Synthesis and Biological Evaluation of a Novel 18F-Labeled Radiotracer for PET Imaging of the Adenosine A2A Receptor

The adenosine A2A receptor (A2AR) has emerged as a potential non-dopaminergic target for the treatment of Parkinson’s disease and, thus, the non-invasive imaging with positron emission tomography (PET) is of utmost importance to monitor the receptor expression and occupancy during an A2AR-tailored therapy. Aiming at the development of a PET radiotracer, we herein report the design of a series of novel fluorinated analogs (TOZ1-TOZ7) based on the structure of the A2AR antagonist tozadenant, and the preclinical evaluation of [18F]TOZ1. Autoradiography proved A2AR-specific in vitro binding of [18F]TOZ1 to striatum of mouse and pig brain. Investigations of the metabolic stability in mice revealed parent fractions of more than 76% and 92% of total activity in plasma and brain samples, respectively. Dynamic PET/magnetic resonance imaging (MRI) studies in mice revealed a brain uptake but no A2AR-specific in vivo binding.

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Development of 18F-Labeled Radiotracers for PET Imaging of the Adenosine A2A Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation

International Journal of Molecular Sciences ◽

10.3390/ijms22052285 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2285

Author(s):

Thu Hang Lai ◽

Susann Schröder ◽

Magali Toussaint ◽

Sladjana Dukić-Stefanović ◽

Mathias Kranz ◽

...

Keyword(s):

Specific Binding ◽

Brain Slices ◽

Total Activity ◽

Biological Evaluation ◽

Adenosine A2a Receptor ◽

Positron Emission ◽

A2a Receptor ◽

Adenosine A2a

The adenosine A2A receptor (A2AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A2AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (PPY). Among those, the highly affine 4-fluorobenzyl derivate (PPY1; Ki(hA2AR) = 5.3 nM) and the 2-fluorobenzyl derivate (PPY2; Ki(hA2AR) = 2.1 nM) were chosen for 18F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [18F]PPY1 and [18F]PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [18F]PPY2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.

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Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes

Scientific Reports ◽

10.1038/s41598-020-80244-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Benjamin Friedman ◽

Carmen Corciulo ◽

Cristina M. Castro ◽

Bruce N. Cronstein

Keyword(s):

Cell Line ◽

Metabolic Stress ◽

Human Cell Line ◽

Adenosine A2a Receptor ◽

Autophagic Flux ◽

A2a Receptor ◽

Adenosine A2a ◽

A2ar Agonist

AbstractAutophagy, a homeostatic pathway upregulated during cellular stress, is decreased in osteoarthritic chondrocytes and this reduction in autophagy is thought to contribute to the development and progression of osteoarthritis (OA). The adenosine A2A receptor (A2AR) is a potent anti-inflammatory receptor and deficiency of this receptor leads to the development of OA in mice. Moreover, treatment using liposomally conjugated adenosine or a specific A2AR agonist improved joint scores significantly in both rats with post-traumatic OA (PTOA) and mice subjected to a high fat diet obesity induced OA. Importantly, A2AR ligation is beneficial for mitochondrial health and metabolism in vitro in primary and the TC28a2 human cell line. An additional set of metabolic, stress-responsive, and homeostatic mediators include the Forkhead box O transcription factors (FoxOs). Data has shown that mouse FoxO knockouts develop early OA with reduced cartilage autophagy, indicating that FoxO-induced homeostasis is important for articular cartilage. Given the apparent similarities between A2AR and FoxO signaling, we tested the hypothesis that A2AR stimulation improves cartilage function through activation of the FoxO proteins leading to increased autophagy in chondrocytes. We analyzed the signaling pathway in the human TC28a2 cell line and corroborated these findings in vivo in a metabolically relevant obesity-induced OA mouse model. We found that A2AR stimulation increases activation and nuclear localization of FoxO1 and FoxO3, promotes an increase in autophagic flux, improves metabolic function in chondrocytes, and reduces markers of apoptosis in vitro and reduced apoptosis by TUNEL assay in vivo. A2AR ligation additionally enhances in vivo activation of FoxO1 and FoxO3 with evidence of enhanced autophagic flux upon injection of the liposome-associated A2AR agonist in a mouse obesity-induced OA model. These findings offer further evidence that A2AR may be an excellent target for promoting chondrocyte and cartilage homeostasis.

