D) is not required. In such studies, the mass of FLB 457 has to be less than 0.5 microg injected to avoid a mass effect of the radioligand itself.     

Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy--a simulation study based on experimental data

The D2 dopamine receptor density ranges from 0.2 to 40 nM among human brain regions. For high density regions radioligands like [(11)C]raclopride provide accurate and reliable estimates of the receptor density. In research on neuropsychiatric disorders there is, however, a growing need for quantitative approaches that accurately measure D2 dopamine receptor occupancy induced by drugs or endogenous dopamine in regions with low receptor density. The new high affinity radioligands [(11)C]FLB 457 and [(123)I]epidepride have been shown to provide a signal for extrasriatal D2 dopamine receptor populations in the human brain in vivo. Initial observations indicate, however, that the time required to reach equilibrium is dependent on receptor density. Ratio analyses may thus not be readily used for comparisons among different brain regions. The aim of the present simulation study was to examine commonly used approaches for calculation of drug induced D2 dopamine receptor occupancy among regions with widely different receptor density. The input functions and the rate constants of [(11)C]FLB 457 and the reference ligand [(11)C]raclopride were first used in a simulation estimating the effect of receptor density on equilibrium time. In a second step we examined how errors produced by inaccurate determination of the binding potential parameter propagate to calculations of drug induced receptor occupancy. The simulations showed a marked effect of receptor density on equilibrium time for [(11)C]FLB 457, but not for [(11)C]raclopride. For [(11)C]FLB 457, a receptor density above about 7 nM caused the time of equilibrium to fall beyond time of data acquisition (1 h). The use of preequilibrium data caused the peak equilibrium and the end time ratio approaches but not the simplified reference tissue model (SRTM) approach to underestimate the binding potential and thus also the drug occupancy calculated for high-density regions. The study supports the use of ratio and SRTM analyses in extrastriatal low-density receptor regions for which the high affinity ligand [(11)C]FLB 457 was developed. However, in high-density regions such as the human striatum simple ratio approaches cannot be validly applied, whereas the SRTM approach has higher potential to provide valid estimates. Interestingly, the results suggest that published data on a proposed extrastriatal selectivity for the antipsychotic drugs clozapine and olanzapine may be due to erroneous estimations of the binding potential when using ratio approaches.     

123I]epidepride binding to cerebellar dopamine D2/D3 receptors is displaceable: implications for the use of cerebellum as a reference region

The low density of cerebellar dopamine D(2)/D(3) receptors provides the basis for using the cerebellum as a representation of free- and non-specifically bound radioligand in positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies. With the development of ultra high-affinity dopamine D(2)/D(3) ligands like [(123)I]epidepride, [(18)F]fallypride, and [(11)C]FLB-457, quantification of extrastriatal low density receptor populations including the cerebellum is possible with important implications for calculation of binding parameters. [(123)I]epidepride-SPECT was performed in 23 patients with schizophrenia before and after 3 months of antipsychotic treatment with either risperidone (n=14) or zuclopenthixol (n=9). In the unblocked situation and partially blocked situation, the average distribution volumes were 5.2+/-1.3 mL/mL and 4.0+/-0.8 mL/mL, respectively. The paired distribution volumes were reduced by 22+/-15% (mean+/-SD) after antipsychotic treatment (p<0.0001, paired Student's t-test). From the paired distribution volumes in cerebellum and extrastriatal regions, the average distribution volume representing free and non-specifically bound [(123)I]epidepride was calculated to be 3.3+/-0.8 mL/mL. Both the % [(123)I]epidepride fraction of plasma radioactivity (p>0.76) and the plasma [(123)I]epidepride concentration (p>0.45) were unchanged after antipsychotic treatment (paired Student's t-test). These results strongly suggest the presence of "non-negligible" specific [(123)I]epidepride binding to dopamine D(2)/D(3) receptors in the cerebellum. Using the cerebellum as a representation of free and non-specifically bound radioligand and neglecting the specifically bound component may lead to results that erroneously imply that antipsychotic drugs bind to extrastriatal dopamine D(2)/D(3) receptors with a higher affinity than to striatal dopamine D(2)/D(3) receptors.     

