First-in-Human Evaluation of 18F-PF-06445974, a PET Radioligand That Preferentially Labels Phosphodiesterase-4B.

Phosphodiesterase-4 (PDE4), which metabolizes the second messenger cyclic adenosine monophosphate (cAMP), has 4 isozymes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4B and PDE4D have the highest expression in the brain and may play a role in the pathophysiology and treatment of depression and dementia. This study evaluated the properties of the newly developed PDE4B-selective radioligand 18F-PF-06445974 in the brains of rodents, monkeys, and humans. Methods: Three monkeys and 5 healthy human volunteers underwent PET scans after intravenous injection of 18F-PF-06445974. Brain uptake was quantified as total distribution volume (V T) using the standard 2-tissue-compartment model and serial concentrations of parent radioligand in arterial plasma. Results: 18F-PF-06445974 readily distributed throughout monkey and human brain and had the highest binding in the thalamus. The value of V T was well identified by a 2-tissue-compartment model but increased by 10% during the terminal portions (40 and 60 min) of the monkey and human scans, respectively, consistent with radiometabolite accumulation in the brain. The average human V T values for the whole brain were 9.5 ± 2.4 mL ⋅ cm-3 Radiochromatographic analyses in knockout mice showed that 2 efflux transporters-permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP)-completely cleared the problematic radiometabolite but also partially cleared the parent radioligand from the brain. In vitro studies with the human transporters suggest that the parent radioligand was a partial substrate for BCRP and, to a lesser extent, for P-gp. Conclusion: 18F-PF-06445974 quantified PDE4B in the human brain with reasonable, but not complete, success. The gold standard compartmental method of analyzing brain and plasma data successfully identified the regional densities of PDE4B, which were widespread and highest in the thalamus, as expected. Because the radiometabolite-induced error was only about 10%, the radioligand is, in the opinion of the authors, suitable to extend to clinical studies.

Brain exposure of the ATM inhibitor AZD1390 in humans-a positron emission tomography study.

BACKGROUND: The protein kinase ataxia telangiectasia mutated (ATM) mediates cellular response to DNA damage induced by radiation. ATM inhibition decreases DNA damage repair in tumor cells and affects tumor growth. AZD1390 is a novel, highly potent, selective ATM inhibitor designed to cross the blood-brain barrier (BBB) and currently evaluated with radiotherapy in a phase I study in patients with brain malignancies. In the present study, PET was used to measure brain exposure of 11C-labeled AZD1390 after intravenous (i.v.) bolus administration in healthy subjects with an intact BBB. METHODS: AZD1390 was radiolabeled with carbon-11 and a microdose (mean injected mass 1.21 µg) was injected in 8 male subjects (21-65 y). The radioactivity concentration of [11C]AZD1390 in brain was measured using a high-resolution PET system. Radioactivity in arterial blood was measured to obtain a metabolite corrected arterial input function for quantitative image analysis. Participants were monitored by laboratory examinations, vital signs, electrocardiogram, adverse events. RESULTS: The brain radioactivity concentration of [11C]AZD1390 was 0.64 SUV (standard uptake value) and reached maximum 1.00% of injected dose at Tmax[brain] of 21 min (time of maximum brain radioactivity concentration) after i.v. injection. The whole brain total distribution volume was 5.20 mL*cm-3. No adverse events related to [11C]AZD1390 were reported. CONCLUSIONS: This study demonstrates that [11C]AZD1390 crosses the intact BBB and supports development of AZD1390 for the treatment of glioblastoma multiforme or other brain malignancies. Moreover, it illustrates the potential of PET microdosing in predicting and guiding dose range and schedule for subsequent clinical studies.

Quantification and reliability of [11C]VC - 002 binding to muscarinic acetylcholine receptors in the human lung - a test-retest PET study in control subjects.

