非损伤性功能成像技术_正电子发射断层扫描术、磁共振波谱分析和动态对比增强磁共振影像学

1、国际会议后续报道1295中国临床药理学与治疗学中国药理学会主办CN34-1206/R,ISSN1009-25012007Nov;12(11:12951298 Noninvasive functional imaging techniques:positronemission tomography(PET,magnetic resonance spectroscopy(MRS, dynamic contrastenhanced magnetic resonance imaging(DCEMlURuediger E.PortGenentech Inc.,South San Francisco,cA

2、94080,USAABS7IRACr In the pharmaceutical industry.there iscurrently increasing interest in nom。nvasive functional im.aging techniques as potential early indicators of drug el-fects in patients.PET allows one to monitor absolute con.centmtions of radio!Iabeled drugs and metabolites.or of li.gands to

3、specific receptors,in tissues,and to visualizemonitoring metabolic conversions in vivo without labeling.drophilic weight contrast agents between blood plasma andinterstitial space in tissue in real time and can be used todetect effects of antivascular or anti-angiogenic COB-pounds.KEY叼崛DS聊1;in vivo;

4、MRS;DCE.MRIIn thepharmaceutical industry,thereis currently astrong interest in applying“imaging”methodsin drug de-velopment,motivated by a desire to determinedrug effectsin humans earlier and more precisely than by conventional clinical measures.The word“imaging”,in this context, refers to noninvasi

5、ve procedures like positron emission tomography(PET,or dynamic contrast-enhanced magnetic resonance imaging(DCEMRIwhich can provide information about the distribution of drugs,the occupancy of specific receptors,or the fimction of vessels in target tissues.These methodsmaybe called“noninvasive func.

6、Received200711-01Accepted200711-15Ruedi Port,MD,correspondence author.Tel:01-650-2251820Email:rport tional”imagingmethods,in contrast to more traditional imaging methods like X-ray scanning or computed tomog-raphy which are also noninvasive but ale primarily used to obtain morphological information.

7、Some resealhers would also imply in vivo magnetic resonance spectroscopy (MRSunder the term“noninvasive functional imaging”, although it produces spectra ratherthan images,because it is another method for obtaining functional information noninvasively.PET images show the localization of radiolabeled

8、 tracers in tissues.Absolute tracer concentrations can be moIlitoI:ed over tillle and can be visualized tlI-eediInen. sionally(Fig1.If the tracer is a drug,then PET call show whether this drug gains access to a target tissue and how long it stays there at what concentrations.Local drug delivery is a

9、 major problem in the treatment of solid ma. 1ignant tumors and PET is a way to study this problem in humans(Fig1.The interpretability of P】四images is limited in that they show concentrations of the radioactive label,regardless of whether it is in the parent compound that was administered or in meta

10、bolites which are formed during the period of observation(usually about one hour.For an unanrbiguous interpretation of PET data,it is best to use tracers that undergo no metabolic conversion or,at most, only013e metabolism step during the period of measuring.The most widely used PET tracer诂Ffluorode

11、oxy glucose(FDGwhich allows one to assess the activity of glucose metabolism in tissues.FDG-PET in malignant tumors is useful for staging and prognosis,and also seems to1296be a potential early indicator of therapeutic effects引.FDG-PET can also help in the early diagnosis of Alzheimers disease2|.PET

12、 with specific labeled ligands has been successfully applied in the development of centralFig 1瑚e patient,76years。liver皿蚓随st商s of a colon carcinomaBecause of the short half-life of most of the radioisotopes used in PI订(two hours for 1蕾,these isotopes are typically generated on the day of the PET exa

13、mination and ale used for automated radiosynthesis of the desired tracer immediately thereafter.3瞄LG涂明曙C RESONANCE SPECTRoS.COPY MRS in vivo allows one to monitor relative concen.trations of compounds of interest in tissues over time.No radioactive labeling is required.Parent compounds and metabolit

14、es ann be followed separately in the same experi-ment41(Fig 2。Sensitivity andspecificity is best withcompoundscontaining fluorine.Concentrations intissue have to be100mol/L or higher to be detectable SO that,fordrugmonitoring,there is often asensitivity problem unless thedrug is administered in gram

15、 doses,like 5一fluorouracil.Sensitivity is much less of a problem when measuring at the site of an interstitial injection(Figs 2,3.Endogenouscompounds which arepresent in highconcentrations,suchascholine,N-acetylaspartate,1actateandcitrate,can also be monitored,forexample tosupport diagnosis andthera

16、pymonitoring in malignantt山I】ors6J.4DYNAMIC CONTR AST.ENHANCED NIAG.N脚C REsl0NANCE D江AG姗Magnetic resonance imaging(MRIuses signa_kfrom water protons.The chemical information available inMRS to discriminate parent drugs and metabolites is traded for spatial information in MRI.The result are imagessho

