title: Synthesis and evaluation of new (18)F-labelled acetamidobenzoxazolone-based radioligands for imaging of the translocator protein (18 kDa, TSPO) in the brain.
abstract: The visualization of the activated microglia/TSPO is one of the main aspects of neuroimaging. Here we describe two new (18)F-labelled molecules, 2-[5-(4-[(18)F]fluoroethoxyphenyl)- ([(18)F]2) and 2-[5-(4-[(18)F]fluoropropyloxyphenyl)- ([(18)F]3) -2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide as novel PET ligands for imaging the translocator protein (18 kDa, TSPO) in the brain. The three-D pharmacophore evaluation and docking studies suggested their high affinity for the TSPO and in vitro binding assays of the TSPO showed binding affinities 6.6 ± 0.7 nM and 16.7 ± 2.5 nM for 2 and 3, respectively. The radiochemical yields for [(18)F]2 and [(18)F]3 were found to be 22 ± 4% (n = 8) and 5 ± 2% (n = 5), respectively at EOB. The radiochemical purity for both was found ≥98% and the specific activity was in the range of 98-364 GBq μmol(-1) at EOS. In vitro autoradiography with an ischemic rat brain showed significantly increased binding on the ipsilateral side compared to the contralateral side. The specificity of [(18)F]2 and [(18)F]3 for binding TSPO was confirmed using the TSPO ligands PK11195 and MBMP. The biodistribution patterns of both PET ligands were evaluated in normal mice by 1 h dynamic PET imaging. In the brain, regional radioactivity reached the maximum very rapidly within 0-4 min for both ligands, similar to (R)[(11)C]PK11195. The metabolite study of [(18)F]2 also favoured a more favourable profile for quantification in comparison to (R)[(11)C]PK11195. In summary, these data indicated that [(18)F]2 and [(18)F]3 have good potential to work as PET ligands, therefore there are merits to use these radioligands for the in vivo evaluation in animal models to see their efficacy in the living brain.
authors.affiliation: Molecular Imaging Centre, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan. zhang@nirs.go.jp.
authors.forename: Anjani K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mishra
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimoda
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Bin
authors.initials: B
authors.lastname: Ji
authors.forename: Masanao
authors.initials: M
authors.lastname: Ogawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000032:analysis* / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000032:analysis* / Q000378:metabolism
chemical_list: D001583:Benzoxazoles; D002352:Carrier Proteins; D005462:Fluorine Radioisotopes; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; C017057:benzoxazolone