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The Diameter of Retinal Arterioles Is Unaffected by Intravascular Administration of the Adenosine A2A Receptor Agonist Regadenoson in Normal Persons

Biomedicine Hub ◽

10.1159/000500563 ◽

2019 ◽

Vol 4 (2) ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Anna Dons-Jensen ◽

Line Petersen ◽

Hans-Erik Bøtker ◽

Toke Bek

Keyword(s):

Intravenous Administration ◽

Receptor Agonist ◽

Adenosine A2a Receptor ◽

Retinal Vessels ◽

Adenosine Receptor Agonists ◽

Retinal Arterioles ◽

A2a Receptor ◽

Adenosine A2a

Background: The neurotransmitter adenosine has been proposed to be involved in the pathogenesis of diabetic retinopathy, which may be due to the vasoactive properties of the compound. Previous studies have shown that adenosine can affect the tone of retinal arterioles in vitro to induce dilatation mediated by A2A and A2Breceptors and constriction mediated by A1 and A3 receptors. Purpose: To investigate effects of intravenous administration of the adenosine A2A receptor agonist regadenoson on the diameter of retinal vessels in vivo. Method: The diameter responses of larger retinal arterioles and venules were evaluated using the dynamic vessel analyser in 20 normal persons (age 22–31 years) after intravenous administration of the adenosine A2A receptor agonist regadenoson during exposure to systemic normoxia and hypoxia. Results: The diameter of retinal arterioles and venules increased significantly during stimulation with flickering light (p < 0.0001). Regadenoson reduced the flicker-induced dilatation of venules during normoxia (p = 0.0006), but otherwise had no effect on vessel diameters (p > 0.08 for all comparisons). Conclusions:Intravenous administration of the adenosine A2A receptor agonist regadenoson had no significant effect on the diameter of retinal arterioles. Future studies should investigate differential effects of intra- and extravascular administration of adenosine receptor agonists on retinal vessels.

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Pharmacological Preconditioning by Adenosine A2a Receptor Stimulation: Features of the Protected Liver Cell Phenotype

BioMed Research International ◽

10.1155/2015/286746 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Elisa Alchera ◽

Chiara Imarisio ◽

Giorgia Mandili ◽

Simone Merlin ◽

Bangalore R. Chandrashekar ◽

...

Keyword(s):

Liver Cell ◽

Cell Damage ◽

Ischemia Reperfusion ◽

Adenosine A2a Receptor ◽

Cell Phenotype ◽

Innovative Strategies ◽

A2a Receptor ◽

Adenosine A2a

Ischemic preconditioning (IP) of the liver by a brief interruption of the blood flow protects the damage induced by a subsequent ischemia/reperfusion (I/R) preventing parenchymal and nonparenchymal liver cell damage. The discovery of IP has shown the existence of intrinsic systems of cytoprotection whose activation can stave off the progression of irreversible tissue damage. Deciphering the molecular mediators that underlie the cytoprotective effects of preconditioning can pave the way to important therapeutic possibilities. Pharmacological activation of critical mediators of IP would be expected to emulate or even to intensify its salubrious effects.In vitroandin vivostudies have demonstrated the role of the adenosine A2a receptor (A2aR) as a trigger of liver IP. This review will provide insight into the phenotypic changes that underline the resistance to death of liver cells preconditioned by pharmacological activation of A2aR and their implications to develop innovative strategies against liver IR damage.

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Correlation between low adenosine A2A receptor expression and hypercholesterolemia: A new component of the cardiovascular risk?

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/j.bbalip.2020.158850 ◽

2021 ◽

Vol 1866 (2) ◽

pp. 158850

Author(s):

Donato Vairo ◽

Carola Giacobbe ◽

Claire Guiol ◽

Marie-Charlotte Chaptal ◽

Maria Donata Di Taranto ◽

...

