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Tozadenant or Preladenant or Vipadenant

D Hesk, S Borges, R Dumpit, S Hendershot, D Koharski, P McNamara, S Ren, S Saluja, V Truong, K Voronin
MK 3814 is a potent and selective antagonist of the A2a receptor. A2a receptor antagonists have the potential for the treatment of Parkinson disease. Three distinct isotopically labelled forms of MK 3814 were synthesized. [(3) H]MK 3814 was prepared for a preliminary absorption, distribution, metabolism, and excretion data (ADME) evaluation of the compound and [(14) C]MK 3814 for more definitive ADME work, including an absorption, metabolism, and excretion study in man. In addition, [(2) H4 ]MK 3814 was prepared as an internal standard for a liquid chromatography mass spectrometry bioanalytical method...
January 27, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
Xiaoyun Zhou, Ronald Boellaard, Kiichi Ishiwata, Muneyuki Sakata, Rudi A Dierckx, Johan de Jong, Shingo Nishiyama, Hiroyuki Ohba, Hideo Tsukada, Erik F de Vries, Philip H Elsinga
[(11)C]Preladenant was developed as a novel PET ligand for the adenosine A2A receptors (A2ARs). The present study aims to evaluate the suitability of [(11)C]preladenant-PET for the quantification of striatal A2ARs and the assessment of A2AR occupancy in the conscious monkey brain. METHODS: [(11)C]Preladenant was i.v. injected into conscious monkeys (n = 4, 18 PET scans) and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modelling...
January 6, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Nobutaka Hattori, Masashi Kikuchi, Noriaki Adachi, David Hewitt, Susan Huyck, Tadayuki Saito
BACKGROUND: Preladenant, an adenosine 2A antagonist, reduced daily OFF time when administered as adjunctive treatment in a previous phase 2 trial in non-Japanese Parkinson's disease (PD) patients on stable doses of levodopa. This study aimed to evaluate preladenant as adjunctive therapy in Japanese patients with PD. METHODS: In this randomized, placebo-controlled, double-blind, 12-week, dose-ranging, phase 2 study, Japanese patients with moderate to severe PD on a stable regimen of levodopa were randomly assigned 1:1:1:1 to preladenant 2 mg, 5 mg, or 10 mg BID or placebo...
August 27, 2016: Parkinsonism & related Disorders
Wolfgang Oertel, Jörg B Schulz
Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain stimulation, and physiotherapy. The arsenal of pharmacotherapies includes L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine. In the later course of the disease, motor complications occur, at which stage different oral formulations of L-Dopa or dopamine agonists with long half-life, a transdermal application or parenteral pumps for continuous drug supply can be subscribed...
October 2016: Journal of Neurochemistry
Xiaoyun Zhou, Philip H Elsinga, Shivashankar Khanapur, Rudi A J O Dierckx, Erik F J de Vries, Johan R de Jong
PURPOSE: [(11)C]Preladenant was developed as a novel adenosine A2A receptor PET radioligand. The aim of this study was to determine the radiation dosimetry of [(11)C]preladenant and to investigate whether dosimetry estimation based on organ harvesting can be replaced by positron emission tomography (PET)/x-ray computed tomography (CT) imaging in rats. PROCEDURES: Male Wistar rats (n = 35) were i.v. injected with [(11)C]preladenant. The tracer biodistribution was determined by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection...
April 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Valérie Mancel, François-Xavier Mathy, Pierre Boulanger, Stephen English, Marie Croft, Christopher Kenney, Tarra Knott, Armel Stockis, Massimo Bani
1. This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of (14)C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease. 2. Six healthy male subjects received a single oral dose of tozadenant (240 mg containing 81.47 KBq of [(14)C]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection...