BACKGROUND: The radioligand [11C]VC-002 was introduced in a small initial study long ago for imaging of muscarinic acetylcholine receptors (mAChRs) in human lungs using positron emission tomography (PET). The objectives of the present study in control subjects were to advance the methodology for quantification of [11C]VC-002 binding in lung and to examine the reliability using a test-retest paradigm. This work constituted a self-standing preparatory step in a larger clinical trial aiming at estimating mAChR occupancy in the human lungs following inhalation of mAChR antagonists. METHODS: PET measurements using [11C]VC-002 and the GE Discovery 710 PET/CT system were performed in seven control subjects at two separate occasions, 2-19 days apart. One subject discontinued the study after the first measurement. Radioligand binding to mAChRs in lung was quantified using an image-derived arterial input function. The total distribution volume (VT) values were obtained on a regional and voxel-by-voxel basis. Kinetic one-tissue and two-tissue compartment models (1TCM, 2TCM), analysis based on linearization of the compartment models (multilinear Logan) and image analysis by data-driven estimation of parametric images based on compartmental theory (DEPICT) were applied. The test-retest repeatability of VT estimates was evaluated by absolute variability (VAR) and intraclass correlation coefficients (ICCs). RESULTS: The 1TCM was the statistically preferred model for description of [11C]VC-002 binding in the lungs. Low VAR (< 10%) across analysis methods indicated good reliability of the PET measurements. The VT estimates were stable after 60 min. CONCLUSIONS: The kinetic behaviour and good repeatability of [11C]VC-002 as well as the novel lung image analysis methodology support its application in applied studies on drug-induced mAChR receptor occupancy and the pathophysiology of pulmonary disorders. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03097380, registered: 31 March 2017.

PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [18F]PF-06684511.

PURPOSE: Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer's disease. [18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [18F]PF-06684511 in healthy volunteers. METHODS: Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (VT) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of VT were calculated as reliability measures. RESULTS: In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 µSv/MBq). The calculated ED was 24.7 ± 0.8 µSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. VT (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of VT (2TCM) were 16.5% (12.4-20.5%) and 0.496 (0.291-0.644). CONCLUSION: The ED of [18F]PF-06684511 was similar to other 18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of VT was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. TRIAL REGISTRATION: EudraCT 2016-001110-19 (registered 2016-08-08).

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [11C]PBR28 HRRT PET study.

PURPOSE: The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. METHODS: [11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. RESULTS: There were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. CONCLUSION: These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.

D1-Dopamine Receptor Availability in First-Episode Neuroleptic Naive Psychosis Patients.

BACKGROUND: Positron emission tomography studies examining differences in D1-dopamine receptor binding between control subjects and patients with schizophrenia have been inconsistent, reporting higher, lower, and no difference in the frontal cortex. Exposure to antipsychotic medication has been suggested to be a likely source of this heterogeneity, and thus there is a need for studies of patients at early stages of the disorder who have not been exposed to such drugs. METHODS: Here, we compared 17 healthy control subjects and 18 first-episode neuroleptic naive patients with schizophrenia or schizophreniform psychosis using positron emission tomography and the D1-dopamine receptor radioligand [11C]SCH23390. RESULTS: We observed a statistically significant difference in the dorsolateral prefrontal cortex. Contrary to our expectations, patients had less D1-dopamine receptor availability with a moderate effect size. In a Bayesian analysis, we show that the data are over 50 times more likely to have occurred under the decrease as opposed to the increase hypothesis. This effect was not global, as our analysis showed that the null hypothesis was preferred over either hypothesis in the striatum. CONCLUSIONS: This investigation represents the largest single sample of neuroleptic-naive patients examined for D1-dopamine receptor availability using PET and suggests a reduction of prefrontal D1-dopamine receptor density in the pathophysiology of schizophrenia. However, further work will be required to reach a consensus.

Venlafaxine ER Blocks the Norepinephrine Transporter in the Brain of Patients with Major Depressive Disorder: a PET Study Using [18F]FMeNER-D2.

