Aims To investigate, for a given energy expenditure ( EE ) rise, the differential effects of glucagon infusion and cold exposure on brown adipose tissue ( BAT ) activation in humans. Methods Indirect calorimetry and supraclavicular thermography was performed in 11 healthy male volunteers before and after: cold exposure; glucagon infusion (at 23 °C); and vehicle infusion (at 23 °C). All volunteers underwent 18 F ‐fluorodeoxyglucose ( 18 F‐FDG ) positron emission tomography ( PET )/ CT scanning with cold exposure. Subjects with cold‐induced BAT activation on 18 F‐FDG PET / CT (n = 8) underwent a randomly allocated second 18 F‐FDG PET / CT scan (at 23 °C), either with glucagon infusion (n = 4) or vehicle infusion (n = 4). Results We observed that EE increased by 14% after cold exposure and by 15% after glucagon infusion (50 ng/kg/min; p < 0.05 vs control for both). Cold exposure produced an increase in neck temperature (+0.44 °C; p < 0.001 vs control), but glucagon infusion did not alter neck temperature. In subjects with a cold‐induced increase in the metabolic activity of supraclavicular BAT on 18 F‐FDG PET / CT , a significant rise in the metabolic activity of BAT after glucagon infusion was not detected. Cold exposure increased sympathetic activation, as measured by circulating norepinephrine levels, but glucagon infusion did not. Conclusions Glucagon increases EE by a similar magnitude compared with cold activation, but independently of BAT thermogenesis. This finding is of importance for the development of safe treatments for obesity through upregulation of EE .
Positron emission tomography (PET) was used to examine whether the dose of pindolol used to augment antidepressant medication achieves a significant occupancy of the serotonin type 1A (5-HT(1A)) autoreceptor in depressed patients receiving medication.The authors examined eight depressed patients on one of two regimes of pindolol (2.5 mg t.i.d. and 5.0 mg t.i.d.) with PET and [11C]WAY-100635.The 5-mg t.i.d. regime achieved a modest (19%) but significant occupancy of the 5-HT(1A) autoreceptor, while the regime used in the vast majority of clinical trials (2.5 mg t.i.d.) did not achieve a significant occupancy.The dose of pindolol used in clinical trials is suboptimal and may explain the inconsistent results. Therefore, a thorough test of pindolol's efficacy will necessitate doses higher than those used in present clinical trials.
Abstract 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 [ 11 C]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 [ 11 C]PHNO binding potential relative to the non-displaceable component (BP ND ) 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 BP ND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BP ND 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. [ 11 C]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.
11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer's disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer's brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer's disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.
The role of glial activation in neuropathology of Alzheimer's disease (AD) is recognised as not just a consequence of amyloid deposition and tau aggregation, but as a contributing factor for their formation. Astrocytes are actively involved in the neuroinflammatory responses. Their activation is associated with over-expression of monoamine-oxidase B and Imidazoline-2 (I2) receptors. The latter is more selectively expressed by astroglia. In this study, we evaluated uptake of the novel PET tracer [11C]-BU99008, targeting the I2 receptors, in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Ten AD/MCI subjects and ten age matched healthy control underwent 3 Tesla MRI and 120 min [11C]BU99008 PET scanning with arterial input, after injection of approximately 300 MBq of [11C]BU99008. Arterially-derived plasma input-function compartmental modelling was used to quantify VT using MIAKATTM (www.miakat.org). Individual brain region of interest atlas was fitted using individual T1-weighted MRI image and a modified CICatlas_v2.0 using unified segmentation in SPM. The reversible two-tissue-compartmental model (2TCM4k) showed the best fit for the data. One-way ANOVA was used to compare [11C]BU99008 uptake between groups. We found a greater difference in the [11C]-BU99008 uptake in frontal (p=0.02, 17% increase), parietal (p=0.03, 15% increase), occipital (p=0.05, 13% increase) medio-temporal lobes (p=0.04, 13% increase) and cerebellum (p=0.04, 14% increase) in the disease (MCI/AD) than in the HC group. Five patients in the cohort were amyloid positive (3 MCI and 2 AD). The amyloid positive population had greater [11C]BU99008 uptake in frontal (p<0.01, 25% increase), temporal (p<0.05, 18% increase), parietal (p<0.01, 24% increase), occipital (p<0.05, 21% increase) and medio-temporal (p<0.01, 21% increase) lobes compared to the HC or to the amyloid negative subjects. This study confirms the [11C]BU99008 PET tracer ability to detect differences in astroglial metabolism consistent with activation between healthy volunteers and people with AD. A higher uptake in the amyloid positive population compared to the amyloid negative and the HCs is consistent with recognised roles for astrocyte activation in AD, e.g., for clearing Aβ deposition. This study demonstrates the potential of [11C]BU99008 as a marker for aspects of the molecular pathology of AD.
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