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Natesan S.,Kings College London | Ashworth S.,Imanova Center for Imaging science | Tang S.-P.,Imanova Center for Imaging science | Salinas C.,Imanova Center for Imaging science | And 6 more authors.
Translational Psychiatry | Year: 2014

A number of phosphodiesterase 10A (PDE10) inhibitors are about to undergo clinical evaluation for their efficacy in treating schizophrenia. As phosphodiesterases are in the same signalling pathway as dopamine D2 receptors, it is possible that prior antipsychotic treatment could influence these enzyme systems in patients. Chronic, in contrast to acute, antipsychotic treatment has been reported to increase brain PDE10A levels in rodents. The aim of this study was to confirm these findings in a manner that can be translated to human imaging studies to understand its consequences. Positron emission tomography (PET) scanning was used to evaluate PDE10A enzyme availability, after chronic haloperidol administration, using a specific PDE10A ligand ([11C]MP-10). The binding of [11C]MP-10 in the striatum and the cerebellum was measured in rodents and a simplified reference tissue model (SRTM) with cerebellum as the reference region was used to determine the binding potential (BPND). In rats treated chronically with haloperidol (2 mg kg-1 per day), there was no significant difference in PDE10A levels compared with the vehicle-treated group (BPND ± s.d.: 3.57 ± 0.64 versus 2.86 ± 0.71). Following PET scans, ex vivo analysis of striatal brain tissue for PDE10A mRNA (Pde10a) and PDE10A enzyme activity showed no significant difference. Similarly, the PDE10A protein content determined by western blot analysis was similar between the two groups, contrary to an earlier finding. The results of the study indicate that prior exposure to antipsychotic medication in rodents does not alter PDE10A levels. © 2014 Macmillan Publishers Limited. Source


Mugnaini M.,Glaxosmithkline | Mugnaini M.,Aptuit S.r.l. | Iavarone L.,Glaxosmithkline | Iavarone L.,Pfizer | And 22 more authors.
Neuropsychopharmacology | Year: 2013

Selective dopamine D3 receptor (D3R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D 3R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D3 Rs (OD3R) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo 125 I(R)-trans-7-hydroxy-2-N-propyl- N-(3'-iodo-2'-propenyl)amino tetralin (125I7OH-PIPAT) autoradiography and 11CPHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D3 Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between OD3R and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and OD3R at every time point, and 100% effect at OD3R values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of OD3R, transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O D3R is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D3R antagonist for the treatment of substance-use disorders. © 2013 American College of Neuropsychopharmacology. All rights reserved. Source


Kaggie J.D.,University of Utah | Hadley J.R.,University of Utah | Badal J.,Brigham Young University | Campbell J.R.,Brigham Young University | And 7 more authors.
Magnetic Resonance in Medicine | Year: 2014

Purpose: The objective of this study was to determine whether a sodium phased array would improve sodium breast MRI at 3 T. The secondary objective was to create acceptable proton images with the sodium phased array in place. Methods: A novel composite array for combined proton/sodium 3 T breast MRI is compared with a coil with a single proton and sodium channel. The composite array consists of a 7-channel sodium receive array, a larger sodium transmit coil, and a 4-channel proton transceive array. The new composite array design utilizes smaller sodium receive loops than typically used in sodium imaging, uses novel decoupling methods between the receive loops and transmit loops, and uses a novel multichannel proton transceive coil. The proton transceive coil reduces coupling between proton and sodium elements by intersecting the constituent loops to reduce their mutual inductance. The coil used for comparison consists of a concentric sodium and proton loop with passive decoupling traps. Results: The composite array coil demonstrates a 2-5× improvement in signal-to-noise ratio for sodium imaging and similar signal-to-noise ratio for proton imaging when compared with a simple single-loop dual resonant design. Conclusion: The improved signal-to-noise ratio of the composite array gives breast sodium images of unprecedented quality in reasonable scan times. © 2013 Wiley Periodicals, Inc. Source


