Spotlight on P2X7 Receptor PET Imaging: A Bright Target or a Failing Star?

Abstract

The homotrimeric P2X7 receptor (P2X7R) is expressed by virtually all cells of the innate and adaptive immune system and plays a crucial role in various pathophysiological processes such as autoimmune and neurodegenerative diseases, inflammation, neuropathic pain and cancer. Consequently, the P2X7R is considered a promising target for therapy and diagnosis. As the development of tracers comes hand-in-hand with the development of potent and selective receptor ligands, there is a rising number of PET tracers available in preclinical and clinical studies. This review analyzes the development of P2X7R positron emission tomography (PET) tracers and their potential in various PET imaging applications.

The P2X7 Receptor as a Mechanistic Biomarker for Epilepsy

“…We now have a substantial body of evidence demonstrating not only the therapeutic potential of targeting the P2X7R during epilepsy but also the proof of concept of its diagnostic capabilities, making this receptor, without doubt, an increasingly promising therapeutic target ( Figure 1 ). While there are still important issues, which will have to be addressed in future studies, including testing P2X7R antagonists in human tissue and the use of larger patient cohorts, with P2X7R antagonists and P2X7R-PET radiotracers already at the clinical trial stage [ 124 , 152 ], it can be hoped that P2X7R-based treatments for epilepsy will reach the clinic within the foreseeable future.…”

“…Of note, several P2X7R-dependent inflammation markers have been shown to be dysregulated in the blood of epilepsy patients (e.g., IL-1β [ 121 , 122 ], IL-18 [ 123 ]), potentially serving as useful surrogate makers of P2X7R activation/inhibition. Critically, diagnostic tools capable of detecting P2X7R protein and P2X7R downstream molecules are already available, including P2X7R-based positron emission tomography (PET) radioligands [ 124 ] and assays able to detect P2X7Rs in fluids such as blood (ELISA) [ 120 ] ( Table 2 ).…”

Two serial filters determine P2X7R cation selectivity, Ser342 in the central pore and lateral acidic residues at the cytoplasmic interface

“…Lysine substitutions of S342 together with D352 or E14 plus D356 in the acidic triangle convert the hP2X7R mutant to a fully Cl - -selective ATP 4- -gated receptor. We conclude that the ion selectivity of wild-type hP2X7R is determined by two sequential filters in one single pathway: (1) a primary size filter, S342, in the membrane center and (2) three cation filters lateral to the channel axis, one per subunit interface, consisting of a total of nine acidic residues at the cytoplasmic interface.…”

“…The P2X7 receptor (P2X7R) is an ATP 4- -gated cation-selective channel that is of great interest as a drug target (1) because of its widespread expression in virtually all immune cells, including microglia (2) and also tumor cells (3), its role in inflammation, and also because of its enigmatic ability to generate large cytotoxic pores (4). Extracellular binding of the ligand ATP 4- opens the channel pore within milliseconds to small cations such as Na + , K + , and Ca 2+ , but also allows permeation of larger organic cations, including Tris + (121 Da), N-methyl-d-glucamine + (NMDG, 195 Da) and cationic DNA-binding dyes such as ethidium + (314 Da) and Yo-Pro-1 2+ (376 Da).…”

Increased Cerebral Level of P2X7R in a Tauopathy Mouse Model by PET Using [18F]GSK1482160

“…Several positron emission tomography (PET) tracers for P2X7R have been developed, 12 ]SMW139 showed a 6 times lower affinity for the rodent P2X7R than the human P2X7R and was rapidly metabolized in mice, with 30+% unmetabolized plasma fraction. 15,21 Increased [ 18 F]JNJ-64413739 uptake was reported in the brain and peripheral organs of animal models of epilepsy 22 and lipopolysaccharide (LPS)-injected mice.…”