BACKGROUND: The in vivo binding of clinical dose of venlafaxine on norepinephrine transporter has been questioned because venlafaxine has higher in vitro affinity to serotonin transporter than that to norepinephrine transporter. Although serotonin transporter occupancy of clinically relevant doses of venlafaxine has been reported, there has been no report of norepinephrine transporter occupancy in the human brain. METHODS: This was an open-label, single center, exploratory positron emission tomography study. Twelve major depressive disorder patients who had responded to venlafaxine extended-release and 9 control subjects were recruited. Each subject participated in one positron emission tomography measurement with [18F]FMeNER-D2. Binding potential in brain was quantified by the area under the curve ratio method with thalamus as target and white matter as reference regions. The difference of binding potential values between control and patient groups divided to 2 dose ranges were evaluated. Norepinephrine transporter occupancy (%) for all the major depressive disorder patients was calculated using mean binding potential of control subjects as baseline. The relationships between dose or plasma concentration of total active moiety and occupancies of norepinephrine transporter were also estimated. RESULTS: The binding potential of the patient group with 150 to 300 mg/d was significantly lower than that in the control subjects group (P = .0004 < .05/2). The norepinephrine transporter occupancy (8-61%) increased in a dose-dependent manner although a clear difference beyond 150 mg/d was not observed. CONCLUSIONS: This study demonstrates that clinically relevant doses of venlafaxine extended-release block the norepinephrine transporter of the major depressive disorder patient's brain. The data support the notion that the antidepressant effect of venlafaxine involves a combination of serotonin transporter and norepinephrine transporter blockades.

[11C]SCH23390 binding to the D1-dopamine receptor in the human brain-a comparison of manual and automated methods for image analysis.

BACKGROUND: The D1-dopamine receptor radioligand [11C]SCH23390 has been frequently used in PET studies. In drug-naïve patients with schizophrenia, the findings have been inconsistent, with decreases, increases, and no change in the frontal cortex D1-dopamine receptors. While these discrepancies are likely primarily due to a lack of statistical power in these studies, we speculated that an additional explanation may be the differences due to methods of image analysis between studies, affecting reliability as well as bias between groups. METHODS: Fifteen healthy subjects underwent two PET measurements with [11C]SCH23390 on the same day. The binding potential (BPND) was compared using a 95% confidence interval following manual and automated delineation of a region of interest (ROI) as well as with and without frame-by-frame realignment. RESULTS: Automated target region delineation produced lower BPND values, while automated delineation of the reference region yielded higher BPND values. However, no significant differences were observed for repeatability using automated and manual delineation methods. Frame-by-frame realignment generated higher BPND values and improved repeatability. CONCLUSIONS: The results suggest that the choice of ROI delineation method is not an important factor for reliability, whereas the improved results following movement correction confirm its importance in PET image analysis. Realignment is therefore especially important for measurements in patient populations such as schizophrenia or Parkinson's disease, where motion artifacts may be more prevalent.

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain.

PURPOSE: Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (11C-THK5351 and 11C-PBB3) in a head-to-head, in vivo, multimodal design. METHODS: Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer's disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer's disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers 11C-THK5351 and 11C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer 11C-AZD2184, a T1-MRI sequence, and neuropsychological assessment. RESULTS: The load and regional distribution of binding differed between 11C-THK5351 and 11C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of 11C-PBB3, but not that of 11C-THK5351, in the temporal lobe resembled that of 11C-AZD2184, with strong correlations detected between 11C-PBB3 and 11C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with 11C-THK5351 than with 11C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with 11C-THK5351 than with 11C-PBB3 binding. CONCLUSION: This research suggests different molecular targets for these tracers; while 11C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of 11C-THK5351 fitted the expected distribution of tau pathology in Alzheimer's disease better and was more closely related to downstream disease markers.

Is dopamine D1 receptor availability related to social behavior? A positron emission tomography replication study.