September 2, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Christine Vala, Thomas J Morley, Xuechun Zhang, Caroline Papin, Adriana Alexandre S Tavares, H Sharon Lee, Cristian Constantinescu, Olivier Barret, Vincent M Carroll, Ronald M Baldwin, Gilles D Tamagnan, David Alagille
Imaging agents that target adenosine type 2A (A2A ) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinson's disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A2A -specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [(123) I]MNI-420 and [(18) F]MNI-444...
September 6, 2016: ChemMedChem
Xiaoyun Zhou, Shivashankar Khanapur, Johan R de Jong, Antoon Tm Willemsen, Rudi Ajo Dierckx, Philip H Elsinga, Erik Fj de Vries
[(11)C]Preladenant was developed as a novel adenosine A2A receptor positron emission tomography radioligand. The present study aims to evaluate the suitability of [(11)C]preladenant positron emission tomography for the quantification of striatal A2A receptor density and the assessment of striatal A2A receptor occupancy by KW-6002. Sixty- or ninety-minute dynamic positron emission tomography imaging was performed on rats. Tracer kinetics was quantified by the two-tissue compartment model, Logan graphical analysis and several reference tissue-based models...
February 2017: Journal of Cerebral Blood Flow and Metabolism
Annalisa Pinna, Wai Kin D Ko, Giulia Costa, Elisabetta Tronci, Camino Fidalgo, Nicola Simola, Qin Li, Mojgan Aghazadeh Tabrizi, Erwan Bezard, Manolo Carta, Micaela Morelli
BACKGROUND: The serotonin 5-HT1A/1B receptor agonist eltoprazine suppressed dyskinetic-like behavior in animal models of Parkinson's disease (PD) but simultaneously reduced levodopa (l-dopa)-induced motility. Moreover, adenosine A2A receptor antagonists, such as preladenant, significantly increased l-dopa efficacy in PD without exacerbating dyskinetic-like behavior. OBJECTIVES: We evaluated whether a combination of eltoprazine and preladenant may prevent or suppress l-dopa-induced dyskinesia, without impairing l-dopa's efficacy in relieving motor signs, in 2 PD models: unilateral 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys...
April 2016: Movement Disorders: Official Journal of the Movement Disorder Society
Robert A Hauser, Fabrizio Stocchi, Olivier Rascol, Susan B Huyck, Rachel Capece, Tony W Ho, Peter Sklar, Christopher Lines, David Michelson, David Hewitt
IMPORTANCE: Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials. OBJECTIVE: To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013...
December 2015: JAMA Neurology
Anne Michel, Patrick Downey, Xavier Van Damme, Catherine De Wolf, Rainer Schwarting, Dieter Scheller
In Parkinson's disease (PD), dopaminergic therapies are often associated with the development of motor complications. Attention has therefore been focused on the use of non-dopaminergic drugs. This study developed a new behavioural method capable of demonstrating the added value of combining adenosinergic and glutamatergic receptor antagonists in unilateral 6-OHDA lesioned rats. Rats were dosed orally with Tozadenant, a selective A2A receptor antagonist, and three different doses of Radiprodil, an NR2B-selective NMDA receptor antagonist...
2015: PloS One
Olivier Rascol, Santiago Perez-Lloret, Joaquim J Ferreira
Levodopa (l-dopa)-induced motor complications, including motor fluctuations and dyskinesia, affect almost all patients with Parkinson's disease (PD) at some point during the disease course, with relevant implications in global health status. Various dopaminergic and nondopaminergic pharmacological approaches as well as more invasive strategies including devices and functional surgery are available to manage such complications. In spite of undisputable improvements during the last decades, many patients remain significantly disabled, and a fully satisfying management of l-dopa-induced motor complications is still an important unmet need of PD therapy...
September 15, 2015: Movement Disorders: Official Journal of the Movement Disorder Society
Mohamad Wessam Alnouri, Stephan Jepards, Alessandro Casari, Anke C Schiedel, Sonja Hinz, Christa E Müller
Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A1, A2A, A2B, and A3, of three species, human, rat, and mouse...
