Specific and non-specific binding of a tracer for the translocator-specific protein in schizophrenia: an [11C]-PBR28 blocking study.

OBJECTIVE: The mitochondrial 18-kDa translocator protein (TSPO) is expressed by activated microglia and positron emission tomography enables the measurement of TSPO levels in the brain. Findings in schizophrenia have shown to vary depending on the outcome measure used and this discrepancy in TSPO results could be explained by lower non-displaceable binding (VND) in schizophrenia, which could obscure increases in specific binding. In this study, we have used the TSPO ligand XBD173 to block the TSPO radioligand [11C]-PBR28 and used an occupancy plot to quantify VND in patients with schizophrenia. METHODS: A total of 7 patients with a diagnosis of schizophrenia were recruited for this study. Each patient received two separate PET scans with [11C]PBR28, one at baseline and one after the administration of the TSPO ligand XBD173. All patients were high-affinity binders (HABs) for the TSPO gene. We used an occupancy plot to quantify the non-displaceable component (VND) using 2TCM kinetic estimates with and without vascular correction. Finally we computed the VND at a single subject level using the SIME method. RESULTS: All patients showed a global and generalized reduction in [11C]PBR28 uptake after the administration of XBD173. Constraining the VND to be equal for all patients, the population VND was estimated to be 1.99 mL/cm3 (95% CI 1.90 to 2.08). When we used vascular correction, the fractional TSPO occupancy remained similar. CONCLUSIONS: In schizophrenia patients, a substantial component of the [11C]PBR28 signal represents specific binding to TSPO. Furthermore, the VND in patients with schizophrenia is similar to that previously reported in healthy controls. These results suggest that changes in non-specific binding between schizophrenia patients and healthy controls do not account for discrepant PET findings in this disorder.

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvß6 integrin inhibitor.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvß6) integrin inhibitor, in participants with IPF. METHODS: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvß6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. RESULTS: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. CONCLUSIONS: This study demonstrated engagement of the αvß6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. TRIAL REGISTRATION: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.

Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system.

Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 ± 28%) and dorsal tiers (-21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.

Evidence for GABA-A receptor dysregulation in gambling disorder: correlation with impulsivity.

As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11 C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11 C]Ro15-4513 total distribution volume (VT ) in the right hippocampus in the GD group compared with HV. We found higher levels of the 'Negative Urgency' construct of impulsivity in GD, and these were positively associated with higher [11 C]Ro15-4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11 C]Ro15-4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.

Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease.

There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.

Loss of phosphodiesterase 10A expression is associated with progression and severity in Parkinson's disease.

The mechanisms underlying neurodegeneration and loss of dopaminergic signalling in Parkinson's disease are still only partially understood. Phosphodiesterase 10A (PDE10A) is a basal ganglia expressed dual substrate enzyme, which regulates cAMP and cGMP signalling cascades, thus having a key role in the regulation of dopaminergic signalling in striatal pathways, and in promoting neuronal survival. This study aimed to assess in vivo the availability of PDE10A in patients with Parkinson's disease using positron emission tomography molecular imaging with (11)C-IMA107, a highly selective PDE10A radioligand. We studied 24 patients with levodopa-treated, moderate to advanced Parkinson's disease. Their positron emission tomography imaging data were compared to those from a group of 12 healthy controls. Parametric images of (11)C-IMA107 binding potential relative to non-displaceable binding (BPND) were generated from the dynamic (11)C-IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue. Corresponding region of interest analysis showed lower mean (11)C-IMA107 BPND in the caudate (P < 0.001), putamen (P < 0.001) and globus pallidus (P = 0.025) in patients with Parkinson's disease compared to healthy controls, which was confirmed with voxel-based analysis. Longer Parkinson's duration correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.65; P = 0.005), putamen (r = -0.51; P = 0.025), and globus pallidus (r = -0.47; P = 0.030). Higher Unified Parkinson's Disease Rating Scale part-III motor scores correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.54; P = 0.011), putamen (r = -0.48; P = 0.022), and globus pallidus (r = -0.70; P < 0.001). Higher Unified Dyskinesia Rating Scale scores in those Parkinson's disease with levodopa-induced dyskinesias (n = 12), correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.73; P = 0.031) and putamen (r = -0.74; P = 0.031). Our findings demonstrate striatal and pallidal loss of PDE10A expression, which is associated with Parkinson's duration and severity of motor symptoms and complications. PDE10A is an enzyme that could be targeted with novel pharmacotherapy, and this may help improve dopaminergic signalling and striatal output, and therefore alleviate symptoms and complications of Parkinson's disease.

