tissue-targeting

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1、Tissue-targetingChineseMedicatJournat2006,"119《j7).'1435—14431435OriginalarticleTissue-targetingleadgenerationandoptimizationfromrandomanddirectedscreeningoftechnetium--99mlabeledtripeptidecomplexlibraries/nvivoZENGJun,LIUCi-yi,XIEWen-hui,HUSi-longandJINMu-xiuKeywords:99mTclabeled;tri

2、pept~delibraries;invivo;randomscreening;directedscreeningBackgroundScreeninglibrariesagainstamoleculartargetfr/vitroareidealizedmodelsthatcannotreflecttherealstateinvivowherebiomoleculescoexistandinteract.C—terminalamidetripeptideslabelledwithTechnetium.99mcanprovideauniquenoninvasive

3、approachtotracealargenumberofcompoundsinvivo.MethodsTheC.terminalamidetripeptidelibrariesweresynthesizedonRinkAmide-MBHAresinusingiterativeandpoolingprotoco1.Technetium(V)OXOcore【Tco"】wasboundtoeachtripeptidevia4deprotonatednitrogenatomstoformalibraryof8000mTctripeptoidcomplexes.Thera

4、diocombinatorialscreening(RCS)invivowascarriedoutonSDratsandA549tumourbearingmice.ResultsSignalsoftissuedistilbutionandmetabolismoflibraileswererecordedbycountingorimagingandtissuetargetingleadsidentifiedbybothrandomanddirectedRCS.Amongthem.mTcRPA.mTcVIGand""11cREShadspecifictissuetar

5、getinginkidney.1iverandtumourrespectively.Thepercentinjecteddosepergramtissueof""11clabelledlcadsintheirtargettissuewashighlystructuredependent.BecausethenontargettissuebindingandthemetabolismofTctripeptoidsublibrariesweresimultaneouslymonitoredsuccessfullybvRCS.theinterferenceofbackg

6、roundactivitywaslimitedtothelowestleve1.Optimizationofrenalfunctionagentfromthelabelledlibrarieswascarriedoutbydirectedscreening."11cDSGwasfinallyidentifiedthemostpromisingagentforrenalfunctionstudies.ConclusionsRCSinvivoisapowerfultoolforthediscoveryoftissuetargetingdrugs.Thepotentia

7、lscreeningbiasisprobablythemajorlimitationoflabelledlibraries.ChinMedJ2006;1l9(171:14351443ombinatorialpeptidelibraries,whichwerefirst一,introducedinearly1990s.1_havebecomeanimportanttoolfordrugdiscovery..Thebasicprincipleintheapplicationofcombinatorialpeptidelibrariesindrugdiscoveryis

8、thatl