BACKGROUND: Associations between dopamine receptor levels and pro- and antisocial behavior have previously been demonstrated in human subjects using positron emission tomography (PET) and self-rated measures of personality traits. So far, only one study has focused on the dopamine D1-receptor (D1-R), finding a positive correlation with the trait social desirability, which is characterized by low dominant and high affiliative behavior, while physical aggression showed a negative correlation. The aim of the present study was to replicate these previous findings using a new independent sample of subjects. MATERIALS AND METHODS: Twenty-six healthy males were examined with the radioligand [11C]SCH-23390, and completed the Swedish universities Scales of Personality (SSP) which includes measures of social desirability and physical trait aggression. The simplified reference tissue model with cerebellum as reference region was used to calculate BPND values in the whole striatum and limbic striatum. The two regions were selected since they showed strong association between D1-R availability and personality scores in the previous study. Pearson's correlation coefficients and replication Bayes factors were then employed to assess the replicability and robustness of previous results. RESULTS: There were no significant correlations (all p values > 0.3) between regional BPND values and personality scale scores. Replication Bayes factors showed strong to moderate evidence in favor no relationship between D1-receptor availability and social desirability (striatum BF01 = 12.4; limbic striatum BF01 = 7.2) or physical aggression scale scores (limbic striatum BF01 = 3.3), compared to the original correlations. DISCUSSION: We could not replicate the previous findings of associations between D1-R availability and either pro- or antisocial behavior as measured using the SSP. Rather, there was evidence in favor of failed replications of associations between BPND and scale scores. Potential reasons for these results are restrictive variance in both PET and personality outcomes due to high sample homogeneity, or that the previous findings were false positives.

Test-retest reproducibility of [11C]-L-deprenyl-D2 binding to MAO-B in the human brain.

BACKGROUND: [11C]-L-deprenyl-D2 is a positron emission tomography (PET) radioligand for measurement of the monoamine oxidase B (MAO-B) activity in vivo brain. The estimation of the test-retest reproducibility is important for accurate interpretation of PET studies. RESULTS: We performed two [11C]-L-deprenyl-D2 scans for six healthy subjects and evaluated the test-retest variability of this radioligand. MAO-B binding was quantified by two tissue compartment model (2TCM) with three rate constants (K 1, k 2, k 3) using metabolite-corrected plasma radioactivity. The λk 3 defined as (K 1/k 2) × k 3 was also calculated. The correlation between MAO-B binding and age, and the effect of partial volume effect correction (PVEc) for the reproducibility were also estimated. %difference of k 3 was 2.6% (medial frontal cortex) to 10.3% (hippocampus), and that of λk 3 was 5.0% (thalamus) to 9.2% (cerebellum). Mean %difference of all regions were 5.3 and 7.0% in k 3 and λk 3, respectively. All regions showed below 10% variabilities except the hippocampus in k 3 (10.3%). Intraclass correlation coefficient (ICC) of k 3 was 0.78 (hippocampus) to 0.98 (medial frontal cortex), and that of λk 3 was 0.78 (hippocampus) to 0.95 (thalamus). Mean ICC were 0.94 and 0.89 in k 3 and λk 3, respectively. The highest positive correlation with age was observed in the hippocampus, as r = 0.75 in k 3 and 0.76 in λk 3. After PVEc, mean %difference were 5.6 and 7.2% in k 3 and λk 3, respectively. Mean ICC were 0.92 and 0.90 for k 3 and λk 3, respectively. These values were almost the same as those before PVEc. CONCLUSIONS: The present results indicate that k 3 and λk 3 of [11C]-L-deprenyl-D2 are reliable parameters for test-retest reproducibility with healthy subjects both before and after PVEc. The studies with patients of larger sample size are required for further clinical applications.

Reliability of volumetric and surface-based normalisation and smoothing techniques for PET analysis of the cortex: A test-retest analysis using [11C]SCH-23390.

Parametric voxelwise analysis is a commonly used tool in neuroimaging, as it allows for identification of regions of effects in the absence of a strong a-priori regional hypothesis by comparing each voxel of the brain independently. Due to the inherent imprecision of single voxel measurements, spatial smoothing is performed to increase the signal-to-noise ratio of single-voxel estimates. In addition, smoothing compensates for imprecisions in anatomical registration, and allows for the use of cluster-based statistical thresholding. Smoothing has traditionally been applied in three dimensions, without taking the tissue types of surrounding voxels into account. This procedure may be suitable for subcortical structures, but is problematic for cortical regions for which grey matter often constitutes only a small proportion of the smoothed signal. New methods have been developed for cortical analysis in which voxels are sampled to a surface, and smoothing is restricted to neighbouring regions along the cortical grey matter in two dimensions. This procedure has recently been shown to decrease intersubject variability and bias of PET data. The aim of this study was to compare the variability, bias and test-retest reliability of volumetric and surface-based methods as they are applied in practice. Fifteen healthy young males were each measured twice using the dopamine D1 receptor radioligand [11C]SCH-23390, and analyses were performed at the level of individual voxels and vertices within the cortex. We found that surface-based methods yielded higher BPND values, lower coefficient of variation, less bias, better reliability and more precise estimates of parametric binding. All in all, these results suggest that surface-based methods exhibit superior performance to volumetric approaches for voxelwise analysis of PET data, and we advocate for their use when a ROI-based analysis is not appropriate.

