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-iodobenzylox,)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, [I-125]2-IBPO was conveniently synthesized from a tributylstannyl precursor by an iododestannylation reaction using sodium [I-125] iodide and hydrogen peroxide with high radiochemical yield. The in vivo tissue distribution studies of [I-125]2-IBPO demonstrated its high initial uptake and prolonged retention in the brain. A selective interaction of [I-125]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 [I-125]2-IBPO suggested that a I-123-labeled counterpart, [I-123]2-IBPO, would have great potential in in viva studies of MAO-B in the human brain with single photon emission computed tomography (SPECT).