Shields G.S.,Glaxosmithkline | Coissi G.S.,Imperial College London | Jimenez-Royo P.,Glaxosmithkline | Gambarota G.,Glaxosmithkline | And 7 more authors.
Muscle and Nerve | Year: 2015

Introduction: Chronic obstructive pulmonary disease (COPD) is associated with metabolic abnormalities in muscles of the lower limbs, but it is not known whether these abnormalities are generalized or limited to specific muscle groups, nor is there an easy way of predicting their presence. Methods: Metabolism in the quadriceps and biceps of 14 COPD patients and controls was assessed during sustained contraction using 31-phosphorus magnetic resonance spectroscopy (31P MRS). T1 MRI was used to measure quadriceps intermuscular adipose tissue (IMAT). Results: COPD patients had prolonged quadriceps phosphocreatine time (patients: 38.8 ± 12.7 s; controls: 25.2 ± 10.6 s; P=0.006) and a lower pH (patents: 6.88 ± 0.1; controls: 6.99 ± 0.06; P=0.002). Biceps measures were not significantly different. IMAT was associated with a nadir pH <7.0 (area under the curve=0.84). Conclusions: Anaerobic metabolism during contraction was characteristic of quadriceps, but not biceps, muscles of patients with COPD and was associated with increased IMAT. Because IMAT can be assessed quickly by conventional MRI, it may be a useful approach for identifying patients with abnormal muscle bioenergetics. © 2014 Wiley Periodicals, Inc. Source


Challapalli A.,Imperial College London | Sharma R.,Imperial College London | Hallett W.A.,Imanova Center for Imaging science | Kozlowski K.,Imperial College London | And 5 more authors.
Journal of Nuclear Medicine | Year: 2014

11C-choline and 18F-fluoromethylcholine ( 18F-FCH) have been used in patients to study tumor metabolic activity in vivo; however, both radiotracers are readily oxidized to respective betaine analogs, with metabolites detectable in plasma soon after injection of the radiotracer. A more metabolically stable FCH analog, 18F- fluoromethyl- [1,2-2H4]choline (18F-D4-FCH), based on the deuterium isotope effect, has been developed. We report the safety, biodistribution, and internal radiation dosimetry profiles of 18F-D4-FCH in 8 healthy human volunteers. Methods: 18F-D4-FCH was intravenously administered as a bolus injection (mean ± SD, 161 ± 2.17 MBq; range, 156-163 MBq) to 8 healthy volunteers (4 men, 4 women). Whole-body (vertex to mid thigh) PET/CT scans were acquired at ± time points, up to 4 h after tracer injection. Serial whole-blood, plasma, and urine samples were collected for radioactivity measurement and plasma radiotracer metabolites. Tissue 18F radioactivities were determined fromquantitative analysis of the images, and time-activity curves were generated. The total numbers of disintegrations in each organ normalized to injected activity (residence times) were calculated as the area under the curve of the time-activity curve normalized to injected activities and standard organ volumes. Dosimetry calculations were performed using OLINDA/EXM 1.1. Results: The injection of 18F-D4-FCH was well tolerated in all subjects, with no radiotracer-related serious adverse event reported. The mean effective dose averaged over both men and women (6SD) was estimated to be 0.025 ± 0.004 (men, 0.022 ± 0.002; women, 0.027 ± 0.002) mSv/MBq. The = organs receiving the highest absorbed dose (mGy/MBq) were the kidneys (0.106 ± 0.03), liver (0.094 ± 0.03), pancreas (0.066 ± 0.01), urinary bladder wall (0.047 ± 0.02), and adrenals (0.046 ± 0.01). Elimination was through the renal and hepatic systems. Conclusion: 18F-D4-FCH is a safe PET radiotracer with a dosimetry profile comparable to other common 18F PET tracers. These data support the further development of 18F-D4-FCH for clinical imaging of choline metabolism. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc. Source

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