September 2015: Purinergic Signalling
Stephanie B Stewart, Jonathan M Koller, Meghan C Campbell, Kevin J Black
A carefully controlled study allowed us to compare the sensitivity of ASL (arterial spin labeling) and BOLD (blood oxygen level dependent) fMRI for detecting the effects of the adenosine A2a antagonist tozadenant in Parkinson disease. The study compared the effect of drug directly or the interaction of the drug with a cognitive task. Only ASL detected the direct effect of tozadenant. BOLD was more sensitive to the cognitive task, which (unlike most drugs) allows on-off comparisons over short periods of time...
2014: PeerJ
Anne Michel, Patrick Downey, Jean-Marie Nicolas, Dieter Scheller
In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (add-on therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch-58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244...
2014: PloS One
Xiaoyun Zhou, Shivashankar Khanapur, Anja P Huizing, Rolf Zijlma, Marianne Schepers, Rudi A J O Dierckx, Aren van Waarde, Erik F J de Vries, Philip H Elsinga
2-(2-Furanyl)-7-[2-[4-[4-(2-[(11)C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine [(11)C]-3 ([(11)C]Preladenant) was developed for mapping cerebral adenosine A2A receptors (A2ARs) with PET. The tracer was synthesized in high specific activity and purity. Tissue distribution was studied by PET imaging, ex vivo biodistribution (BD), and in vitro autoradiography (ARG) experiments. Regional brain uptake of [(11)C]-3 was consistent with known A2ARs distribution, with highest uptake in striatum...
November 13, 2014: Journal of Medicinal Chemistry
Olivier Barret, Jonas Hannestad, David Alagille, Christine Vala, Adriana Tavares, Caroline Papin, Thomas Morley, Krista Fowles, Hsiaoju Lee, John Seibyl, Dominique Tytgat, Marc Laruelle, Gilles Tamagnan
UNLABELLED: Motor symptoms in Parkinson disease (PD) are caused by a loss of dopamine input from the substantia nigra to the striatum. Blockade of adenosine 2A (A(2A)) receptors facilitates dopamine D(2) receptor function. In phase 2 clinical trials, A(2A) antagonists (istradefylline, preladenant, and tozadenant) improved motor function in PD. We developed a new A(2A) PET radiotracer, (18)F-MNI-444, and used it to investigate the relationship between plasma levels and A(2A) occupancy by preladenant and tozadenant in nonhuman primates (NHP)...
October 2014: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Robert A Hauser, C Warren Olanow, Karl D Kieburtz, Emmanuelle Pourcher, Any Docu-Axelerad, Mark Lew, Olexandr Kozyolkin, Ann Neale, Chris Resburg, Uwe Meya, Christopher Kenney, Stephen Bandak
BACKGROUND: Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A2A receptor antagonist that improves motor function in animal models of Parkinson's disease. We aimed to assess the safety and efficacy of tozadenant as an adjunct to levodopa in patients with Parkinson's disease who have motor fluctuations on levodopa. METHODS: We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations (at least 2·5 h off-time per day)...
August 2014: Lancet Neurology
Gerard Rosse
No abstract text is available yet for this article.
January 10, 2013: ACS Medicinal Chemistry Letters
Stefka Gyoneva, Dimitrios Davalos, Dipankar Biswas, Sharon A Swanger, Ethel Garnier-Amblard, Francis Loth, Katerina Akassoglou, Stephen F Traynelis
Microglia, the resident immune cells of the central nervous system, exist in either a "resting" state associated with physiological tissue surveillance or an "activated" state in neuroinflammation. We recently showed that ATP is the primary chemoattractor to tissue damage in vivo and elicits opposite effects on the motility of activated microglia in vitro through activation of adenosine A2A receptors. However, whether systemic inflammation affects microglial responses to tissue damage in vivo remains largely unknown...
August 2014: Glia
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