Synthesis and characterization of radioiodinated MD-230254: a new ligand for potential imaging of monoamine oxidase B activity by single photon emission computed tomography.
A series of iodinated analogues of MD-230254 was synthesized and evaluated for inhibitory potency and selectivity toward monoamine oxidase B (MAO-B). Among them, 5-[4-(2-iodobenzyloxy)phenyl]-3-(cyanoethyl)-1,3,4-oxadiazole-2(3H)one (2-IBPO) was found to have high inhibitory potency and selectivity toward MAO-B (IC50=2.0 nM, MAO-A/MAO-B >50000). Analysis of the inhibition kinetics indicated that 2-IBPO acts in a two-step mechanism as a competitive, slow, and tight-binding inhibitor of MAO-B with a Ki value of 2.4 nM and an overall Ki* value at an equilibrium of 3.8 nM. The new radioligand for MAO-B, [125I]2-IBPO was conveniently synthesized from a tributylstannyl precursor by an iododestannylation reaction using sodium [125I]iodide and hydrogen peroxide with high radiochemical yield. The in vivo tissue distribution studies of [125I]2-IBPO demonstrated its high initial uptake and prolonged retention in the brain. A selective interaction of [125I]2-IBPO with MAO-B was confirmed by the pretreatment experiment with well known MAO specific inhibitors, l-deprenyl, Ro-16-6491, clorgyline, and Ro-41-1049. These very desirable characteristics of [125I]2-IBPO suggested that a 123I-labeled counterpart, [123I]2-IBPO, would have great potential in in vivo studies of MAO-B in the human brain with single photon emission computed tomography (SPECT).
Hirata
Masahiko
M
Osaka University of Pharmaceutical Sciences, Takatsuki, Japan. hirata@oysun01.oups.ac.jp
Kagawa
Shinya
S
Yoshimoto
Mitsuyoshi
M
Ohmomo
Yoshiro
Y
D000818:Animals; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010069:Oxadiazoles; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
D008996:Monoamine Oxidase Inhibitors; D010069:Oxadiazoles; D010080:Oxazoles; D019275:Radiopharmaceuticals; C081104:5-(4-(benzyloxy)phenyl)-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one; D008995:Monoamine Oxidase