title: Synthesis and characterization of [¹²⁵I]2-iodo N-[(S)-{(S)-1-methylpiperidin-2-yl}(phenyl)methyl]3-trifluoromethyl-benzamide as novel imaging probe for glycine transporter 1.
abstract: In this study, 2-iodo substituted 1-methylpiperidin-2-yl benzamide derivatives were synthesized and evaluated as candidate SPECT imaging agents for glycine transporter 1 (GlyT1). In JAR cells, which predominantly express GlyT1, 2-iodo N-[(S)-{(S)-1-methylpiperidin-2-yl}(phenyl)methyl]3-trifluoromethyl-benzamide (5) showed excellent inhibitory activity of [(3)H]glycine uptake (IC(50)=2.4 nM). Saturation assay in rat cortical membranes revealed that [(125)I]5 had a single high affinity binding site with a K(d) of 1.54 nM and a B(max) of 3.40 pmol/mg protein. In vitro autoradiography demonstrated that [(125)I]5 showed consistent accumulation with GlyT1 expression. The in vitro binding was greatly inhibited by GlyT1 inhibitors but not by other site ligands, which suggested the high specific binding of [(125)I]5 with GlyT1. In the biodistribution and ex vivo autoradiography studies using mice, [(125)I]5 showed high blood-brain barrier permeability (1.68-2.17% dose/g at 15-60 min) and similar regional brain distribution pattern with in vitro results. In addition, pre-treatment of GlyT1 ligands resulted in significant decrease of [(125)I]5 binding in the GlyT1-rich regions. This preliminary study demonstrated that radio-iodinated 5 is a promising SPECT imaging probe for GlyT1.
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. t-fuchi@nagasaki-u.ac.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fuchigami
authors.forename: Mamoru
authors.initials: M
authors.lastname: Haratake
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Magata
authors.forename: Terushi
authors.initials: T
authors.lastname: Haradahira
authors.forename: Morio
authors.initials: M
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000378:metabolism; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D005998:Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000032:analysis*; D020128:Inhibitory Concentration 50; D007457:Iodine Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D010865:Pilot Projects; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D016339:Spectrometry, Mass, Fast Atom Bombardment; D018709:Statistics, Nonparametric; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D001549:Benzamides; D003287:Contrast Media; D050487:Glycine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D010880:Piperidines; D019275:Radiopharmaceuticals; D005998:Glycine