scholarly journals Characterization of in vivo Pharmacokinetic Properties of the Dopamine D1 Receptor Agonist DAR-0100A in Nonhuman Primates Using PET with [11C] NNC112 and [11C] Raclopride

2010 ◽  
Vol 31 (1) ◽  
pp. 293-304 ◽  
Author(s):  
Mark Slifstein ◽  
Raymond F Suckow ◽  
Jonathan A Javitch ◽  
Thomas Cooper ◽  
Jeffrey Lieberman ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
D1 Receptor ◽  
D1 Receptors ◽  
Detectable Effect ◽  
Positron Emission ◽  
Pharmacokinetic Properties ◽  
D1 Agonist ◽  
Different Doses

DAR-0100A, the active enantiomer of dihydrexidine, is a potent dopamine D1 agonist under investigation for treatment of cognitive impairment and negative symptoms of schizophrenia. We measured the dose–occupancy relationship for DAR-0100A at D1 receptors using positron emission tomography (PET) imaging in baboons with [11C] NNC112 and its binding to D2 with [11C] raclopride. Two baboons were scanned with [11C] NNC112 at baseline and after three different doses of DAR-0100A. Two baboons were scanned with [11C] raclopride at baseline and after one dose of DAR-0100A. Occupancy (ΔBPND) was computed in the striatum and cortex. A clear relationship was observed between plasma concentration of DAR-0100A and ΔBPND. ΔBPND was larger in the striatum than in the cortex, consistent with reports showing that 25% of [11C] NNC112 BPND in the cortex is attributed to 5-HT2A. Plasma EC50 estimates ranged from 150 to 550 ng/mL according to the constraints on the model. There was no detectable effect of DAR-0100A on [11C] raclopride BPND. These data suggest that at doses likely to be administered to patients, occupancy will not be detectable with [11C] NNC112 PET and binding of DAR-0100A to D2 will be negligible. This is the first demonstration with PET of a significant occupancy by a full D1 agonist in vivo.

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

scholarly journals Kinetic Analysis of Drug–Target Interactions with PET for Characterization of Pharmacological Hysteresis

2013 ◽  
Vol 33 (5) ◽  
pp. 700-707 ◽  
Author(s):  
Cristian Salinas ◽  
David Weinzimmer ◽  
Graham Searle ◽  
David Labaree ◽  
Jim Ropchan ◽  
...  
Keyword(s):  
Simulated Data ◽  
Receptor Occupancy ◽  
Volume Of Distribution ◽  
Data Sets ◽  
Suitable Model ◽  
Dose Selection ◽  
Care Needs ◽  
Positron Emission

In vivo characterization of the brain pharmacokinetics of novel compounds provides important information for drug development decisions involving dose selection and the determination of administration regimes. In this context, the compound-target affinity is the key parameter to be estimated. However, if compounds exhibit a dynamic lag between plasma and target bound concentrations leading to pharmacological hysteresis, care needs to be taken to ensure the appropriate modeling approach is used so that the system is characterized correctly and that the resultant estimates of affinity are correct. This work focuses on characterizing different pharmacokinetic models that relate the plasma concentration to positron emission tomography outcomes measurements (e.g., volume of distribution and target occupancy) and their performance in estimating the true in vivo affinity. Measured (histamine H3 receptor antagonist—GSK189254) and simulated data sets enabled the investigation of different modeling approaches. An indirect pharmacokinetic-receptor occupancy model was identified as a suitable model for the calculation of affinity when a compound exhibits pharmacological hysteresis.

scholarly journals Two Zinc Uptake Systems Contribute to the Full Virulence of Listeria monocytogenes during GrowthIn VitroandIn Vivo

2011 ◽  
Vol 80 (1) ◽  
pp. 14-21 ◽  
Author(s):  
David Corbett ◽  
Jiahui Wang ◽  
Stephanie Schuler ◽  
Gloria Lopez-Castejon ◽  
Sarah Glenn ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Zinc Uptake ◽  
Detectable Effect ◽  
Intracellular Growth ◽  
Content Type ◽  
Zinc Sensing ◽  
Identification And Characterization ◽  
Cell Deletion

ABSTRACTWe report here the identification and characterization of two zinc uptake systems, ZurAM and ZinABC, in the intracellular pathogenListeria monocytogenes. Transcription of both operons was zinc responsive and regulated by the zinc-sensing repressor Zur. Deletion of eitherzurAMorzinAhad no detectable effect on growth in defined media, but a doublezurAM zinAmutant was unable to grow in the absence of zinc supplementation. Deletion ofzinAhad no detectable effect on intracellular growth in HeLa epithelial cells. In contrast, growth of thezurAMmutant was significantly impaired in these cells, indicating the importance of the ZurAM system during intracellular growth. Notably, the deletion of bothzinAandzurAMseverely attenuated intracellular growth, with the double mutant being defective in actin-based motility and unable to spread from cell to cell. Deletion of eitherzurAMorzinAhad a significant effect on virulence in an oral mouse model, indicating that both zinc uptake systems are importantin vivoand establishing the importance of zinc acquisition during infection byL. monocytogenes. The presence of two zinc uptake systems may offer a mechanism by whichL. monocytogenescan respond to zinc deficiency within a variety of environments and during different stages of infection, with each system making distinct contributions under different stress conditions.

