201532-02-7Relevant articles and documents
Isoindol-1-one analogues of 4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridyl)- p-iodobenzamido]ethyl]piperazine (p-MPPI) as 5-HT1(A) receptor ligands
Zhuang, Zhi-Ping,Kung, Mei-Ping,Mu, Mu,Kung, Hank F.
, p. 157 - 166 (2007/10/03)
In developing radioiodinated antagonists for in vivo imaging of 5- HT(1A) receptors with SPECT, a series of new arylpiperazine benzamido derivatives, including 4-(2'-methoxyphenyl)-l-[2'-[N-(2-pyridyl)-p- iodobenzamido]ethyl]piperazine (p-MPPI, 31) (K(d) = 0.36 nM), as potential ligands for 5-HT1(A) receptors were reported previously. However, rapid in vivo metabolism may have caused the breakdown of the amide bond of [123I]- 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-iodo-2-{2-[4-(2- methoxyphenyl)piperazin-1-yl]ethyl}-3-phenyl-2,3-dihydroisoindol-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(i) values of 0.05, 0.65, and 0.07 nM, respectively. The affinities for 5-HT1(A) 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-dihydroisoindol-1-one, 29, were 1.09, 2.54, and 14.9 nM, respectively. Compared to [125I]-31, iodinated cyclized amide derivatives [125I]-21 and [125I]-27 displayed a slower metabolism in human liver microsomal and cytosolic preparations. Biodistribution of [125I]-21 and [125I]-27 in rats (after an iv injection) displayed moderate to low brain uptakes with little or no specific localization in hippocampal region, where 5-HT1(A) 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-HT1(A) receptors in vivo. Additional structural modifications may be needed to correct the unfavorable properties displayed for these iodinated cyclized amide derivatives for in vivo biodistribution in rats.
