(11)C-JNJ-54173717

(11)C-JNJ-54173717 is a high-affinity radiotracer for the human P2X7R (hP2X7R). Biodistribution and radiometabolite studies were performed. Viral vectors encoding either enhanced green fluorescent protein-hP2X7R or 3flag-hP2X7R were engineered and validated in cell culture. hP2X7R was regionally overexpressed in the rat striatum after stereotactic injection of viral vectors. Dynamic small-animal PET studies were performed in vector-injected rats and in healthy monkeys using (11)C-JNJ-54173717.

The affinity of JNJ-54173717 was 1.6 ± 0.1 nM in a rat cortex P2X7R membrane binding assay. In a functional assay at the recombinant human and rat P2X7R orthologs, the half maximal inhibitory concentration (IC50) of JNJ-54173717 was 4.2 ± 0.01 nM and 7.6 ± 0.01 nM, respectively. The rat biodistribution study showed that (11)C-JNJ-54173717 crossed the blood-brain barrier and was cleared from plasma mainly via the hepatobiliary pathway. A polar radiometabolite was found in rat plasma. No radiometabolites were detected in rat brain. Dynamic small-animal PET showed binding of (11)C-JNJ-54173717 in the striatum expressing hP2X7R, with rapid washout from the noninjected control striatum and other brain regions. Likewise, (11)C-JNJ-54173717 PET signal was blocked by a chemically distinct P2X7R ligand, indicating specific binding to P2X7R in the monkey brain.

JNJ-54173717 is a high-affinity P2X7R antagonist. An animal rat model stably expressing hP2X7R was developed and validated, identifying favorable characteristics for (11)C-JNJ-54173717 as a PET radioligand for in vivo visualization of hP2X7R. (11)C-JNJ-54173717 selectively visualized P2X7R in the monkey brain, and this radioligand will be further evaluated in a clinical setting to study P2X7R expression levels in neurodegenerative disorders.

Purinergic P2X receptors have a wide distribution within the body and modulate a number of physiological processes, being also involved in the development and progression of inflammation-, neuroinflammation-, neurodegeneration-, and cancer-related diseases. Radioligands that can detect specific P2X receptor subtypes and reveal their level of expression are of key importance for the development of novel P2X modulators, for the depiction of the involvement of these proteins in physio-pathological processes, and for the availability of novel diagnostic tools to be used for imaging experiments in vivo. Here we review and summarise the various P2X-targeting radioligands developed and reported to date, ranging from analogues of the endogenous P2X agonist ATP to the more recent and P2X subtype-selective allosteric modulators. Many of the high-affinity radioligands described are only suitable as in vitro receptor probes. No viable P2X3 or P2X4 radioligands for in vivo positron emission tomography (PET) imaging have been developed and reported to date. However, P2X7 antagonists, such as [11C]SMW139, [11C]GSK1482160, [11C]JNJ-54173717, and [18F]JNJ-64413739, have been successfully applied to PET imaging in the brain.