RT Journal Article
SR Electronic
T1 Preclinical Evaluation of a P2X7 Receptor–Selective Radiotracer: PET Studies in a Rat Model with Local Overexpression of the Human P2X7 Receptor and in Nonhuman Primates
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1436
OP 1441
DO 10.2967/jnumed.115.169995
VO 57
IS 9
A1 Dieter Ory
A1 Sofie Celen
A1 Rik Gijsbers
A1 Chris Van Den Haute
A1 Andrey Postnov
A1 Michel Koole
A1 Caroline Vandeputte
A1 José-Ignacio Andrés
A1 Jesus Alcazar
A1 Meri De Angelis
A1 Xavier Langlois
A1 Anindya Bhattacharya
A1 Mark Schmidt
A1 Michael A. Letavic
A1 Wim Vanduffel
A1 Koen Van Laere
A1 Alfons Verbruggen
A1 Zeger Debyser
A1 Guy Bormans
YR 2016
UL http://jnm.snmjournals.org/content/57/9/1436.abstract
AB The P2X7 receptor (P2X7R) orchestrates neuroinflammation, and this is the basis for an increased interest in the development of antagonists inhibiting P2X7R function in the brain. This study provides the preclinical evaluation of 11C-JNJ-54173717, a PET tracer for P2X7R in both rats and nonhuman primates. Methods: 11C-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 11C-JNJ-54173717. Results: 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 11C-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 11C-JNJ-54173717 in the striatum expressing hP2X7R, with rapid washout from the noninjected control striatum and other brain regions. Likewise, 11C-JNJ-54173717 PET signal was blocked by a chemically distinct P2X7R ligand, indicating specific binding to P2X7R in the monkey brain. Conclusion: JNJ-54173717 is a high-affinity P2X7R antagonist. An animal rat model stably expressing hP2X7R was developed and validated, identifying favorable characteristics for 11C-JNJ-54173717 as a PET radioligand for in vivo visualization of hP2X7R. 11C-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.