scholarly journals PET Imaging of the Adenosine A2A Receptor in the Rotenone-Based Mouse Model of Parkinson’s Disease with [18F]FESCH Synthesized by a Simplified Two-Step One-Pot Radiolabeling Strategy

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1633
Author(s):  
Susann Schröder ◽  
Thu Hang Lai ◽  
Magali Toussaint ◽  
Mathias Kranz ◽  
Alexandra Chovsepian ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Animal ◽  
Imaging Study ◽  
Adenosine A2a Receptor ◽  
Emission Tomography ◽  
One Pot ◽  
Positron Emission ◽  
A2a Receptor ◽  
Adenosine A2a

The adenosine A2A receptor (A2AR) is regarded as a particularly appropriate target for non-dopaminergic treatment of Parkinson’s disease (PD). An increased A2AR availability has been found in the human striatum at early stages of PD and in patients with PD and dyskinesias. The aim of this small animal positron emission tomography/magnetic resonance (PET/MR) imaging study was to investigate whether rotenone-treated mice reflect the aspect of striatal A2AR upregulation in PD. For that purpose, we selected the known A2AR-specific radiotracer [18F]FESCH and developed a simplified two-step one-pot radiosynthesis. PET images showed a high uptake of [18F]FESCH in the mouse striatum. Concomitantly, metabolism studies with [18F]FESCH revealed the presence of a brain-penetrant radiometabolite. In rotenone-treated mice, a slightly higher striatal A2AR binding of [18F]FESCH was found. Nonetheless, the correlation between the increased A2AR levels within the proposed PD animal model remains to be further investigated.

scholarly journals Efficacy of Istradefylline, an Adenosine A2A Receptor Antagonist, as Adjunctive Therapy to Levodopa in Parkinson’s Disease: A Pooled Analysis of 8 Phase 2b/3 Trials

2021 ◽  
pp. 1-13
Author(s):  
Robert A. Hauser ◽  
Nobutaka Hattori ◽  
Hubert Fernandez ◽  
Stuart H. Isaacson ◽  
Hideki Mochizuki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Receptor Antagonist ◽  
Repeated Measures ◽  
Pooled Analysis ◽  
Adenosine A2a Receptor ◽  
A2a Receptor ◽  
Adenosine A2a Receptor Antagonist ◽  
Adenosine A2a ◽  
Off Time

Background: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson’s disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Objective: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline. Methods: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n = 3,245); four of these studies were the basis for istradefylline’s FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor. Results: Among 2,719 patients (placebo, n = 992; 20 mg/day, n = 848; 40 mg/day, n = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], –0.38 h [–0.61, –0.15]) and 40 mg/day (–0.45 h [–0.68, –0.22], p <  0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, –0.75 h [–1.10, –0.40]; 40 mg/day, –0.82 h [–1.17, –0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%). Conclusion: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated.

scholarly journals Die adenosien A1- en A2A-reseptoraffiniteit van ’n reeks 3,4-dihidropirimidoon-analoë

2017 ◽  
Vol 36 (1) ◽  
Author(s):  
Runako M. Katsidzira ◽  
Mietha M. Van der Walt ◽  
Jacobus J. Bergh ◽  
Gisella Terre’Blanche
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Adenosine A2a Receptor ◽  
Adenosine A1 Receptor ◽  
Receptor Affinity ◽  
A2a Receptors ◽  
A2a Receptor ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Adenosine A2a

Parkinson’s disease is a complex neurodegenerative condition with current treatment only focussed on symptomatic therapy that does not slow or stop the progression of the disease. Since the discovery that adenosine A1 and A2A receptors are potential drug targets for the therapy of Parkinson’s disease, various research groups have attempted to identify adenosine antagonists. So the possibility exists that the administration of an adenosine A2A receptor antagonist may prevent further neurodegeneration. Furthermore, the antagonism of adenosine A1 receptors has the potential of treating Parkinson’s disease-associated cognitive deficits. Therefore, dual antagonism of adenosine A1 and A2A receptors would be of great benefit since this would potentially treat both the motor as well as the cognitive impairment associated with Parkinson’s disease. Based on the observation that a series of 1,4-dihydropyridine derivatives possess adenosine A1 and A2A receptor affinity, the current study investigated the potential of the structurally related 3,4-dihydropyrimidone analogues as adenosine A1 and A2A receptor antagonists. Overall, the 3,4-dihyropyrimidone analogues were found to possess weak affinity for the adenosine A2A receptor, but more promising adenosine A1 receptor affinity was found, ranging in the low micromolar range. Among the investigated compounds, the p-bromophenyl substituted dihydropyrimidone (6b) possesses the best adenosine A1 receptor affinity with a Ki value of 7.39 µM. In conclusion, this 3,4-dihydropyrimidone derivative can be used as a lead for the design of novel adenosine A1 receptor antagonists, although further structural modifications are required to enhance the adenosine A2A receptor affinity before a clinically viable candidate will be available as potential treatment of Parkinson’s disease.

scholarly journals Effect of Adenosine A2a Receptor Antagonist In Haloperidol Induced Model of Parkinson’s Disease.

2021 ◽  
Author(s):  
Syeda Najam Zehra ◽  
Ishrat Younus ◽  
Saima Mahmood Malhi ◽  
Muhammad Liaquat Raza ◽  
Azfar Athar Ishaqui ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Receptor Antagonist ◽  
Adenosine A2a Receptor ◽  
Adenosine A2a Receptor Antagonists ◽  
A2a Receptor ◽  
Parkinson’S Diseases ◽  
Adenosine A2a Receptor Antagonist ◽  
New Treatment ◽  
Adenosine A2a

Abstract One of the major causes of neurological disorders is degeneration of neurons which is commonly termed as Neurodegeneration. It is well documented that two of the neurodegenerative disorders i.e., Alzheimer’s Disease & Parkinson Disease comes in top fifteen causes of deaths in United States of America. Due to the neuroprotective property of adenosine A2a receptor antagonists (ZM241385) was evaluated in haloperidol mouse model of Parkinson’s disease. Our results reveal significant antidopaminergic effects of adenosine A2A receptor antagonist that support its utilization as a new treatment approach in Parkinson’s diseases.

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