Development of [(11)C]MFTC for PET imaging of fatty acid amide hydrolase in rat and monkey brains.
We developed 2-methylpyridin-3-yl-4-(5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine-1-[(11)C]carboxylate ([(11)C]MFTC) as a promising PET tracer for in vivo imaging of fatty acid amide hydrolase (FAAH) in rat and monkey brains. [(11)C]MFTC was synthesized by reacting 3-hydroxy-2-methylpyridine (2) with [(11)C]phosgene ([(11)C]COCl2), followed by reacting with 4-(5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine (3), with a 20 ± 4.6% radiochemical yield (decay-corrected, n = 30) based on [(11)C]CO2 and 40 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in FAAH-rich organs, including the lung, liver, and kidneys. Positron emission tomography (PET) summation images of rat brains showed high radioactivity in the frontal cortex, cerebellum, and hippocampus, which was consistent with the regional distribution pattern of FAAH in rodent brain. Pretreatment with MFTC or FAAH-selective URB597 significantly reduced the uptake in the brain. PET imaging of monkey brain showed relatively high uptake in the whole brain, particularly in the occipital cortex, which was also inhibited by treatment with MFTC or URB597. More than 96% of the total radioactivity was irreversible in the brain homogenate of rats 5 min after the radiotracer injection. The specific in vivo FAAH binding indicates that [(11)C]MFTC is a promising PET tracer for visualizing FAAH in the brain.
Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.
Katsushi
K
Kumata
Joji
J
Yui
Akiko
A
Hatori
Jun
J
Maeda
Lin
L
Xie
Masanao
M
Ogawa
Tomoteru
T
Yamasaki
Yuji
Y
Nagai
Yoko
Y
Shimoda
Masayuki
M
Fujinaga
Kazunori
K
Kawamura
Ming-Rong
MR
Zhang
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008253:Macaca mulatta; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D013045:Species Specificity; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001549:Benzamides; D002219:Carbamates; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D019275:Radiopharmaceuticals; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
FAAH; PET; [11C]COCl2; [11C]MFTC; fatty acid amide hydrolase; irreversible specific binding