17、wing the distribution of water in the body.Again,noVradiolabeling is required.There is nosensitivity problem2棚rat鼬蝴Ms脚l伽蝴删A because 0f thehi小姐tu血concen眦ion of water in tis.t蕾MR spectra of tumor紫“曼105:i要曲如。她如吼“?d inj8c-sues(68mol/L.Spatial res01ution is higher tllall w i t h t i on of 30mol floxuridi

18、ne(2.5%of优m.Temporal resolution:4,5min.、。一一x-a【is represents d&rence in res鲫锄ce f蛔uencv f曲I st趾daId(伍nuom P阱.Measurements can be made such that signal intensiacetic acid.The areas under the rq:sonce础are proportional to山e ty is increased in the presence of a contrast agent,usually amounls of flox

19、uridine(一90ppmand its埘Hmry metabolite,5tluorouracil a head7metal chelate like gadolinium diethylene triamine (一94pp岫iII m10r111e 10cal di。11ina“on 0f the pE唧dmg and the for。pentaacetic acid(Gd.DTPA,gadopentetate.DCEMRh叫rs如她ini枷on.仳ex唧ment co州be repeated in她S8fne afli一1m一1es the掣删acqInsl10n oi1。1ages

20、 at regular mter-mal if desiIed.(Frd套renceE4,witll kirId咿nission 0f s呻驽er Science vals during and after the administration of a contrast and Business Media.agent,for example every five seconds for five minutes.生国!垣鏖垫理堂望渔痘堂至塑堕!;12(!These images then allow one to literally watch the distilbution of th

21、e contrast agent in and out of target tissues, like malignant tumors.GdDTPA is hilghly polar and does not CroSS cell membranes;it is not bound to tissue compo-nents.Its kinetics in tissue reflect the distribution be一§誊薹8藿牙”一#3tumm#9S.c.O120240time after injedion frainooo口一oo一ooooc;一91297tween b

22、lood plasma and the interstitial space which depends on blood flow,and on the density and permeabilityof capillaries.Thus,monitoring GdDTPA kinetics in tissue can give information on drug effects on vessel functionin target tissues71(Fig4.嚣2t帅0r#4tumor0120240time after injection(rain群10S.c.墨重j呈墨量。暑重

23、t_工9q2-c!窨P=苫暑一石9呈,。苫3ACI rats,Morris helmtoma3924A,located subcutaneouslyBolus injection of30mol floxuridine either intratumorally(Morris hepatoma3924A,#16or subcutaneously(#710.1节MR siva intensities measured /n v/vo at tlle injection site versus time aftel administration.FiUed ciwles:floxuridine;o

24、pen eiwles:5一fluomuracfl(metabolite.Pd【加1y-scale:amount of parent drug remaining at the岫ecfon site.7rhe local phannacokineties of the parent drug and its primary.metabolite wel'e noninvasively monitored for up to five hours.LDcol disposition or floxuridine is rapid in subcuIarleous tissue witIl

25、half-Iife0f69min whereas in tunlols。tIel'e is always a slow c哪eneot of disposition with half-fife varying from112to5hours.(From referenceJ,with kind permission of Sp_ringe,Seience and Business Media.JMalignant tulnOl'S诵tl rapid GdDTPA exchange between blood plasma and the interstitial space

26、seem to be 10re responsive to chemotherapythan those with slow exchange.掌呻一t8曲8nlj量SnP088吣一8时8曲r肇8nP88nIj 套霉西I硝co(嚣0§oS8n一R并牙竹1298be幻re bevaclzumab afler bevacIzumabtitle(rainPig4Recurrent#obL嬲toma5CONCIJsK弼NPET,MRS in vivo,and DCEMRI can provide in-Chin J Ctin Pharmacol Ther2007Nov;12(11 forma

27、tion about distribution,metabolism and binding pm.cesses in tissues in a noninvasive way.Measurements call be made before and after drug treatment in order to detect drug effects.PET Call determine absolute concentrations of a radiolabel with hi【gh sensitivity,MRS in vivo Call monitor metabolic proc

28、esses without radiolabeling but with lower sensitivity.and DCEMRI can show the distribution of nonradioactive contrast agents in tissues with hiigh temporal resolution.A11of these methods hold great promise as potentially powerful tools for drug development as well as for more basic research looking

29、 at mechanisms of dmg effects at the tissue level.REFE皿ENI】强,%bet删.Use of PEq"for monitoring cancer thempy and for predictionoutcomelJj.J Nucl Med,2005;49:983995.2Coimbra A,Wmiams DS,HosteflerED.role of MRI and PET/SPECT in AlzheimerS diseaselJj.Curt Top Med Chem, 2006;6:629647.3Brooks DJ.Positron emission tomography and single-photon emission comput