Zhuang Z P, Kung M P, Mu M, Kung H F
Department of Radiology, University of Pennsylvania, Philadelphia 19104, USA.
J Med Chem. 1998 Jan 15;41(2):157-66. doi: 10.1021/jm970296s.
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]p iperazine (p-MPPI, 31) (Kd = 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 [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 Ki 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 [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 i.v. 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 vivo biodistribution in rats.
在研发用于单光子发射计算机断层扫描（SPECT）体内成像5-HT1A受体的放射性碘化拮抗剂时，之前报道了一系列新的芳基哌嗪苯甲酰胺衍生物，包括4-(2'-甲氧基苯基)-1-[2'-[N-(2"-吡啶基)-对碘苯甲酰胺基]乙基]哌嗪（p-MPPI，31）（解离常数Kd = 0.36 nM），作为5-HT1A受体的潜在配体。然而，快速的体内代谢可能导致了[123I]-31酰胺键的断裂，使其作为人体体内成像剂过时。为提高31的体内稳定性，设计并合成了一系列环化酰胺类似物。研究了这些新衍生物的体外结合、代谢稳定性及体内生物分布。几种五元环异吲哚-1-酮显示出非常高的体外结合亲和力，特别是2-{2-[4-(2-甲氧基苯基)哌嗪-1-基]乙基}-6-硝基-3-苯基-2,3-二氢异吲哚-1-酮（15）、3-羟基-6-碘-2-{2-[4-(2-甲氧基苯基)哌嗪-1-基]乙基}-3-苯基-2,3-二氢异吲哚-1-酮（18）和6-碘-2-{2-[4-(2-甲氧基苯基)哌嗪-1-基]乙基}-3-苯基-2,3-二氢异吲哚-1-酮（21），其解离常数Ki值分别为0.05、0.65和0.07 nM。其他环化酰胺衍生物5-(4-溴苯基)-1-{2-[4-(2-甲氧基苯基)哌嗪-1-基]乙基}吡咯烷-2-酮（25）、5-(4-碘苯基)-1-{2-[4-(2-甲氧基苯基)哌嗪-1-基]乙基}吡咯烷-2-酮（27）和2-{2-[4-(2-甲氧基苯基)哌嗪-1-基]乙基}-2,3-二氢异吲哚-1-酮（29）对5-HT1A受体的亲和力分别为1.09、2.54和14.9 nM。与[125I]-31相比，碘化环化酰胺衍生物[125I]-21和[125I]-27在人肝微粒体和胞质制剂中代谢较慢。[125I]-21和[125I]-27在大鼠体内（静脉注射后）的生物分布显示，脑摄取中等至低，在5-HT1A受体集中的海马区域几乎没有或没有特异性定位。这些数据表明，新的碘化配体显示出高结合亲和力和更好的代谢稳定性，但在体内对5-HT1A受体的选择性结合出乎意料地低。可能需要进一步的结构修饰来纠正这些碘化环化酰胺衍生物在大鼠体内生物分布中显示出的不利性质。
