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Titolo:
ISOINDOL-1-ONE ANALOGS OF -[N-(2''-PYRIDYL)-P-IODOBENZAMIDO]ETHYL]PIPERAZINE (P-MPPI) AS 5-HT1A RECEPTOR LIGANDS
Autore:
ZHUANG ZP; KUNG MP; MU M; KUNG HF;
Indirizzi:
UNIV PENN,DEPT RADIOL,3700 MARKET ST,ROOM 305 PHILADELPHIA PA 19104 UNIV PENN,DEPT RADIOL PHILADELPHIA PA 19104 UNIV PENN,DEPT PHARMACOL PHILADELPHIA PA 19104
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 2, volume: 41, anno: 1998,
pagine: 157 - 166
SICI:
0022-2623(1998)41:2<157:IAO->2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
RAT-BRAIN; H-3 WAY-100635; IN-VITRO; ANTAGONIST; RADIOLIGAND; AGONIST; NAN-190; PET; DERIVATIVES; AFFINITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
45
Recensione:
Indirizzi per estratti:
Citazione:
Z.P. Zhuang et al., "ISOINDOL-1-ONE ANALOGS OF -[N-(2''-PYRIDYL)-P-IODOBENZAMIDO]ETHYL]PIPERAZINE (P-MPPI) AS 5-HT1A RECEPTOR LIGANDS", Journal of medicinal chemistry, 41(2), 1998, pp. 157-166

Abstract

In developing radioiodinated antagonists for in vivo imaging of 5-HT1A receptors with SPECT, a series of new arylpiperazine benzamido derivatives, including -[N-(2''-pyridyl)-p-iodobenzamido]ethyl]piperazine (p-MPPI, 31) (K-d = 0.36 nM), as potential ligands for 5-HT1A receptorswere reported previously. However, rapid in vivo metabolism may have caused the breakdown of the amide bond of [I-123]-31 and rendered thisagent 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- ethyl)-6-nitro-3-phenyl-2,3-dihydroisoindol-1-one, 15, 3-hydroxy-6- n-1-yl]ethyl}-3-phenyl-2,3-dihydroisoinidol-1-one, 18, and in-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, l)-1-(2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethyl} pyrrolidin-2-one, 25, (4-iodophenyl)-1-(2-[4-(2-methoxyphenyl)piperazin- 1-yl]ethyl)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, 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 thatthe new iodinated;ligands showed high binding affinities and better metabolic stability but displayed unexpectedly low selective binding to5-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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/02/20 alle ore 14:57:56