title: Synthesis and evaluation of novel carbon-11 labeled oxopurine analogues for positron emission tomography imaging of translocator protein (18 kDa) in peripheral organs.
abstract: To develop a PET ligand for imaging TSPO in peripheral organs, we designed three novel oxopurine analogues [(11)C]3a-c (LogD: 1.81-2.17) by introducing a pyridine ring in place of a benzene ring in the lead compound [(11)C]2 (LogD: 3.48). The desmethyl precursors 10 for radiosynthesis were synthesized by reacting glycine 7 with picolylamines 4, followed by hydrolysis and by Curtius rearrangement with diphenylphosphoryl azide. Methylation of 10a-c with methyl iodide produced unlabeled compounds 3a-c. The radiosynthesis of [(11)C]3a-c was performed by reacting 10a-c with [(11)C]methyl iodide. Compounds 3a-c displayed high or moderate in vitro binding affinities (K(i): 5-40 nM) for TSPO. PET with [(11)C]3a-c in rats showed high uptake in the lung, heart, and kidney, which are organs with high TSPO expression. Metabolite analysis with [(11)C]3a showed that radioactivity in these organs mainly corresponded with unchanged [(11)C]3a. PET with [(11)C]3a using a rat model of lung inflammation showed a significant signal in the lipopolysaccharide-treated lung.
authors.affiliation: Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanamoto
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Wakizaka
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Masanao
authors.initials: M
authors.lastname: Ogawa
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Fukumura
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000378:metabolism*; D006321:Heart / Q000000981:diagnostic imaging; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D011014:Pneumonia / Q000000981:diagnostic imaging* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011688:Purinones / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D011688:Purinones; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; C069997:Tspo protein, rat