Alfentanil increases cortical dopamine D2/D3 receptor binding in healthy subjects

Animal studies have shown that opioids modulate the function of dopaminergic neurons. The effect of alfentanil on cortical and thalamic binding of the D2/D3 receptor ligand [(11)C]FLB 457 was evaluated in eight healthy subjects with positron emission tomography. The simplified reference tissue model was used to calculate tracer binding potential (BP) during a baseline condition and target-controlled infusion of alfentanil, and the results were analyzed using a comparison group not receiving opioid. Behavioral and analgesic effects of alfentanil were also evaluated. In the region-of-interest analysis, alfentanil increased the BP of [(11)C]FLB 457 in the medial frontal cortex (P=0.0027), dorsolateral prefrontal cortex (P=0.027) superior temporal cortex (P=0.028), and medial thalamus (P=0.003) These results were confirmed in a voxel-based analysis, which further revealed an opioid-induced increase in [(11)C]FLB 457 BP in the anterior cingulate cortex (P<0.001). Alfentanil induced euphoria (P=0.003) and analgesia (P=0.006) Cheerfulness (r=0.918, P=0.001) and euphoria (r=0.982, P<0.001) were associated with increased BP of [(11)C]FLB 457 in the left posterior cingulate cortex, but the analgesic effect of alfentanil did not correlate with changes in [(11)C]FLB 457 BP. The results of this study demonstrate opioid-dopamine interactions in frontal and temporal cortical regions and the thalamus in healthy subjects. Increased D2/D3 tracer binding during opioid infusion may reflect decreased synaptic dopamine levels. The association of the uplifting effect of alfentanil with increased D2/D3 binding in the posterior cingulate cortex suggests that cortical dopamine may be involved in the behavioral effects of opioids.     

Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity

The pain modulatory role of dopamine D2 receptors of the human forebrain was studied by determining the association between dopamine D2 receptor binding potential and the response to experimental pain. Nineteen healthy male volunteers participated in a dopamine D2 receptor positron emission tomography study. The extrastriatal regions of interest studied with [11C]FLB 457 as radioligand (n = 11) were the anterior cingulum, the medial and lateral thalamus, the medial and lateral frontal cortex, and the medial and lateral temporal cortex. The striatal regions of interest studied with [11C]raclopride (n = 8) were the caudate nucleus and the putamen. The latency to the ice water-induced cold pain threshold and tolerance were determined in a separate psychophysical test session. Moreover, the cutaneous heat pain threshold and its elevation by concurrent cold pain in the contralateral hand were determined in each subject. Cold pain threshold was inversely correlated with D2 binding potential in the right putamen and the cold pain tolerance was inversely correlated with D2 binding potential in the right medial temporal cortex. The magnitude of heat pain threshold elevation induced by concurrent cold pain was directly correlated with D2 binding potential in the left putamen. Other correlations of D2 binding potentials in varying brain regions with sensory responses were not significant. A psychophysical control study (n = 10) showed that cold pain responses were identical in the right and left hand. The results indicate that dopamine D2 receptor binding potential in the human forebrain, particularly in the striatum, may be an important parameter in determining the individual cold pain response and the potential for central pain modulation. Accordingly, an individual with only few available D2 receptors in the forebrain is likely to have a high tonic level of pain suppression, combined with a low capacity to recruit more (dopaminergic) central pain inhibition by noxious conditioning stimulation.     

Measuring dopamine neuromodulation in the thalamus: using [F-18]fallypride PET to study dopamine release during a spatial attention task

We used the highly selective D2/D3 dopamine PET radioligand [F-18]fallypride to demonstrate that cognitive task induced dopamine release can be measured in the extrastriatal region of the thalamus, a region containing 10-fold fewer D2 dopamine receptors than the striatum. Human studies were acquired on 8 healthy volunteers using a single [F-18]fallypride injection PET imaging session. A spatial attention task, previously demonstrated to increase FDG uptake in the thalamus, was initiated following a period of radioligand uptake. Thalamic dopamine release was statistically tested by measuring time-dependent alterations in the kinetics (focusing on specific binding) of the [F-18]fallypride using the linearized extension of the simplified reference region model. Voxel-based analysis of the dynamic PET data sets revealed a high correlation (r = 0.86, P = 0.0067) between spatial attention task performance and thalamic dopamine release. Various aspects of the kinetic model were analyzed to address concerns such as blood flow artifacts and model bias, as well as issues with task timing and regional variations in D2/D3 receptor density. In addition to the thalamus, measurement of dopamine neuromodulation using [F-18]fallypride and a single injection PET protocol can be extended to other extrastriatal regions of the brain, such as the amygdala, hippocampus, and regions of the temporal cortex. However, issues of task timing and detection sensitivity will vary depending on regional D2/D3 dopamine receptor density. Measurements of extrastriatal dopamine neuromodulation hold great promise to further our understanding of extrastriatal dopamine involvement in normal cognition and neuropsychiatric pathology.     