In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects.

Phosphodiesterase 10A (PDE10A) is an enzyme highly enriched in the striatal medium spiny neurons. It is involved in the regulation of cytoplasmic levels of cAMP and cGMP and signaling within the basal ganglia. This study with PDE10A radioligand [18F]MNI-659 was designed to measure the enzyme occupancy of PF-02545920 in 8 healthy male volunteers (48 ± 4 years) after a single oral dose (10 mg or 20 mg) and to evaluate safety and tolerability. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function for the quantification of [18F]MNI-659 binding to PDE10A. The occupancy of PF-02545920 was calculated with two different methods: In Method 1, [18F]MNI-659 enzyme occupancy was calculated from the estimates of binding potential, using the cerebellum as a reference region; in Method 2, occupancy was estimated from the slope of the revised Lassen's plot. Serum concentrations of PF-02545920 were measured to determine the relationship between concentration and occupancy. Based on Method 1, striatal PDE10A occupancy increased with increasing PF-02545920 dose: 14-27% at 10 mg dose (N = 4) and 45-63% at 20 mg dose (N = 3). Comparable occupancies were observed using Lassen's plot Method 2: 10 mg: 14-37%; 20 mg: 46-55%. The relationship between exposure and occupancy was best described using an Emax model. The serum concentration associated with 50% occupancy was estimated to be 93.2 ng/mL. Single oral doses of 10 mg or 20 mg of PF-02545920 were safe and well tolerated in healthy male volunteers [NCT# 01918202].

Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer's disease and elderly controls after oral administration of sembragiline.

PURPOSE: In Alzheimer's disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminergic neurotransmitters, reduce the formation of toxic ROS and reduce neuroinflammation (reactive astrocytosis), potentially leading to neuroprotection. Sembragiline (also referred as RO4602522, RG1577 and EVT 302 in previous communications) is a potent, selective and reversible inhibitor of MAO-B developed as a potential treatment for AD. METHODS: This study assessed the relationship between plasma concentration of sembragiline and brain MAO-B inhibition in patients with AD and in healthy elderly control (EC) subjects. Positron emission tomography (PET) scans using [11C]-L-deprenyl-D2 radiotracer were performed in ten patients with AD and six EC subjects, who received sembragiline each day for 6-15 days. RESULTS: At steady state, the relationship between sembragiline plasma concentration and MAO-B inhibition resulted in an Emax of ∼80-90 % across brain regions of interest and in an EC50 of 1-2 ng/mL. Data in patients with AD and EC subjects showed that near-maximal inhibition of brain MAO-B was achieved with 1 mg sembragiline daily, regardless of the population, whereas lower doses resulted in lower and variable brain MAO-B inhibition. CONCLUSIONS: This PET study confirmed that daily treatment of at least 1 mg sembragiline resulted in near-maximal inhibition of brain MAO-B enzyme in patients with AD.

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans.

