Characterization of a novel acetamidobenzoxazolone-based PET ligand for translocator protein (18 kDa) imaging of neuroinflammation in the brain.
We developed the novel positron emission tomography (PET) ligand 2-[5-(4-[(11)C]methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide ([(11)C]MBMP) for translocator protein (18 kDa, TSPO) imaging and evaluated its efficacy in ischemic rat brains. [(11)C]MBMP was synthesized by reacting desmethyl precursor (1) with [(11)C]CH3 I in radiochemical purity of ≥ 98% and specific activity of 85 ± 30 GBq/μmol (n = 18) at the end of synthesis. Biodistribution study on mice showed high accumulation of radioactivity in the TSPO-rich organs, e.g., the lungs, heart, kidneys, and adrenal glands. The metabolite analysis in mice brain homogenate showed 80.1 ± 2.7% intact [(11)C]MBMP at 60 min after injection. To determine the specific binding of [(11)C]MBMP with TSPO in the brain, in vitro autoradiography and PET studies were performed in an ischemic rat model. In vitro autoradiography indicated significantly increased binding on the ipsilateral side compared with that on the contralateral side of ischemic rat brains. This result was supported firmly by the contrast of radioactivity between the ipsilateral and contralateral sides in PET images. Displacement experiments with unlabelled MBMP or PK11195 minimized the difference in uptake between the two sides. In summary, [(11)C]MBMP is a potential PET imaging agent for TSPO and, consequently, for the up-regulation of microglia during neuroinflammation.
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India.
Anjani K
AK
Tiwari
Joji
J
Yui
Masayuki
M
Fujinaga
Katsushi
K
Kumata
Yoko
Y
Shimoda
Tomoteru
T
Yamasaki
Lin
L
Xie
Akiko
A
Hatori
Jun
J
Maeda
Nobuki
N
Nengaki
Ming-Rong
MR
Zhang
D000083:Acetanilides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D021461:Animals, Outbred Strains; D001345:Autoradiography; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry; D002545:Brain Ischemia / Q000000981:diagnostic imaging* / Q000209:etiology / Q000473:pathology; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D021621:Imaging, Three-Dimensional; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology; D007249:Inflammation; D008024:Ligands; D008297:Male; D051379:Mice; D017628:Microglia / Q000000981:diagnostic imaging* / Q000378:metabolism; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000032:analysis*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000032:analysis*; D014018:Tissue Distribution
C000588856:2-(5-(4-methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-methyl-N-phenylacetamide; D000083:Acetanilides; D001583:Benzoxazoles; C463819:Bzrp protein, mouse; D002250:Carbon Radioisotopes; D008024:Ligands; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; D018079:Receptors, GABA
[11C]MBMP; microglia activation; neuroinflammation; positron emission tomography; translocator protein (18 kDa)