Extrastriatal dopamine D2 receptors: distribution, pharmacological characterization and region-specific regulation by clozapine.

The distribution of dopamine D2 receptors in the rat brain was determined by quantitative autoradiography of the binding of [125I]epidepride and the effects of chronic drug administration on regulation of receptors in striatal and extrastriatal brain regions were characterized. [125I]Epidepride (2200 Ci/mmol) bound with high affinity to coronal tissue sections from the rat brain (Kd = 78 pM), and specific binding was detected in a number of discrete layers, nuclei or regions of the hippocampus, thalamus, cerebellum and other extrastriatal sites. Pharmacological analysis of radioligand binding to hippocampal and cerebellar membranes indicated binding to dopamine D2 receptors, and approximately 10% of the binding appeared to represent low affinity idazoxan-displaceable binding to alpha-2 adrenoceptors. The binding to extrastriatal regions resembled previously reported radioligand binding to dopamine D2 receptors in striatal and cortical membranes. Chronic (14 day) administration of two dopamine D2 receptor antagonists, either the typical neuroleptic haloperidol (1.5 mg/kg i.p.) or the atypical neuroleptic clozapine (30 mg/kg i.p.), caused a significant increase in the density of [125I]epidepride binding sites in the medial prefrontal cortex and parietal cortex. Only haloperidol caused a significant increase in the density of [3H]spiperone and [125I]epidepride binding sites in the striatum and a slight increase in [125I]epidepride binding sites in the hippocampus. Similar administration of amphetamine (5 mg/kg i.p.) had no significant effect on the density of dopamine D2 receptors in any brain region examined. In addition, no drug-induced changes in the characteristics of dopamine D2 receptors in discrete areas of the cerebellum were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors

Dopamine's role in inhibitory control is well recognized and its disruption may contribute to behavioral disorders of discontrol such as obesity. However, the mechanism by which impaired dopamine neurotransmission interferes with inhibitory control is poorly understood. We had previously documented a reduction in dopamine D2 receptors in morbidly obese subjects. To assess if the reductions in dopamine D2 receptors were associated with activity in prefrontal brain regions implicated in inhibitory control we assessed the relationship between dopamine D2 receptor availability in striatum with brain glucose metabolism (marker of brain function) in ten morbidly obese subjects (BMI > 40 kg/m²) and compared it to that in twelve non-obese controls. PET was used with [¹¹C]raclopride to assess D2 receptors and with [¹⁸F]FDG to assess regional brain glucose metabolism. In obese subjects striatal D2 receptor availability was lower than controls and was positively correlated with metabolism in dorsolateral prefrontal, medial orbitofrontal, anterior cingulate gyrus and somatosensory cortices. In controls correlations with prefrontal metabolism were not significant but comparisons with those in obese subjects were not significant, which does not permit to ascribe the associations as unique to obesity. The associations between striatal D2 receptors and prefrontal metabolism in obese subjects suggest that decreases in striatal D2 receptors could contribute to overeating via their modulation of striatal prefrontal pathways, which participate in inhibitory control and salience attribution. The association between striatal D2 receptors and metabolism in somatosensory cortices (regions that process palatability) could underlie one of the mechanisms through which dopamine regulates the reinforcing properties of food.     

Limitations of Small Animal PET Imaging with [18F]FDDNP and FDG for Quantitative Studies in a Transgenic Mouse Model of Alzheimer’s Disease

Purpose  We evaluated the usefulness of small animal brain positron emission tomography (PET) imaging with the amyloid-beta (Aβ) probe 2-(1-{6-[(2-[¹⁸F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malonitrile ([¹⁸F]FDDNP) and with 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) for detection and quantification of pathological changes occurring in a transgenic mouse model of Alzheimer’s disease (Tg2576 mice). Procedures  [¹⁸F]FDDNP (n = 6) and FDG-PET scans (n = 3) were recorded in Tg2576 mice (age 13–15 months) and age-matched wild-type litter mates. Brain volumes of interest were defined by co-registration of PET images with a 3D MOBY digital mouse phantom. Regional [¹⁸F]FDDNP retention in mouse brain was quantified in terms of the relative distribution volume (DVR) using Logan’s graphical analysis with cerebellum as a reference region. Results  Except for a lower maximum brain uptake of radioactivity in transgenic animals, the regional brain kinetics as well as DVR values of [¹⁸F]FDDNP appeared to be similar in both groups of animals. Also for FDG, regional radioactivity retention was almost identical in the brains of transgenic and control animals. Conclusions  We could not detect regionally increased [¹⁸F]FDDNP binding and regionally decreased FDG binding in the brains of Tg2576 transgenic versus wild-type mice. However, small group differences in signal might have been masked by inter-animal variability. In addition, technical limitations of the applied method (partial volume effect, spatial resolution) for measurements in such small organs as mouse brain have to be taken into consideration.     

