Increase of 20-HETE synthase after brain ischemia in rats revealed by PET study with 11C-labeled 20-HETE synthase-specific inhibitor.
20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite known to be produced after cerebral ischemia, has been implicated in ischemic and reperfusion injury by mediating vasoconstriction. To develop a positron emission tomography (PET) probe for 20-HETE synthase imaging, which might be useful for monitoring vasoconstrictive processes in patients with brain ischemia, we synthesized a (11)C-labeled specific 20-HETE synthase inhibitor, N'(4-dimethylaminohexyloxy)phenyl imidazole ([(11)C]TROA). Autoradiographic study showed that [(11)C]TROA has high-specific binding in the kidney and liver consistent with the previously reported distribution of 20-HETE synthase. Using transient middle cerebral artery occlusion in rats, PET study showed significant increases in the binding of [(11)C]TROA in the ipsilateral hemisphere of rat brains after 7 and 10 days, which was blocked by co-injection of excess amounts of TROA (10 mg/kg). The increased [(11)C]TROA binding on the ipsilateral side returned to basal levels within 14 days. In addition, quantitative real-time PCR revealed that increased expression of 20-HETE synthase was only shown on the ipsilateral side on day 7. These results indicate that [(11)C]TROA might be a useful PET probe for imaging of 20-HETE synthase in patients with cerebral ischemia.
RIKEN, Center for Molecular Imaging Science, Kobe, Japan.
Toshiyuki
T
Kawasaki
Toshiyuki
T
Marumo
Keiko
K
Shirakami
Tomoko
T
Mori
Hisashi
H
Doi
Masaaki
M
Suzuki
Yasuyoshi
Y
Watanabe
Shigeyuki
S
Chaki
Atsuro
A
Nakazato
Yukio
Y
Ago
Hitoshi
H
Hashimoto
Toshio
T
Matsuda
Akemichi
A
Baba
Hirotaka
H
Onoe
D000818:Animals; D001345:Autoradiography; D002545:Brain Ischemia / Q000000981:diagnostic imaging* / Q000201:enzymology*; D002250:Carbon Radioisotopes; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D004797:Enzyme-Linked Immunosorbent Assay; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D007553:Isotope Labeling; D008137:Longitudinal Studies; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D007093:Imidazoles; C576244:N'-(4-dimethylaminohexyloxy)phenylimidazole; D019275:Radiopharmaceuticals; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D042926:Cytochrome P-450 CYP4A