Isoindol-1-one analogues of 4-(2′-methoxyphenyl)-1-[2′-[N-(2"-pyridyl)-p-iodobenzamido]ethyl]piperazine (p-MPPI) as 5-HT1A receptor ligands

In developing radioiodinated antagonists for in vivo imaging of 5-HT1A receptors with SPECT, a series of new arylpiperazine benzamido derivatives, including 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridyl)-p-iodobenzamido]ethyl]piperazine (p-MPPI, 31) (K-d = 0.36 nM), as potential ligands for 5-HT1A receptors were reported previously. However, rapid in vivo metabolism may have caused the breakdown of the amide bond of [I-123]-31 and rendered this agent obsolete as an in vivo imaging agent in humans. To improve the in vivo stability of 31, a series of cyclized amide analogues were designed and synthesized. In vitro binding, metabolic stability, and in vivo biodistribution of these new derivatives were investigated. Several five-membered-ring isoindol-1-ones displayed very high in vitro binding affinity, especially 2-{2-[4-(2- methoxyphenyl)piperazin-1-yl]ethyl)-6-nitro-3-phenyl-2,3-dihydroisoindol-1-one, 15, 3-hydroxy-6- 2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-3-phenyl-2,3-dihydroisoinidol-1-one, 18, and 6-iodo-2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl)-3-phenyl-2,3-dihydroisoindol-1-one, 21, which showed K-1 values of 0.05, 0.65, and 0.07 nM, respectively. The affinities for 5-HT1A receptors of other cyclized amide derivatives, 5-(4-bromophenyl)-1-(2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethyl} pyrrolidin-2-one, 25, 5-(4-iodophenyl)-1-(2-[4-(2-methoxyphenyl)piperazin- 1-yl]ethyl)pyrrolidin-2-one, 27, and 2-(2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-2,3-dihydro- isoindol-1-one, 29, were 1.09, 2.54, and 14.9 nM, respectively. Compared to [I-125]-31, iodinated cyclized amide derivatives [I-125]-21 and [I-125]-27 displayed a slower metabolism in human liver microsomal and cytosolic preparations. Biodistribution of [I-125]-21 and [I-125]-21 in rats (after an iv injection) displayed moderate to low brain uptakes with little or no specific localization in hippocampal region, where 5-HT1A receptors are concentrated. These data indicate that the new iodinated;ligands showed high binding affinities and better metabolic stability but displayed unexpectedly low selective binding to 5-HT1A receptors in vivo. Additional structural modifications may be needed to correct the unfavorable properties displayed for these iodinated cyclized amide derivatives for in vise biodistribution in rats.