Keyword(s):

Cardiovascular Risk ◽

Adenosine A2a Receptor ◽

Receptor Expression ◽

A2a Receptor ◽

Adenosine A2a

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Lipopolysaccharide and TNF-α modify adenosine A2A receptor expression and function in equine monocytes

Veterinary Immunology and Immunopathology ◽

10.1016/j.vetimm.2009.12.001 ◽

2010 ◽

Vol 135 (3-4) ◽

pp. 289-295 ◽

Cited By ~ 10

Author(s):

Wan-chun Sun ◽

Londa J. Berghaus ◽

James N. Moore ◽

David J. Hurley ◽

Michel L. Vandenplas ◽

...

Keyword(s):

Adenosine A2a Receptor ◽

Receptor Expression ◽

Tnf Α ◽

A2a Receptor ◽

And Function ◽

Adenosine A2a

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Characterization of the trigeminovascular actions of several adenosine A2A receptor antagonists in an in vivo rat model of migraine

The Journal of Headache and Pain ◽

10.1186/s10194-018-0867-x ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 10

Author(s):

Kristian A. Haanes ◽

Alejandro Labastida-Ramírez ◽

Kayi Y. Chan ◽

René de Vries ◽

Brian Shook ◽

...

Keyword(s):

Rat Model ◽

Adenosine A2a Receptor ◽

Receptor Antagonists ◽

Adenosine A2a Receptor Antagonists ◽

A2a Receptor ◽

Adenosine A2a

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Different Adenosine A2A Receptor Expression in Peripheral Cells from Elderly Patients with Vascular Dementia and Alzheimer's Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-131652 ◽

2014 ◽

Vol 40 (1) ◽

pp. 45-49 ◽

Cited By ~ 10

Author(s):

Cristina Gussago ◽

Beatrice Arosio ◽

Martina Casati ◽

Evelyn Ferri ◽

Federica Gualandris ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Elderly Patients ◽

Vascular Dementia ◽

Adenosine A2a Receptor ◽

Receptor Expression ◽

A2a Receptor ◽

Adenosine A2a ◽

Peripheral Cells

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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 ◽

10.3390/molecules25071633 ◽

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.

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PET imaging of cannabinoid type 2 receptors with [11C]A-836339 did not evidence changes following neuroinflammation in rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16685105 ◽

2017 ◽

Vol 37 (3) ◽

pp. 1163-1178 ◽

Cited By ~ 14

Author(s):

Geraldine Pottier ◽

Vanessa Gómez-Vallejo ◽

Daniel Padro ◽

Raphaël Boisgard ◽

Frédéric Dollé ◽

...

Keyword(s):

Cerebral Ischemia ◽

Pet Imaging ◽

Receptor Expression ◽

Brain Inflammation ◽

Cb2 Receptor ◽

Future Studies ◽

Positron Emission

Cannabinoid type 2 receptors (CB2R) have emerged as promising targets for the diagnosis and therapy of brain pathologies. However, no suitable radiotracers for accurate CB2R mapping have been found to date, limiting the investigation of the CB2 receptor expression using positron emission tomography (PET) imaging. In this work, we report the evaluation of the in vivo expression of CB2R with [11C]A-836339 PET after cerebral ischemia and in two rat models of neuroinflammation, first by intrastriatal LPS and then by AMPA injection. PET images and in vitro autoradiography showed a lack of specific [11C]A-836339 uptake in these animal models demonstrating the limitation of this radiotracer to image CB2 receptor under neuroinflammatory conditions. Further, using immunohistochemistry, the CB2 receptor displayed a modest expression increase after cerebral ischemia, LPS and AMPA models. Finally, [18F]DPA-714-PET and immunohistochemistry demonstrated decreased neuroinflammation by a selective CB2R agonist, JWH133. Taken together, these findings suggest that [11C]A-836339 is not a suitable radiotracer to monitor in vivo CB2R expression by using PET imaging. Future studies will have to investigate alternative radiotracers that could provide an accurate binding to CB2 receptors following brain inflammation.

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