Isoindol-1-one Analogues of 4-(2‘-methoxyphenyl)-1-[2‘-[N-(2‘‘-pyridyl)-p-iodobenzamido]ethyl]piperazine (p-MPPI) as 5-HT_1A Receptor Ligands

Abstract

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.

The Use of Lithium Amides in the Palladium‐Mediated Synthesis of [Carbonyl‐11C]Amides

“…[15] A colourless oil was obtained after purification by preparative TLC (dichloromethane/methanol, 10:1), yield: 0.069 g (42 %). [16] A colourless oil was obtained after purification by preparative TLC (dichloromethane/methanol, 10:1), yield: 0.160 g (51 %). [17] A solution of benzoyl chloride in dichloromethane was added dropwise to an ice-bath cooled solution of amine 2 and triethylamine in dichloromethane.…”

Synthesis of Polyheterocyclic Pyrrolo[3,4-b]pyridin-5-ones via a One-Pot (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2) Process. A Suitable Alternative towards Novel Aza-Analogues of Falipamil

“…Besides, piperazine is a common structural motif in bioactive products, and thus it is considered a privileged linker in medicinal chemistry [5]. For example, Kung et al described that various compounds containing the isoindolin-1-one system that are piperazine-linked to other heterocycles exhibit strong binding affinity to the 5-hydroxytryptamine 1A receptor [6]. In the same way, Couture et al synthesized various piperazine-linked isoindolin-1-ones like the compound 2 (Figure 1), bearing in mind its possible use for further SAR studies [7].…”

Synthesis of Phosphonic Acids Possessing Isoindolin-1-one Moiety: Unexpected Acid-Catalyzed C-P-Bond Cleavage

“…Isoindolin-1-ones have attracted considerable attention because of their high biological (e.g., antihypertensive, 1 antipsychotic, 2 antivirus, 3 antileukemic, 4 etc.) activity.…”