TY - JOUR
T1 - Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [ 11 C]GSK1482160 for neuroinflammatory response
AU - Han, Junbin
AU - Liu, Hui
AU - Liu, Chunling
AU - Jin, Hongjun
AU - Perlmutter, Joel S.
AU - Egan, Terrance M.
AU - Tu, Zhude
N1 - Publisher Copyright:
© 2017 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2017
Y1 - 2017
N2 - Objective The P2X7 receptor (P2X7R) is a key regulatory element in the neuroinflammatory cascade that provides a promising target for imaging neuroinflammation. GSK1482160, a P2X7R modulator with nanomolar binding affinity and high selectivity, has been successfully radiolabeled and utilized for imaging P2X7 levels in a mouse model of lipopolysaccharide-induced systemic inflammation. In the current study, we further characterized its binding profile and determined whether [ 11 C]GSK1482160 can detect changes in P2X7R expression in a rodent model of multiple sclerosis. Methods [ 11 C]GSK1482160 was synthesized with high specific activity and high radiochemical purity. Radioligand saturation and competition binding assays were performed for [ 11 C]GSK1482160 using HEK293-hP2X7R living cells. Micro-PET studies were carried out in nonhuman primates. In vitro autoradiography and immunohistochemistry studies were then carried out to evaluate tracer uptake and P2X7 expression in experimental autoimmune encephalomyelitis (EAE) rat lumbar spinal cord at EAE-peak and EAE-remitting stages compared with sham rats. Results [ 11 C]GSK1482160 binds to HEK293-hP2X7R living cells with high binding affinity (K d =5.09±0.98 nmol/l, K i =2.63±0.6 nmol/l). Micro-PET studies showed high tracer retention and a homogeneous distribution in the brain of nonhuman primates. In the EAE rat model, tracer uptake of [ 11 C]GSK1482160 in rat lumbar spinal cord was the highest at the EAE-peak stage (277.74±79.74 PSL/mm 2), followed by the EAE-remitting stage(149.00±54.14 PSL/mm 2) and sham (66.37±1.48 PSL/mm 2). The tracer uptake correlated strongly with P2X7-positive cell counts, activated microglia numbers, and disease severity. Conclusion We conclude that [ 11 C]GSK1482160 has the potential for application in monitoring neuroinflammation.
AB - Objective The P2X7 receptor (P2X7R) is a key regulatory element in the neuroinflammatory cascade that provides a promising target for imaging neuroinflammation. GSK1482160, a P2X7R modulator with nanomolar binding affinity and high selectivity, has been successfully radiolabeled and utilized for imaging P2X7 levels in a mouse model of lipopolysaccharide-induced systemic inflammation. In the current study, we further characterized its binding profile and determined whether [ 11 C]GSK1482160 can detect changes in P2X7R expression in a rodent model of multiple sclerosis. Methods [ 11 C]GSK1482160 was synthesized with high specific activity and high radiochemical purity. Radioligand saturation and competition binding assays were performed for [ 11 C]GSK1482160 using HEK293-hP2X7R living cells. Micro-PET studies were carried out in nonhuman primates. In vitro autoradiography and immunohistochemistry studies were then carried out to evaluate tracer uptake and P2X7 expression in experimental autoimmune encephalomyelitis (EAE) rat lumbar spinal cord at EAE-peak and EAE-remitting stages compared with sham rats. Results [ 11 C]GSK1482160 binds to HEK293-hP2X7R living cells with high binding affinity (K d =5.09±0.98 nmol/l, K i =2.63±0.6 nmol/l). Micro-PET studies showed high tracer retention and a homogeneous distribution in the brain of nonhuman primates. In the EAE rat model, tracer uptake of [ 11 C]GSK1482160 in rat lumbar spinal cord was the highest at the EAE-peak stage (277.74±79.74 PSL/mm 2), followed by the EAE-remitting stage(149.00±54.14 PSL/mm 2) and sham (66.37±1.48 PSL/mm 2). The tracer uptake correlated strongly with P2X7-positive cell counts, activated microglia numbers, and disease severity. Conclusion We conclude that [ 11 C]GSK1482160 has the potential for application in monitoring neuroinflammation.
KW - P2X7 receptor
KW - PET radioligand
KW - experimental autoimmune encephalomyelitis
KW - neuroinflammation
UR - http://www.scopus.com/inward/record.url?scp=85016085720&partnerID=8YFLogxK
U2 - 10.1097/MNM.0000000000000660
DO - 10.1097/MNM.0000000000000660
M3 - Article
C2 - 28338530
AN - SCOPUS:85016085720
SN - 0143-3636
VL - 38
SP - 372
EP - 382
JO - Nuclear Medicine Communications
JF - Nuclear Medicine Communications
IS - 5
ER -