Potential Therapeutic Applications of Adenosine A_2A Receptor Ligands and Opportunities for A_2A Receptor Imaging

Abstract

Adenosine A 2A receptors (A 2A Rs) are highly expressed in the human striatum, and at lower densities in the cerebral cortex, the hippocampus, and cells of the immune system. Antagonists of these receptors are potentially useful for the treatment of motor fluctuations, epilepsy, postischemic brain damage, or cognitive impairment, and for the control of an immune checkpoint during immunotherapy of cancer. A 2A R agonists may suppress transplant rejection and graft-versus-host disease; be used to treat inflammatory disorders such as asthma, inflammatory bowel disease, and rheumatoid arthritis; be locally applied to promote wound healing and be employed in a strategy for transient opening of the blood-brain barrier (BBB) so that therapeutic drugs and monoclonal antibodies can enter the brain. Increasing A 2A R signaling in adipose tissue is also a potential strategy to combat obesity. Several radioligands for positron emission tomography (PET) imaging of A 2A Rs have been developed in recent years. This review article presents a critical overview of the potential therapeutic applications of A 2A R ligands, the use of A 2A R imaging in drug development, and opportunities and limitations of PET imaging in future research. C

Chemical Probes for the Adenosine Receptors

“…In contrast to the development of tritiated or 125 I radioligands, in the last few years great efforts have been made in the field of radiotracers for imaging [14]. In particular, several examples of 11 C or 18 F derivatives for the different AR subtypes have been reported.…”

“…A quite extensive SAR study on the adenosine nucleus for obtaining other covalent ligands for human ARs was performed by Jorg and coworkers [16], who obtained a series of compounds of These studies led to the discovery of a compound named DITC-APEC (2-[(2-aminoethyl-aminocarbonylethyl)phenylethylamino]-5'-N-ethyl-carboxamidoadenosine, APEC) (14), which was able to induce concentration dependent coronary vasodilation that persisted for a long time, even after washout. This suggests that compound 14 irreversibly bound A2A AR in guinea pig coronary arteries [44].…”

“…Radioactive ligands, properly called radioligands, are the oldest class of AR probes, and still represent the principal tool in drug discovery since their use in binding assays [7]. Recently, the broad interest in radioactive ligands is due to their development as radiotracers in positron emission tomography (PET), leading to new diagnostic possibilities [13,14]. On the other hand, covalent ligands for GPCRs, which were in the past used as tools to purify, isolate or pharmacologically characterize receptors, have recently attracted the interest of the scientific community for their ability to stabilize their target protein, increasing the probability of obtaining X-ray crystal structures [10].…”

Molecular docking and network connections of active compounds from the classical herbal formula Ding Chuan Tang

“…The biological processes associated with ADORA2A demonstrate involvement in cell-cell signaling, the cellular defense response and the inflammatory response (Uniprot). Multiple experimental studies have shown agonist ligands of ADORA2A reduce respiratory inflammation (Van Waarde et al, 2018). This research suggests the prospect of the DCT-compounds successfully docked with ADORA2A to display similar agonistic biological effects for asthma.…”

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

“…187 In general, radio-ligands that lack the xanthine structure appear to have better specificity for the A 2A R subtype and allow quantitative imaging of A 2A R in the mammalian striatum, but even these are less effective at imaging other areas of the brain. 188 [ 11 C]SCH442416 was the first non-xanthine ligand that was suitable for mapping of A 2A R using PET. 189 Recently, [ 11 C]preladenant has been used to quantify A 2A R binding sites in the rat brain.…”