18F-Endothelin-1, a positron emission tomography (PET) radioligand for the endothelin receptor system: radiosynthesis and in vivo imaging using microPET

2002 ◽  
Vol 103 (s2002) ◽  
pp. 4S-8S ◽  
Author(s):  
Peter JOHNSTRÖM ◽  
Neil G. HARRIS ◽  
Tim D. FRYER ◽  
Olivier BARRET ◽  
John C. CLARK ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Radiochemical Yield ◽  
Emission Tomography ◽  
Receptor System ◽  
Endothelin 1 ◽  
Positron Emission ◽  
Pharmacokinetic Properties ◽  
Rats And Mice ◽  
Lung And Kidney

Positron emission tomography (PET) is a powerful technique with the sensitivity to image and quantify receptor-bound radioligands in vivo. Recent progress in PET scanner technology has resulted in the development of dedicated tomographs designed for small animals, with resolution that allows the delineation of discrete organs and their larger substructures in rats and mice. Our aim was to determine whether endothelin-1 (ET-1) could be labelled with 18F, and whether the resulting 18F-ET-1 would have the required pharmacokinetic properties to permit binding and imaging of ET receptors in vivo. 18F-ET-1 could be produced in a total radiochemical yield of 5.9±0.7% in 207±3min (n = 20). Specific radioactivities were in the range 220–370GBq/µmol, and the radiochemical purity of the isolated 18F-ET-1 was >95%. In vivo distribution in the rat was studied using microPET. High levels of 18F-ET-1 uptake were found in lung and kidney, whereas liver showed moderate levels of uptake. The resolution of the microPET scanner was sufficient to differentiate heterogeneous uptake in subrenal structures in the rat.

scholarly journals Risperidone and 5-HT2A Receptor Antagonists Attenuate and Reverse Cocaine-Induced Hyperthermia in Rats

2020 ◽  
Vol 23 (12) ◽  
pp. 811-820
Author(s):  
Tsuyoshi Okada ◽  
Katsutoshi Shioda ◽  
Akiko Makiguchi ◽  
Shiro Suda
Keyword(s):  
In Vivo Microdialysis ◽  
D1 Receptor ◽  
D1 Receptors ◽  
Receptor Antagonists ◽  
Induced Hyperthermia ◽  
Definitive Therapy ◽  
Before And After ◽  
Sch 23 390 ◽  
Related Mortality

Abstract Background Cocaine (benzoylmethylecgonine) is one of the most widely used illegal psychostimulant drugs worldwide, and mortality from acute intoxication is increasing. Suppressing hyperthermia is effective in reducing cocaine-related mortality, but a definitive therapy has not yet been found. In this study, we assessed the ability of risperidone to attenuate acute cocaine-induced hyperthermia and delineated the mechanism of its action. Methods Rats were injected i.p. with saline, risperidone, ketanserin, ritanserin, haloperidol, or SCH 23 390 before and after injection of cocaine (30 mg/kg) or with WAY-00 635, SB 206 553, or sulpiride before cocaine injection; thereafter, the rectal temperature was measured every 30 minutes for up to 4 hours. In vivo microdialysis was used to reveal the effect of risperidone on cocaine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline concentrations in the anterior hypothalamus. For post-administration experiments, saline or risperidone (0.5 mg/kg) were injected into rats, and cocaine (30 mg/kg) was injected 15 minutes later. For every 30 minutes thereafter, DA, 5-HT, and noradrenaline levels were measured for up to 240 minutes after cocaine administration. Results Risperidone, 5-HT2A receptor antagonists, and D1 receptor antagonistic drugs prevented and reversed cocaine-induced hyperthermia. In contrast, receptor antagonists for 5-HT1A, 5-HT2B/2C, and D2 did not alter cocaine-induced hyperthermia. Risperidone treatment further attenuated cocaine-induced elevation of DA. Conclusions Our results indicate that risperidone attenuates cocaine-induced hyperthermia primarily by blocking the activities of the 5-HT2A and D1 receptors and may be potentially useful for treating cocaine-induced acute hyperthermia in humans.