Connectivity-based functional analysis of dopamine release in the striatum using diffusion-weighted MRI and positron emission tomography.

The striatum acts in conjunction with the cortex to control and execute functions that are impaired by abnormal dopamine neurotransmission in disorders such as Parkinson's and schizophrenia. To date, in vivo quantification of striatal dopamine has been restricted to structure-based striatal subdivisions. Here, we present a multimodal imaging approach that quantifies the endogenous dopamine release following the administration of d-amphetamine in the functional subdivisions of the striatum of healthy humans with [(11)C]PHNO and [(11)C]Raclopride positron emission tomography ligands. Using connectivity-based (CB) parcellation, we subdivided the striatum into functional subregions based on striato-cortical anatomical connectivity information derived from diffusion magnetic resonance imaging (MRI) and probabilistic tractography. Our parcellation showed that the functional organization of the striatum was spatially coherent across individuals, congruent with primate data and previous diffusion MRI studies, with distinctive and overlapping networks. d-amphetamine induced the highest dopamine release in the limbic followed by the sensory, motor, and executive areas. The data suggest that the relative regional proportions of D2-like receptors are unlikely to be responsible for this regional dopamine release pattern. Notably, the homogeneity of dopamine release was significantly higher within the CB functional subdivisions in comparison with the structural subdivisions. These results support an association between local levels of dopamine release and cortical connectivity fingerprints.

Spatio-temporal pharmacokinetic model based registration of 4D PET neuroimaging data.

In dynamic positron emission tomography (PET) neuroimaging studies, where scan durations often exceed 1h, registration of motion-corrupted dynamic PET images is necessary in order to maintain the integrity of the physiological, pharmacological, or biochemical information derived from the tracer kinetic analysis of the scan. In this work, we incorporate a pharmacokinetic model, which is traditionally used to analyse PET data following any registration, into the registration process itself in order to allow for a groupwise registration of the temporal time frames. The new method is shown to achieve smaller registration errors and improved kinetic parameter estimates on validation data sets when compared with image similarity based registration approaches. When applied to measured clinical data from 10 healthy subjects scanned with [(11)C]-(+)-PHNO (a dopamine D3/D2 receptor tracer), it reduces the intra-class variability on the receptor binding outcome measure, further supporting the improvements in registration accuracy. Our method incorporates a generic tracer kinetic model which makes it applicable to different PET radiotracers to remove motion artefacts and increase the integrity of dynamic PET studies.

Amphetamine induced endogenous opioid release in the human brain detected with [¹¹C]carfentanil PET: replication in an independent cohort.

This study aimed to replicate a previous study which showed that endogenous opioid release, following an oral dose of amphetamine, can be detected in the living human brain using [11C]carfentanil positron emission tomography (PET) imaging. Nine healthy volunteers underwent two [11C]carfentanil PET scans, one before and one 3 h following oral amphetamine administration (0.5 mg/kg). Regional changes in [11C]carfentanil BPND from pre- to post-amphetamine were assessed. The amphetamine challenge led to significant reductions in [11C]carfentanil BPND in the putamen, thalamus, frontal lobe, nucleus accumbens, anterior cingulate, cerebellum and insula cortices, replicating our earlier findings. None of the participants experienced significant euphoria/'high', supporting the use of oral amphetamine to characterize in vivo endogenous opioid release following a pharmacological challenge. [11C]carfentanil PET is able to detect changes in binding following an oral amphetamine challenge that reflects endogenous opioid release and is suitable to characterize the opioid system in neuropsychiatric disorders.

Discovery and Model-Informed Drug Development of a Controlled-Release Formulation of Nonracemic Amisulpride that Reduces Plasma Exposure but Achieves Pharmacodynamic Bioequivalence in the Brain.

