ISOINDOL-1-ONE ANALOGS OF -[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 deriva tives, including -[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 c aused 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 i n vivo stability of 31, a series of cyclized amide analogues were desi gned and synthesized. In vitro binding, metabolic stability, and in vi vo biodistribution of these new derivatives were investigated. Several five-membered-ring isoindol-1-ones displayed very high in vitro bindi ng affinity, especially 2-{2-[4-(2- ethyl)-6-nitro-3-phenyl-2,3-dihydr oisoindol-1-one, 15, 3-hydroxy-6- n-1-yl]ethyl}-3-phenyl-2,3-dihydrois oinidol-1-one, 18, and in-1-yl]ethyl)-3-phenyl-2,3-dihydroisoindol-1-o ne, 21, which showed K-1 values of 0.05, 0.65, and 0.07 nM, respective ly. The affinities for 5-HT1A receptors of other cyclized amide deriva tives, l)-1-(2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethyl} pyrrolidin-2 -one, 25, (4-iodophenyl)-1-(2-[4-(2-methoxyphenyl)piperazin- 1-yl]ethy l)pyrrolidin-2-one, 27, and 2-methoxyphenyl)piperazin-1-yl]ethyl}-2,3- dihydro- isoindol-1-one, 29, were 1.09, 2.54, and 14.9 nM, respectivel y. Compared to [I-125]-31, iodinated cyclized amide derivatives [I-125 ]-21 and [I-125]-27 displayed a slower metabolism in human liver micro somal and cytosolic preparations. Biodistribution of [I-125]-21 and [I -125]-21 in rats (after an iv injection) displayed moderate to low bra in uptakes with little or no specific localization in hippocampal regi on, where 5-HT1A receptors are concentrated. These data indicate that the new iodinated;ligands showed high binding affinities and better me tabolic stability but displayed unexpectedly low selective binding to 5-HT1A receptors in vivo. Additional structural modifications may be n eeded to correct the unfavorable properties displayed for these iodina ted cyclized amide derivatives for in vise biodistribution in rats.