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Århus, Denmark

Plisson C.,Glaxosmithkline | Salinas C.,Glaxosmithkline | Weinzimmer D.,Yale University | Labaree D.,Yale University | And 8 more authors.
Nuclear Medicine and Biology | Year: 2011

Introduction: The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [ 11C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET. Methods: A procedure was developed for labeling MP-10 with carbon-11. [ 11C]MP-10 was evaluated in vivo both in the pig and baboon brain. Results: Alkylation of the corresponding desmethyl compound with [ 11C]methyl iodide produced [ 11C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [ 11C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1-2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [ 11C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [ 11C]MP-10 were slower, reaching peak tissue concentrations at 30-60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [ 11C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V T) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP ND) as the outcome measure of specific binding. Quantification of [ 11C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP ND estimates consistent with those obtained by the two-tissue compartment model. Conclusion: We demonstrated that [ 11C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET. © 2011 Elsevier Inc. Source

Plisson C.,Imanova Ltd. | Plisson D.,Yale University | Jakobsen S.,Aarhus Center | Natesan S.,Kings College London | And 13 more authors.
Journal of Nuclear Medicine | Year: 2014

Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported 11C-MP-10. Methods: On the basis of in vitro data, IMA102, IMA104, IMA107, and IMA106 were identified as potential PDE10A radioligand candidates and labeled with either 11C via N-methylation or with 18F through an SN2 reaction, in the case of IMA102. These candidates were compared with 11C-MP-10 in pilot in vivo studies in the pig brain. On the basis of these data, 11C-IMA106 and 11C-IMA107 were taken into further evaluation and comparison with 11C-MP-10 in the primate brain. Finally, the most promising radioligand candidate was progressed into human evaluation. Results: All 5 tracers were produced with good radiochemical yield and specific activity. All candidates readily entered the brain and demonstrated a heterogeneous distribution consistent with the known expression of PDE10A. Baseline PET studies in the pig and baboon showed that 11C-IMA107 and 11C-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of 11C-IMA107 and 11C-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of 11CIMA107 and 11C-MP-10 were well described by a 2-tissue-compartment model, allowing robust estimates of the regional total volume of distribution. Blockade with unlabeled MP-10 confirmed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential as the outcome measure of specific binding. Conclusion: 11C-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of 11C-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that 11C-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain. © 2014 SNMMI; all rights reserved. Source

Itenov T.S.,Copenhagen University | Christensen P.H.,Dako Denmark | Jensen J.-U.,Copenhagen University | Bestle M.H.,Copenhagen University | And 37 more authors.
Journal of Clinical Laboratory Analysis | Year: 2014

Background: Neutrophil gelatinase associated lipocalin (NGAL) is proposed as a biomarker of acute kidney injury (AKI). NGAL has been studied in a range of body fluids including serum and EDTA plasma. The aim of the present study was to establish relationship between serum NGAL concentrations and EDTA plasma NGAL concentrations in patients admitted to intensive care units (ICUs) and whether these determinations are directly comparable in this setting. Methods: NGAL was measured in 40 paired samples of serum and EDTA plasma from 25 patients admitted to intensive care with a commercial particle-enhanced turbidimetric immunoassay (The NGAL Test™, BioPorto Diagnostics A/S, Gentofte, Denmark) on a Roche Hitachi 917 (Roche-Hitachi, Inc., Tokyo, Japan) analyzer. Results: Serum NGAL concentrations ranged from 26.8 to 1,808 ng/ml (median 281 ng/ml, interquartile range (IQR) 453 ng/ml). EDTA plasma NGAL concentrations ranged from 25.7 to 1,752 ng/ml (median 225 ng/ml, IQR 352 ng/ml). The difference in NGAL concentrations in paired serum and EDTA plasma samples (serum- plasma) ranged from -13.8 to 321 ng/ml (median 79 ng/ml, IQR 116 ng/ml; difference from zero, P < 0.0001, Wilcoxon's signed rank test). Although serum and EDTA plasma values were correlated (Spearman's r = 0.95, P < 0.0001), Deming regression analysis showed a slope of 1.1 that was not significantly different from unity (95% confidence interval (CI) 1.0-1.1) and a highly significant intercept of 67.9 ng/ml with a wide confidence interval (95% CI 29.8-106). Conclusion: NGAL concentration values measured in serum and EDTA plasma cannot be directly compared and should not be used as equivalents in studies of patients admitted to intensive care. © 2014 Wiley Periodicals, Inc. Source

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