Nonracemic amisulpride (SEP-4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP-4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled-release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24-hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non-human primates produced significantly greater D2R occupancies during a gradual 6-hour administration compared with a single bolus; (iii) concentration-occupancy curves were left-shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model-informed drug development to continue in Phase III using the non-bioequivalent CR formulation with diminished QT prolongation as dose-equivalent to the immediate release (IR) formulation utilized in Phase II.

Mathematical modelling of [¹¹C]-(+)-PHNO human competition studies.

The D(2)/D(3) agonist radioligand [(11)C]-(+)-PHNO is currently the most suitable D(3) imaging agent available, despite its limited selectivity for the D(3) over the D(2). Given the collocation of D(2) and D(3) receptors, and generally higher densities of D(2), the separation of D(2) and D(3) information from [(11)C]-(+)-PHNO PET data are somewhat complex. This complexity is compounded by recent data suggesting that [(11)C]-(+)-PHNO PET scans might be routinely performed in non-tracer conditions (with respect to D(3) receptors), and that the cerebellum (used as a reference region) might manifest some displaceable binding signal. Here we present the modelling and analysis of data from two human studies which employed an adequate dose range of selective D(3) antagonists (GSK598809 and GSK618334) to interrogate the [(11)C]-(+)-PHNO PET signal. Models describing the changes observed in the PET volume of distribution (V(T)) and binding potential (BP(ND)) were used to identify and quantify a [(11)C]-(+)-PHNO mass dose effect at the D(3), and displaceable signal in the cerebellum, as well as providing refined estimates of regional D(3) fractions of [(11)C]-(+)-PHNO BP(ND). The dose of (+)-PHNO required to occupy half of the available D(3) receptors (ED(50)(PHNO,D3)) was estimated as 40ng/kg, and the cerebellum BP(ND) was estimated as 0.40. These findings confirm that [(11)C]-(+)-PHNO human PET studies are in fact routinely performed under non-tracer conditions. This suggests that (+)-PHNO injection masses should be minimised and tightly controlled in order to mitigate the mass dose effect. The specific binding detected in the cerebellum was modest but could have a significant effect, for example on estimates of D(3) potency in drug occupancy studies. A range of methods for the analysis of future [(11)C]-(+)-PHNO data, incorporating models for the effects quantified here, were developed and evaluated. The comparisons and conclusions drawn from these can inform the design and analysis of future PET studies with [(11)C]-(+)-PHNO.

Orbitofrontal connectivity with resting-state networks is associated with midbrain dopamine D3 receptor availability.

Animal research and human postmortem evidence highlight the importance of brain dopamine D3 receptor (D3R) function in multiple neuropsychiatric disorders, including addiction. Separate anatomical and functional neuroimaging findings implicate disrupted frontal cortical connectivity with distributed brain networks in processes relevant for these diseases. This potential conjunction between molecular and functional markers has not, however, been tested directly. Here, we used a novel combination of [(11)C]-(+)-PHNO positron emission tomography and resting-state functional magnetic resonance imaging in the same healthy individuals to investigate whether differences in midbrain D3R availability are associated with functional interactions between large-scale networks and regions involved in reward processing and cognition. High midbrain D3R availability was associated with reduced functional connectivity between orbitofrontal cortex (OFC) and networks implicated in cognitive control and salience processing. The opposite pattern was observed in subcortical reward circuitry and the "default mode" network, which showed greater connectivity with OFC in individuals with high D3R availability. These findings demonstrate that differential interactions between OFC and networks implicated in cognitive control and reward are associated with midbrain D3R availability, consistent with the hypothesis that dopamine D3R signaling is an important molecular pathway underlying goal-directed behavior.

Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge.

BACKGROUND: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. METHODS: Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16-30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [11C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region. RESULTS: Following d-amphetamine administration, frontal nondisplaceable binding potential (BPND) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBPND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041). CONCLUSIONS: This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE.

Adenosine A2A receptor in schizophrenia: an in vivo brain PET imaging study.