Central D2Receptors and Negative Symptoms of Schizophrenia

1994 ◽  
Vol 164 (1) ◽  
pp. 27-34 ◽  
Author(s):  
J. L. Martinot ◽  
M. L. Paillère-Martinot ◽  
C. Loc'h ◽  
Y. Lecrubier ◽  
M. H. Dao-Castellana ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Matched Control ◽  
Emission Tomography ◽  
Dopamine System ◽  
Positron Emission ◽  
Density Index ◽  
Drug Naïve ◽  
The Mean ◽  
Drug Free

Mostin vivostudies of striatal D2receptor (SD2R) density with positron emission tomography in schizophrenia have attempted to relate this variable to the diagnosis of the illness. In the present study, a relationship between SD2R and clinical dimensions of this psychosis was searched for in a highly selected group of young negative schizophrenics (8 drug-naïve and 2 drug-free). The SD2R density index measuredin vivousing76Br-bromolisuride and PET correlated negatively (r= 0.80,P< 0.01) with a psychomotor dimension of schizophrenia involving blunted affect and alogia. The mean SD2R index of the patients did not differ from that of age-matched control subjects. Therefore, this behavioural dimension accounts for the variance of the SD2R, suggesting that the striatal dopamine system modulates symptoms such as flattened affect and alogia.

scholarly journals Imaging Cortical Dopamine D1 Receptors Using [11C]NNC112 and Ketanserin Blockade of the 5-HT2A Receptors

2009 ◽  
Vol 30 (5) ◽  
pp. 985-993 ◽  
Author(s):  
Ana M Catafau ◽  
Graham E Searle ◽  
Santiago Bullich ◽  
Roger N Gunn ◽  
Eugenii A Rabiner ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Emission Tomography ◽  
D1 Receptors ◽  
Lower Amount ◽  
Quantification Method ◽  
Positron Emission ◽  
Selective Ligands ◽  
Pet Scans

[11C]NNC112 (8-chloro-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-IH-3-benzazepine), a selective positron-emission tomography (PET) ligand for the D1 receptor (R) over the 5-HT2A R in vitro, has shown lower selectivity in vivo, hampering measurement of D1 R in the cortex. [11C]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [11C]NNC112 in vivo D1 R selectivity, and (2) develop a feasible methodology for imaging cortical D1 R without contamination by 5-HT2A R. Seven healthy volunteers underwent [11C]NNC112 PET scans at baseline and after a 5-HT2A R-blocking dose of ketanserin (0.15 mg/kg, i.v.). Percent BPND change between the post-ketanserin and baseline scans was calculated. Irrespective of the quantification method used, ketanserin pretreatment led to significant decrease of BPND in the cortical (∼30%) and limbic regions (∼20%) but not in the striatum, which contains a much lower amount of 5-HT2A R. Therefore, ketanserin allows D1 R signal to be detected by [11C]NNC112 PET without significant 5-HT2A R contamination. These data confirm the presence of a significant 5-HT2A R contribution to cortical [11C]NNC112 signal, and call for caution in the interpretation of published [11C]NNC112 PET findings on cortical D1 R in humans. In the absence of more selective ligands, [11C]NNC112 PET with ketanserin can be used for cortical D1 R imaging in vivo.

scholarly journals Reduced mu opioid receptor availability in schizophrenia revealed with [11C]-carfentanil positron emission tomographic Imaging

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Abhishekh H. Ashok ◽  
Jim Myers ◽  
Tiago Reis Marques ◽  
Eugenii A. Rabiner ◽  
Oliver D. Howes
Keyword(s):  
Opioid Receptor ◽  
Negative Symptoms ◽  
Molecular Mechanisms ◽  
Mu Opioid Receptor ◽  
Mu Opioid ◽  
Reward Function ◽  
Positron Emission ◽  
Global Increase ◽  
Hedonic Processing

Abstract Negative symptoms, such as amotivation and anhedonia, are a major cause of functional impairment in schizophrenia. There are currently no licensed treatments for negative symptoms, highlighting the need to understand the molecular mechanisms underlying them. Mu-opioid receptors (MOR) in the striatum play a key role in hedonic processing and reward function and are reduced post-mortem in schizophrenia. However, it is unknown if mu-opioid receptor availability is altered in-vivo or related to negative symptoms in schizophrenia. Using [11 C]-carfentanil positron emission tomography (PET) scans in 19 schizophrenia patients and 20 age-matched healthy controls, here we show a significantly lower MOR availability in patients with schizophrenia in the striatum (Cohen’s d = 0.7), and the hedonic network. In addition, we report a marked global increase in inter-regional covariance of MOR availability in schizophrenia, largely due to increased cortical-subcortical covariance.

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