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Identification and evaluation of [11C]GSK931145 as a novel ligand for imaging the type 1 glycine transporter with positron emission tomography
Synapse (New York, N.Y.), 2010-07, Vol.64 (7), p.542-549
Passchier, J.
Gentile, G.
Porter, R.
Herdon, H.
Salinas, C.
Jakobsen, S.
Audrain, H.
Laruelle, M.
Gunn, R.N.
2010
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
Passchier, J.
Gentile, G.
Porter, R.
Herdon, H.
Salinas, C.
Jakobsen, S.
Audrain, H.
Laruelle, M.
Gunn, R.N.
Titel
Identification and evaluation of [11C]GSK931145 as a novel ligand for imaging the type 1 glycine transporter with positron emission tomography
Ist Teil von
Synapse (New York, N.Y.), 2010-07, Vol.64 (7), p.542-549
Ort / Verlag
Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Erscheinungsjahr
2010
Quelle
Wiley-Blackwell Full Collection
Beschreibungen/Notizen
The type‐1 glycine transporter (GlyT1) is an important target for the development of new medications for schizophrenia. A specific and selective positron emission tomography (PET) GlyT1 ligand would facilitate drug development studies to determine whether a drug reaches this target and help establish suitable doses for clinical trials. This article describes the evaluation of three candidate GlyT1 PET radioligands (GSK931145, GSK565710, and GSK991022) selected from a library of compounds based on favorable physicochemical and pharmacological properties. Each candidate was successfully labeled using [11C]methyl iodide or [11C]methyl triflate and administered to a pig pre‐ and postadministration with a pharmacological dose of a GlyT1 inhibitor to determine their suitability as PET ligands in the porcine brain in vivo. All three candidate ligands were analyzed quantitatively with compartment analyses employing a plasma input function. [11C]GSK931145 showed good brain penetration and a heterogeneous distribution in agreement with reported GlyT1 localization. Following pretreatment with GSK565710, uptake of [11C]GSK931145 was reduced to homogeneous levels. Although [11C]GSK565710 also showed good brain penetration and a heterogeneous distribution, the apparent level of specific binding was reduced compared to [11C]GSK931145. In contrast, [11C]GSK991022 showed a much lower brain penetration and resultant signal following pretreatment with GSK565710. Based on these findings [11C]GSK931145 was identified as the most promising ligand for imaging GlyT1 in the porcine brain, possessing good brain penetration, specific signal, and reversible kinetics. [11C]GSK931145 is now being progressed into higher species. Synapse 64:542–549, 2010. © 2010 Wiley‐Liss, Inc.
Sprache
Englisch
Identifikatoren
ISSN: 0887-4476, 1098-2396
eISSN: 1098-2396
DOI: 10.1002/syn.20760
Titel-ID: cdi_proquest_miscellaneous_733327866
Format
–
Schlagworte
Animals
,
Brain
,
Brain - diagnostic imaging
,
Brain - metabolism
,
Carbon Radioisotopes
,
Clinical trials
,
Computed tomography
,
Dose-Response Relationship, Drug
,
Drug development
,
glycine
,
Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors
,
Glycine Plasma Membrane Transport Proteins - metabolism
,
Glycine transporter
,
GlyT1
,
Hydrocarbons, Iodinated - pharmacology
,
Kinetics
,
Ligands
,
Mental disorders
,
Mesylates - pharmacology
,
Neuroimaging
,
NMDAR
,
PET
,
Positron emission tomography
,
Positron-Emission Tomography - methods
,
Radioisotopes
,
Radiopharmaceuticals - administration & dosage
,
Radiopharmaceuticals - pharmacokinetics
,
Schizophrenia
,
Swine
,
Synapses
,
Time Factors
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