Adenosine A2A receptors are highly enriched in the basal ganglia system, a region that is functionally implicated in schizophrenia. Preclinical evidence suggests a cross-regulation between adenosine A2A and dopamine D2 receptors in this region and that it is linked to the sensitization of the dopamine system. However, the relationship between A2A receptor availability and schizophrenia has not been directly examined in vivo in patients with this disorder. To investigate, using positron emission tomography (PET), the availability of A2A receptors in patients diagnosed with schizophrenia in comparison to matched healthy controls. A2A receptor availability was measured using the PET tracer [11C]SCH442416. Twelve male patients with chronic schizophrenia were compared to 13 matched healthy subjects. All patients were medicated with antipsychotics and none presented with any motor or extrapyramidal symptoms. Binding potential (BPND), a ratio measure between specific and non-specific tracer uptake, were compared between the groups for the caudate, putamen, accumbens and globus pallidum. There was no differences between A2A receptor binding potential (BPND) of schizophrenia patients in the caudate (p = 0.16), putamen (p = 0.86), accumbens (p = 0.44) and globus pallidum (p = 0.09) to that of matched healthy subjects. There was also no significant correlation between [11C]SCH442416 binding and severity of psychotic symptoms (p = 0.2 to 0.82) or antipsychotic dosage (p = 0.13 to 0.34). By showing that A2A receptor availability in medicated patients with chronic male schizophrenia is not different than in healthy controls, this study does not support the primary role of this receptor in the pathogenesis of schizophrenia.

Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [11C]PHNO PET.

The use of positron emission tomography (PET) in early-phase development of novel drugs targeting the central nervous system, is well established for the evaluation of brain penetration and target engagement. However, when novel targets are involved a suitable PET ligand is not always available. We demonstrate an alternative approach that evaluates the attenuation of amphetamine-induced synaptic dopamine release by a novel agonist of the orphan G-protein-coupled receptor GPR139 (TAK-041). GPR139 agonism is a novel candidate mechanism for the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction. Ten healthy volunteers underwent [11C]PHNO PET at baseline, and twice after receiving an oral dose of d-amphetamine (0.5 mg/kg). One of the post-d-amphetamine scans for each subject was preceded by a single oral dose of TAK-041 (20 mg in five; 40 mg in the other five participants). D-amphetamine induced a significant decrease in [11C]PHNO binding potential relative to the non-displaceable component (BPND) in all regions examined (16-28%), consistent with increased synaptic dopamine release. Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BPND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BPND was generally higher after the 40 mg than the 20 mg TAK-041 dose, with the difference between doses reaching statistical significance in the putamen. Our findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [11C]PHNO PET is a practical method to detect the effects of novel drugs on the brain dopaminergic system in healthy volunteers, in the early stages of drug development.

Imaging dopamine receptors in humans with [11C]-(+)-PHNO: dissection of D3 signal and anatomy.

[(11)C]-(+)-PHNO is a D3 preferring PET radioligand which has recently opened the possibility of imaging D3 receptors in the human brain in vivo. This imaging tool allows characterisation of the distribution of D3 receptors in vivo and further investigation of their functional role. The specific [(11)C]-(+)-PHNO signal is a mixture of D3 and D2 components with the relative magnitude of each component determined by the regional receptor densities. An accurate and reproducible delineation of regions of interest (ROI) is therefore important for optimal analysis of human PET data. We present a set of anatomical guidelines for the delineation of D3 relevant ROIs including substantia nigra, hypothalamus, ventral pallidum/substantia innominata, ventral striatum, globus pallidus and thalamus. Delineation of these structures using this approach allowed for high intra- and inter-operator reproducibility. Subsequently we used a selective D3 antagonist to dissect the total [(11)C]-(+)-PHNO signal in each region into its D3 and D2 components and estimated the regional fraction of the D3 signal (f(PHNO)(D3)). In descending order of magnitude the following results for the f(PHNO)(D3) were obtained: hypothalamus=100%, substantia nigra=100%, ventral pallidum/substantia innominata=75%, globus pallidus=65%, thalamus=43%, ventral striatum=26% and precommissural-ventral putamen=6%. An automated approach for the delineation of these anatomical regions of interest was also developed and investigated in terms of its reproducibility and accuracy.

Advances in biomathematical modeling for PET neuroreceptor imaging.

The quantitative application of PET neuroreceptor imaging to study pathophysiology, diagnostics and drug development has continued to benefit from associated advances in biomathematical imaging methodology. We review some of these advances with particular focus on multi-modal image processing, tracer kinetic modeling, occupancy studies and discovery and development of novel radioligands.:

Specificity of translocator protein-targeted positron emission tomography in inflammatory joint disease.

