Roger N. Gunn

Dopamine Transmission in the Human Striatum during Monetary Reward Tasks

Previous studies have demonstrated the ability of the [11C]raclopride positron emission tomography (PET) technique to measure behaviorally induced changes in endogenous dopamine transmission in humans. However, these studies have lacked well matched sensorimotor control conditions, making it difficult to know what sensory, cognitive, or motor features contributed to changes in dopaminergic activity. Here we report on [11C]raclopride PET studies in which healthy humans performed card selection tasks for monetary rewards. During separate scans, subjects completed a variable ratio (VR) reward schedule with a 25% reward rate in which they did not know the outcome of their responses in advance, a fixed ratio (FR) 25% reward schedule in which outcomes were fully predictable, and a sensorimotor control (SC) condition involving similar sensory and motor demands but no rewards. Relative to the SC condition, the FR schedule produced only modest increases in dopamine transmission and no decreases relative to the SC condition. In contrast, the VR schedule produced significant increases in dopamine transmission in the left medial caudate nucleus while simultaneously producing significant decreases in other areas of the caudate and putamen. These data indicate: (1) the feasibility of measuring alterations in dopamine transmission even after controlling for sensorimotor features and (2) the complex and regionally specific influence of VR schedules on dopamine transmission. The implications of these results are discussed in relation to conflicting models of dopaminergic functioning arising from studies using electrophysiological and microdialysis techniques in animals.

Two Binding Sites for [3H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation

[11C]PBR28, a radioligand targeting the translocator protein (TSPO), does not produce a specific binding signal in approximately 14% of healthy volunteers. This phenomenon has not been reported for [11C]PK11195, another TSPO radioligand. We measured the specific binding signals with [3H]PK11195 and [3H]PBR28 in brain tissue from 22 donors. Overall, 23% of the samples did not generate a visually detectable specific autoradiographic signal with [3H]PBR28, although all samples showed [3H]PK11195 binding. There was a marked reduction in the affinity of [3H]PBR28 for TSPO in samples with no visible [3H]PBR28 autoradiographic signal (K i =188±15.6 nmol/L), relative to those showing normal signal (K i =3.4±0.5 nmol/L, P<0.001). Of this latter group, [3H]PBR28 bound with a two-site fit in 40% of cases, with affinities (K i ) of 4.0±2.4 nmol/L (high-affinity site) and 313±77 nmol/L (low-affinity site). There was no difference in Kd or Bmax for [3H]PK11195 in samples showing no [3H]PBR28 autoradiographic signal relative to those showing normal [3H]PBR28 autoradiographic signal. [3H]PK11195 bound with a single site for all samples. The existence of three different binding patterns with PBR28 (high-affinity binding (46%), low-affinity binding (23%), and two-site binding (31%)) suggests that a reduction in [11C]PBR28 binding may not be interpreted simply as a reduction in TSPO density. The functional significance of differences in binding characteristics warrants further investigation.

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 (BPND) in eight cortical regions. Under controlled conditions, [11C]FLB 457 BPND was 30–70% higher compared with [11C]fallypride BPND in cortical regions. Amphetamine induced DA release led to a significant decrease in [11C]FLB 457 BPND in five out the eight cortical regions evaluated. In contrast, no significant decrease in [11C]fallypride BPND 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.

Pittsburgh Compound B (11C-PIB) and Fluorodeoxyglucose (18 F-FDG) PET in Patients With Alzheimer Disease, Mild Cognitive Impairment, and Healthy Controls

Amyloid load in the brain using Pittsburgh compound B (11C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using fluorodeoxyglucose (18F-FDG) PET were evaluated in patients with mild Alzheimer disease (AD, n = 18), mild cognitive impairment (MCI, n = 24), and controls (CTR, n = 18). 11C-PIB binding potential (BPND) was higher in prefrontal cortex, cingulate, parietal cortex, and precuneus in AD compared to CTR or MCI and in prefrontal cortex for MCI compared to CTR. For 18F-FDG, regional cerebral metabolic rate for glucose (rCMRGlu) was decreased in precuneus and parietal cortex in AD compared to CTR and MCI, with no MCI—CTR differences. For the AD—CTR comparison, precuneus BPND area under the receiver operating characteristic (ROC) curve (AUC) was 0.938 and parietal cortex rCMRGlu AUC was 0.915; for the combination, AUC was 0.989. 11C-PIB PET BPND clearly distinguished diagnostic groups and combined with 18F-FDG PET rCMRGlu, this effect was stronger. These PET techniques provide complementary information in strongly distinguishing diagnostic groups in cross-sectional comparisons that need testing in longitudinal studies.

Modeling Dynamic PET-SPECT Studies in the Wavelet Domain

This work develops a theoretical framework and corresponding algorithms for the modeling of dynamic PET-SPECT studies both in time and space. The problem of estimating the spatial dimension is solved by applying the wavelet transform to each scan of the dynamic sequence and then performing the kinetic modeling and statistical analysis in the wavelet domain. On reconstruction through the inverse wavelet transform, one obtains parametric images that are consistent estimates of the spatial patterns of the kinetic parameter of interest. The theoretical setup allows the use of linear techniques currently used in PET-SPECT for kinetic analysis. The method is applied to artificial and real data sets. The application to dynamic PET-SPECT studies was performed both for validation purposes, when the spatial patterns are known, and for illustration of the advantages offered by the technique in case of tracers with an unknown pattern of distribution.