RATIONALE: Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABAA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABAAα2,3 receptor positive modulators with limited sedative effects. OBJECTIVES: The current study aimed to confirm target engagement at GABAA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABAA receptor occupancy, and tolerability. METHOD: Two PET studies, using high-resolution research tomography (HRRT) and the radioligand [11C]flumazenil, were performed in 12 subjects at baseline and after administration of single oral doses of AZD7325 (0.2 to 30 mg) and AZD6280 (5 to 40 mg). PET images were analyzed using a simplified reference tissue model, and regional binding potentials (BPND) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABAA receptor occupancy was described by hyperbolic function, and K i,plasma (plasma concentration required for 50% receptor occupancy) was estimated. Assessments of safety and tolerability included recording of adverse events, vital signs, electrocardiogram, and laboratory tests. RESULTS: The [11C]flumazenil binding was reduced in a dose-dependent, saturable manner by both agents. Maximum receptor occupancy could be reached for both compounds without causing sedation or cognitive impairment. The K i,plasma estimates for AZD7325 and AZD6280 were 15 and 440 nmol/l, respectively. CONCLUSION: High GABAA receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects.

A human [(11)C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor.

Phosphodiesterase 10A (PDE10A) is selectively expressed in the striatal regions in the brain and may play a role in modulating dopaminergic and glutamatergic second messenger pathways. PDE10A inhibitors are expected to be useful in treating neuropsychiatric disorders such as schizophrenia and Huntington's disease. In this study, the brain kinetics of [(11)C]T-773 in the human brain and test-retest reproducibility of the outcome measures were evaluated. Subsequently, the occupancy of a novel PDE10A inhibitor, TAK-063, was measured using [(11)C]T-773. Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [(11)C]T-773: two baseline PETs and one postdose PET (3hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3hours and 23hours) for eight subjects. Kinetic model analysis was performed with arterial input functions. PDE10A occupancy was calculated as the percent change of the binding specific to PDE10A (Vs) total distribution volume (VT), which was calculated as the VT of the putamen minus the VT of the cerebellum. Regional brain uptake was highest in the putamen. Time-activity curves of the brain regions were described with two tissue-compartment (2TC) models. The mean VT was 5.5±0.7 in the putamen and 2.3±0.5 in the cerebellum in the baseline PET. Absolute VT variability between the two baseline scans was less than 7%. Reproducibility of VT was excellent. PDE10A occupancy in the putamen ranged from 2.8% to 72.1% at 3hours after a single administration of 3 to 1000mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100mg of TAK-063. In conclusion, [(11)C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.

Dopamine D1 receptor availability is related to social behavior: a positron emission tomography study.

Dysfunctional interpersonal behavior is thought to underlie a wide spectrum of psychiatric disorders; however, the neurobiological underpinnings of these behavioral disturbances are poorly understood. Previous molecular imaging studies have shown associations between striatal dopamine (DA) D2-receptor binding and interpersonal traits, such as social conformity. The objective of this study was to explore, for the first time, the role of DA D1-receptors (D1-Rs) in human interpersonal behavior. Twenty-three healthy subjects were examined using positron emission tomography and the radioligand [(11)C]SCH23390, yielding D1-R binding potential values. Striatal D1-R binding was related to personality scales selected to specifically assess one dimension of interpersonal behavior, namely a combination of affiliation and dominance (i.e., the Social Desirability, Verbal Trait Aggression and Physical Trait Aggression scales from Swedish Universities Scales of Personality). An exploratory analysis was also performed for extrastriatal brain regions. D1-R binding potential values in the limbic striatum (r = .52; p = .015), associative striatum (r = .55; p = .009), and sensorimotor striatum (r = .67; p = .001) were positively related to Social Desirability scores. D1-R binding potential in the limbic striatum (r = -.51; p = .019) was negatively associated with Physical Trait Aggression scores. For extrastriatal regions, Social Desirability scores showed positive correlations in the amygdala (r = .60; p = .006) and medial frontal cortex (r = .60; p = .004). This study provides further support for the role of DA function in the expression of disaffiliative and dominant traits. Specifically, D1-R availability may serve as a marker for interpersonal behavior in humans. Associations were demonstrated for the same dimension of interpersonal behavior as for D2-R, but in the opposite direction, suggesting that the two receptor subtypes are involved in the same behavioral processes, but with different functional roles.

A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066 - estimating occupancy in the absence of a reference region.

AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [(11)C]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived from each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret.

In vivo TSPO imaging in patients with multiple sclerosis: a brain PET study with [18F]FEDAA1106.