¹⁸F]FDOPA uptake in the raphe nuclei complex reflects serotonin transporter availability. A combined [¹⁸F]FDOPA and [¹¹C]DASB PET study in Parkinson's disease

Brain uptake of [¹⁸F]FDOPA, measured with PET, reflects the activity of aromatic amino acid decarboxylase, an enzyme largely expressed in monoaminergic nerve terminals. This enzyme catalyzes a number of decarboxylation reactions including conversion of l-dopa into dopamine and 5-hydroxytryptophan into serotonin. For more than 20 years [¹⁸F]FDOPA PET has been used to assess dopaminergic nigrostriatal dysfunction in patients with Parkinson's disease (PD). More recently, however, [¹⁸F]FDOPA PET has also been employed as a marker of serotoninergic and noradrenergic function in PD patients. In this study, we provide further evidence in support of the view that [¹⁸F]FDOPA PET can be used to evaluate the distribution and the function of serotoninergic systems in the brain.Eighteen patients with PD were investigated with both [¹⁸F]FDOPA and [¹¹C]DASB PET, the latter being a marker of serotonin transport (SERT) availability. We then assessed the relationship between measurements of the two tracers within brain serotoninergic structures. [¹⁸F]FDOPA uptake in the median raphe nuclei complex of PD patients was significantly correlated with SERT availability in the same structure. Trends towards significant correlations between [¹⁸F]FDOPA Ki values and [¹¹C]DASB binding values were also observed in the hypothalamus and the anterior cingulate cortex, suggesting a serotoninergic contribution to [¹⁸F]FDOPA uptake in these regions. Conversely, no correlations were found in brain structures with mixed dopaminergic, serotoninergic and noradrenergic innervations, or with predominant dopaminergic innervation.These findings provide evidence that [¹⁸F]FDOPA PET represents a valid marker of raphe serotoninergic function in PD and supports previous studies where [¹⁸F]FDOPA PET has been used to assess serotoninergic function in PD.     

Wavelet-aided parametric mapping of cerebral dopamine D2 receptors using the high affinity PET radioligand [11C]FLB 457

The study of human neuroreceptor systems by means of positron emission tomography (PET) and suitable radioligands has proven to be of great importance in research on normal brain functions and the pathophysiology and treatment of neuropsychiatric disorders. A for long identified goal is to produce detailed parametric maps of showing neuroreceptor binding parameters for the entire human brain in vivo. The application of wavelet filters has recently been proposed as a solution to handle the inherently low signal-to-noise ratio of PET images. In the present study we applied the wavelet approach to data obtained from 10 healthy subjects who were examined with [11C]FLB 457. This high affinity dopamine D2-receptor antagonist provides a signal from a range of regions with a hundredfold difference in receptor density and should thus be suitable for evaluation of the wavelet approach. For cross-validation purposes the data were analysed with four methods: a traditional region-of-interest (ROI) based analysis, a pixel-based analysis and two variants of wavelet-aided analyses. In both variants the wavelet filter was spatially applied, but a two-dimensional filter was used in one case and a three-dimensional one in the other. The same linear-graphical binding potential (BP) estimation step was used for all methods and the results of the three parametric mapping techniques were compared to the reference ROI-based method by calculating the average BP of representative ROIs. The pixel-based and the two-dimensional-wavelet-based methods yielded highly correlated but systematically lower values when compared to the reference ROI-based method. The approach utilising three-dimensional wavelet filters yielded BP maps with regional averages closely matching the values of the ROI-based method. The results show that the combination of three-dimensional spatial wavelet filtering with established parameter estimation procedures provides detailed, accurate maps of radioligand binding parameters. Such maps can be used for in inter-individual or multi-condition comparisons of binding parameters at subregional levels.     