OBJECTIVE: Expression of the translocator protein (TSPO) on inflammatory cells has facilitated imaging of synovitis with TSPO-targeted positron emission tomography (PET). We aimed to quantitatively assess the specificity of the second-generation TSPO PET radioligand, [11C]PBR28, and to generate simplified PET protocols in patients with inflammatory joint disease (IJD) in this pilot study. METHODS: Three IJD patients (two rheumatoid arthritis and one osteoarthritis) with knee involvement underwent dynamic [11C]PBR28-PET scans before and after administration of 90 mg of oral emapunil (XBD-173), a TSPO ligand the same day. Radial arterial blood sampling was performed throughout the scan, and total radioactivity and radioactive metabolites were obtained. A semi-automated method was used to generate regions of interest. Standardized uptake value (SUV) and SUV ratio corrected for activity in bone and blood between 50 and 70 min (SUVr50-70 bone, SUVr50-70 blood, respectively) and PET volume of distribution (VT) of the radioligand were calculated. RESULTS: A mean [11C]PBR28 radioactivity of 378 (range 362-389) MBq was administered. A significant decrease (p < 0.05) in VT, SUVr50-70 bone and SUVr50-70 blood observed after oral emapunil confirmed the TSPO specificity of [11C]PBR28. A decrease in SUV was not observed in the post-block scan. CONCLUSION: [11C]PBR28 is TSPO-specific radioligand in IJD patients. Simplified PET protocols with static PET acquisition can be used in the management and evaluation of novel therapeutics that target TSPO overexpressing cells.

Integrin αvß6 Positron Emission Tomography Imaging in Lung Cancer Patients Treated With Pulmonary Radiation Therapy.

PURPOSE: Post radiation therapy (RT) lung fibrosis is a major barrier to improved cure rate in lung cancer. Integrin αvß6 plays a key role in fibrogenesis by activating transforming growth factor-ß. Positron emission tomography (PET) studies with a fluorine-18 radiolabelled αvß6 radioligand, [18F]-FBA-A20FMDV2, were performed to assess uptake, and the relationship to RT dose parameters was explored. METHODS AND MATERIALS: Recently treated non-small cell lung cancer patients (<6 months after RT) had [18F]-FBA-A20FMDV2-PET scans, coregistered with the RT planning computed tomography and segmented to RT doses of >40 Gy (excluding tumor), 25 to 40 Gy, 15 to 25 Gy, 8 to 15 Gy, and <8 Gy. PET uptake (standardized uptake value; SUV) corrected for tissue density between 10 and 60 minutes (SUV10-60) was calculated and compared with RT dose, dose per fraction, and biological effective dose (BED). PET uptake was also evaluated in healthy volunteers. RESULTS: Six non-small cell lung cancer (3 male; 3 female) subjects scanned between 6 and 22 weeks after RT and 6 healthy volunteers (3 males; 3 females) were evaluated. Higher mean PET uptake (SUV10-60) was observed in the irradiated lung compared with the healthy lung (2.97 vs 1.99; P < .05). A significant and positive pharmacodynamic relationship was observed between radioligand uptake (SUV10-60) and dose per RT fraction (r2 = 0.63; P < .001) and with BED for fibrosis (r2 = 0.38; P < .001 for α/ß 3 Gy and r2 = 0.33; P < 0.001 for α/ß 5 Gy). CONCLUSIONS: Higher uptake in the irradiated lung and a pharmacodynamic relationship between αvß6 radioligand uptake versus RT dose per fraction and BED for lung fibrosis is consistent with RT induced activation of αvß6 integrin and supports a role for αvß6 in the induction of lung fibrosis after pulmonary RT. αvß6-PET imaging may potentially aid in the assessment and management of radiation-induced pulmonary fibrosis.

Serotonin release measured in the human brain: a PET study with [11C]CIMBI-36 and d-amphetamine challenge.

Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 h after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 min, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum) - 1. ∆BPNDfrontal = 1 - (BPNDfrontal post-dose/BPNDfrontal baseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal. Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13% (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson's disease is enabled.