BACKGROUND: The activation of microglia, in general, and the upregulation of the translocator protein (18 kDa) (TSPO) system, in particular, are key features of neuroinflammation, of which the in vivo visualization and quantitative assessment are still challenging due to the lack of appropriate molecular imaging biomarkers. Recent positron emission tomography (PET) studies using TSPO radioligands such as [11C]PK11195 and [11C]PBR28 have indicated the usefulness of these PET biomarkers in patients with neuroinflammatory diseases, including multiple sclerosis (MS). [18F]FEDAA1106 is a recently developed PET radioligand for the in vivo quantification of TSPO. In the present study, we aimed at investigating the diagnostic usefulness of [18F]FEDAA1106 in patients with MS. METHODS: Nine patients (three on the interferon beta therapy and six without immunomodulatory therapy; seven females/two males; age 34.2 ± 9.1 years old) with relapsing-remitting MS in acute relapse and with gadolinium (Gd)-enhancing lesion(s) in the magnetic resonance imaging (MRI) scans and five healthy controls (four females/one male, age 38.0 ± 9.7 years old) were investigated in this study. Genetic information about the TSPO binding could not be obtained because knowledge about the importance of genetic background for TSPO binding was not available at the time the study was performed. Dynamic PET measurements were performed using an ECAT EXACT HR system (CTI/Siemens, Knoxville, TN, USA) for a total of 150 min, with a 30-min break after the injection of 153.4 ± 10.2 MBq of [18F]FEDAA1106. Metabolite-corrected arterial plasma samples were used to calculate the input function. PET data were analyzed in the following ways: (1) region-of-interest analysis for cortical and subcortical regions was performed using a two-tissue compartment kinetic model in order to estimate binding potentials (BPND) and distribution volume (VT), (2) the feasibility of the estimation of BPND and VT was investigated for MS lesions, and (3) VT parametric images by a Logan plot and standard uptake value (SUV) images were visually compared with the corresponding MRI, focusing on MRI-identified MS lesions. RESULTS: There were no significant differences in the BPND or VT values between patients with MS and healthy controls. Robust BPND and VT values could not be obtained for most MS lesions due to noisy time-activity curves. Visual inspection of VT and SUV images in all nine patients did not reveal high uptake of the radioligand inside and beyond MRI-identified active MS lesions with the exception of one Gd-enhanced MS lesion in the whole patient population. CONCLUSIONS: In our study, [18F]FEDAA1106 as a PET radioligand could neither differentiate patients with MS from healthy controls nor detect active plaques in the brain of MS patients. Stratification with respect to genetics and binder status might help to uncover the differences between the groups, which could not be detected here. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01031199.

A PET study with [11C]AZ10419369 to determine brain 5-HT1B receptor occupancy of zolmitriptan in healthy male volunteers.

AIM: To investigate the occupancy at brain 5-hydroxytryptamine (5-HT) 1B receptors in human subjects after administration of the antimigraine drug zolmitriptan. METHODS: Positron emission tomography (PET) studies were undertaken using the radioligand [(11)C]AZ10419369 in eight control subjects at baseline and after administration of zolmitriptan orodispersible tablets. The subjects were examined after two consecutive administrations of 10 mg zolmitriptan, approximately 1 week apart. Two of the subjects were subsequently examined after administration of 5 mg zolmitriptan. One week after the last administration of zolmitriptan five of the subjects underwent additional PET measurements without drug pretreatment. RESULTS: After administration of 10 mg zolmitriptan, mean receptor occupancy was 4-5%. No consistent changes in 5-HT1B receptor binding were observed for subjects who received 5 mg zolmitriptan. There was a statistically significant negative relationship between binding potential ( BP ND) and plasma concentration of zolmitriptan and the active metabolite 183C91, respectively. All of the five subjects who were examined 1 week after dosing with zolmitriptan showed higher BP ND post drug administration compared with baseline. CONCLUSION: This is the first demonstration of CNS 5-HT1B receptor occupancy of a triptan. The findings are consistent with the low receptor occupancy previously reported in PET studies with agonists at other G protein coupled receptors.