First Evaluation of [11C]R116301 as an In Vivo Tracer of NK1 Receptors in Man

Purpose  NK1 receptors have been implicated in various neuropsychiatric and other disorders. R116301 is a selective NK1 receptor antagonist. In this pilot study, [¹¹C]R116301 was evaluated as a potential positron emission tomography (PET) ligand for the NK1 receptor. Procedures  Two dynamic PET studies were performed in three normal volunteers before and after a blocking dose of aprepitant. Data were analyzed using striatum to cerebellum standardized uptake value (SUV) ratios. Results  Baseline SUV ratios at 60–90 min after injection ranged from 1.22 to 1.70. Following aprepitant administration, this specific signal was completely blocked. Aprepitant administration did not significantly affect uptake in cerebellum, confirming the absence of NK1 receptors in cerebellum. Conclusion  These preliminary results indicate that [¹¹C]R116301 has potential as a radioligand for in vivo assessment of NK1 receptors in the human brain.     

Imaging the Dopamine System with <Emphasis Type="Italic">In Vivo</Emphasis> [<Superscript>11</Superscript>C]raclopride Displacement Studies: Understanding the True Mechanism

Measuring changes in dopamine (DA) levels in humans using radioligand-displacement studies and positron emission tomography (PET) has provided important empirical findings in diseases and normal neurophysiology. These studies are based on the assumption that DA exerts a competitive inhibition on D₂-radioligand binding. However, the transfer of this hypothesis to a proven mechanism has not been fully achieved yet and an accumulating number of studies challenge it. In addition, new evidence suggests that DA exerts a noncompetitive inhibition on D₂-radioligand binding under amphetamine conditions. This article reviews the theoretical basis for the DA competition hypothesis, the in vivo and in vitro evidences supporting a noncompetitive action of DA on D₂-radioligand binding under amphetamine conditions, and discusses possible mechanisms underlying this noncompetitive interaction. Finally, we propose that such noncompetitive interactions may have important implications for how one interprets findings obtained from radioligand-displacement PET studies in neuropsychiatric diseases, especially in schizophrenia in which a dysregulation of the DA-promoted internalization of D₂ receptors was recently suggested.     

In vivo quantification of dopamine transporters in mice with unilateral 6-OHDA lesions using [11C]methylphenidate and PET

Quantification of the binding of [¹¹C]methylphenidate to the dopamine transporter (DAT) using positron emission tomography (PET) is often used to evaluate the integrity of dopaminergic neurons in the striatal regions of the brain. Over the past decade, many genetically engineered mouse models of human disease have been developed and have become particularly useful for the study of disease onset and progression over time. Quantitative imaging of small structures such as the mouse brain is especially challenging. Thus, the aims of this study were (1) to evaluate the accuracy of quantifying DAT binding using in vivo PET and (2) to examine the impact of different methodologies.

Methods

Eight mice were scanned with [¹¹C]methylphenidate under true or transient equilibrium conditions using a bolus and constant infusion protocol or a bolus injection protocol to evaluate the accuracy of the Logan graphical approach for [¹¹C]methylphenidate imaging in mice. Displacement with unlabeled methylphenidate (0.1, 3 and 10 mg/kg) was used to verify specific binding. In a second experiment, 30 mice were lesioned by injection of 6-hydroxydopamine (6-OHDA) at doses of 0, 2 or 4 μg (n = 10) into the right striatum to assess the dose-dependent correlation between the PET signal and dopaminergic degeneration. In addition, we performed test-retest experiments and used ex vivo autoradiography (AR) to validate the effect of partial volume on the accuracy of the [¹¹C]methylphenidate PET quantification in the mouse striatum.

Results

The binding potentials (BP_ND) calculated from the Logan graphical analysis under transient equilibrium conditions (1.03 ± 0.1) were in excellent agreement with those calculated at true equilibrium (1.07 ± 0.1). Displacement of specific binding with 0.1, 3 and 10 mg/kg methylphenidate resulted in 38%, 77% and 81% transporter occupancy in the striatum. Intra-striatal injections of 6-OHDA caused a dose-dependent decrease in the specific binding of [¹¹C]methylphenidate to the DAT in the striatum. The BP_ND was reduced by 49% and 61% after injection with 2 and 4 μg of 6-OHDA, respectively. The test-retest reproducibility was 6% in the healthy striatum and 27% in the lesioned striatum. In addition, only a small (15%) difference was found between the [¹¹C]methylphenidate DVR-1 values determined by PET and AR on the healthy side, and no differences were observed on the lesioned side.

Conclusion

The present work demonstrates for the first time that [¹¹C]methylphenidate PET is useful for the quantification of striatal dopamine transporters at the dopaminergic nerve terminals in the mouse striatum; therefore, this marker may be used as a biomarker in genetically engineered mouse models of neurodegenerative disorders. However, only changes resulting in greater than 10% differences in BP_ND values can reliably be detected in vivo.