Within-subject comparison of striatal D2 receptor occupancy measurements using [123I]IBZM SPECT and [11C]Raclopride PET.

Antipsychotic-induced D2 receptor occupancy values tend to be lower when measured with [(123)I]IBZM SPECT than with [(11)C]Raclopride PET. To clarify this issue, D2 receptor occupancy was measured in the same subjects using both techniques. Twenty patients with schizophrenia on monotherapy with risperidone (n=7; 3-9 mg/d), olanzapine (n=5; 5-20 mg/d) or clozapine (n=8; 150-450 mg/d) at stable doses, and ten healthy volunteers (HV) underwent both a [(123)I]IBZM SPECT and a [(11)C]Raclopride PET examinations in random order on different days within a week. Patients with schizophrenia were scanned at a fixed interval after last dose administration. Quantification of receptor availability was performed using the most conventional methods from the literature: the tissue ratio derived specific uptake ratios (SUR) were used for SPECT, and simplified reference tissue model (SRTM) derived binding potentials (BP(ND)) for PET. Analysis was performed using both occipital cortex and cerebellum as reference regions for both modalities. Striatal D2 receptor occupancy was measured as the percentage reduction of [(123)I]IBZM SUR or [(11)C]Raclopride BP(ND) compared to the population average measured in HV using the same modality. Occupancy values measured by SPECT were lower than those measured with PET, by 12.4% and 13.8% when occipital cortex and cerebellum were used as reference regions. This difference should be taken in consideration when interpreting reported antipsychotic striatal D2 receptor occupancy values from the literature.

PET studies in drug development: Methodological considerations.

Positron emission tomography (PET), as an in vivo pharmacological imaging tool in experimental medicine, is playing an increasing role in drug development. There are two areas where PET is particularly useful in this respect, namely biodistribution and drug occupancy studies. Radiotracer design, the properties of the molecular targets which can be studied and the quantitative estimation of pharmacological endpoints will be discussed in relation to these applications, with particular reference to studies in brain.:

Unexpectedly high affinity of a novel histamine H3 receptor antagonist, GSK239512, in vivo in human brain, determined using PET

This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H3 receptors (RO) in healthy human volunteers.

Wavelet variance components in image space for spatiotemporal neuroimaging data

Neuroimaging studies place great emphasis on not only the estimation but also the standard error estimates of underlying parameters derived from a temporal model. This allows inferences to be made about the signal estimates and resulting conclusions to be drawn about the underlying data. It can often be advantageous to interrogate temporal models after spatial transformation of the data into the wavelet domain. Wavelet bases provide a multiresolution decomposition of the spatial data dimension and an ensuing reduction in spatial correlation. However, widespread acceptance of these wavelet techniques has been hampered by the limited ability to reconstruct both parametric and error estimates into the image domain after analysis of temporal models in the wavelet domain. This paper introduces a derivation and a fast implementation of a method for the calculation of the variance of the parametric images obtained from wavelet filters. The technique is proposed for a class of estimators that have been shown to be useful in neuroimaging studies. The techniques are demonstrated for both functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) data sets.

Monoamine Transporter Occupancy of a Novel Triple Reuptake Inhibitor in Baboons and Humans Using Positron Emission Tomography

The selection of a therapeutically meaningful dose of a novel pharmaceutical is a crucial step in drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between the plasma concentration of a drug and its target occupancy, optimizing dose selection and reducing the time and cost of early development. Triple reuptake inhibitors (TRIs), also referred to as serotonin-norepinephrine-dopamine reuptake inhibitors, enhance monoaminergic neurotransmission by blocking the action of the monoamine transporters, raising extracellular concentrations of those neurotransmitters. GSK1360707 [(1R,6S)-1-(3,4-dichlorophenyl)-6-(methoxymethyl)-4-azabicyclo[4.1.0]heptane] is a novel TRI that until recently was under development for the treatment of major depressive disorder; its development was put on hold for strategic reasons. We present the results of an in vivo assessment of the relationship between plasma exposure and transporter blockade (occupancy). Studies were performed in baboons (Papio anubis) to determine the relationship between plasma concentration and occupancy of brain serotonin reuptake transporter (SERT), dopamine reuptake transporter (DAT), and norepinephrine uptake transporter (NET) using the radioligands [11C]DASB [(N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine], [11C]PE2I [N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane], and [11C]2-[(2-methoxyphenoxy)phenylmethyl]morpholine (also known as [11C]MRB) and in humans using [11C]DASB and [11C]PE2I. In P. anubis, plasma concentrations resulting in half-maximal occupancy at SERT, DAT, and NET were 15.16, 15.56, and 0.97 ng/ml, respectively. In humans, the corresponding values for SERT and DAT were 6.80 and 18.00 ng/ml. GSK1360707 dose-dependently blocked the signal of SERT-, DAT-, and NET-selective PET ligands, confirming its penetration across the blood-brain barrier and blockade of all three monoamine transporters in vivo.