Doze, Petra

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   University of GroningenBeta-adrenergic receptor imaging with positron emission tomographyDoze, PetraIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2001Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Doze, P. (2001). Beta-adrenergic receptor imaging with positron emission tomography. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 07-06-2022IXSummary and Concluding RemarksIn yivo quantil ication of B-adrenoccptors in the brain, hcart and lung could be very valuablcfor the investigation of thesc rcceptors in ncuropathologies, myocardial and pulmonarydiseascs, irnd for monitoring the elfects of treatment. The airn of this thesis was thedevelopment of a method to image p-adrenoceptors in thc human brain and hcart with PETand the validation of a tracer kinetic model to ir yi lo quantify receptor dcnsities.Cereb ral p-adrenoceptor imagingFor quantif ication of B-aclrenoceptors in the brain, the radioligand S-l '-[ ' 'F]tluorocarazololscemed to be an cxccllent candiclate. It is a fluorinated analog of thc potent, non-subtypeselcctive p-adrenoceptor antagonist carazolol, and exhibits specific in vivrt bincling to ccrebral(14), rnyocardial and puluronary ( 1 5) p-adlcnoceptors in hurnarrs. ln ordcr to assess (ccrebral)p,adrenoceptor clensitics (8,,,,,.) quantitativcly with PET and S- l '-11*F]tluorocarazolol, a tracerkinetic rnodel 15) is requirecl. Chapter I l clemonstrated that S-l '-[ '*Flf luorocarazolol mccrts allthe requircments for a traccr-kinetic nrodel such as proposed by Delfbrge ct a/ (5). Thescinclude lor.v metabolite levcls in brain, saturabil ity and revcrsitri l i ty of thc receptor binding inrats.S- I '-[rEF]fluorocarazolol levcls in brain were relatively low. This aflccts thc countstatistics and theretbre thc quality of the PET irnages. In chapter III the possibil i ty tocnhancc fhe cerebral uptake of S-l '-[ lsF]tluorocarazolol, without aftccting its regionaldistribution. was dcmonstrated by modulating the transmembranc protein P-glycoprotein u ithCyclosporin A in the blood-brain ban'ier (BBB) of rats. Coadministration of P-gp rnodulatorsrnay thereforc improve the quality of PET images of p-adrenoceptors in thc brain. However,the ntodulator Cyclosporin A cannot be uscd in healthy voluntcers, because of its toxicity(12). More potent and highly specific P-gp modulators, such as t-Y335979 (2) and the non-imrnunosuppressive cyclosporin D analog SDZ PSC 831 (10) have already been rcporled.Because of thcir potcncy ancl specificity, such conrpounds may be suitablc fbr application inhurnan PET studies.Since the application of a tracer kinct ic model requires mult iple inject ions and the addit ionof carr ier to thc radiol igand, a toxicological stucly of S-l ' - ;rEFlf luorocarazolol (see chapterI! ' )  was perfbrmecl. Unfortunately. the introduction of f luotinc in the B-blocker carazololt ' ielded a compound lvi t l .r  strong r lutagenic potency as r.ncasurecl by the Amcs test. Thereforc.carr icr-added studies with S-1'-1'*F]f luorocaruzolol in hurnans arc precluded. Fufiher rcscarchto elucidatc i f  this radiol igand is a r isk to humans should addrcss the genotoxic and/orcarcinogenic potcncy of S-f luorocarazolol in rnammalian ccl ls and in ( long tcrm) rn l i loexpeflmcnts.Toxicity test ing of ncwly developed radioactive pharmaccuticals dif fers nrarkcdly f iomnrost rnedicinal products, becausc rnostly small ,  not pharmacological ly act ive cluanti t ies arcinvolvcd and repeated studics are exceptional. Therefore, rcpcatcd dose toxicity studies ofnovcl ladiopharrnaceuticals rnay be omitted, but single dose toxicit l 'and genotoxicit t 'studiesshould be irrcluclcd, bcfbre the test drugs ale irdnrinistcrcd to hurnans. This approach r.vasrecently dcmonstrated fbr thc radiol igand P-C'lT (7). To propcrly assess the possiblegcnotoxicity of a ncwly developed racl iol igand. a battcry of tests is recommcnded by theInternational ( 'ont 'erence on Harnronization of Tcchnical Requircrncnts fbr Registrat ion ofPharrnaceuticals 1or Hunrau Llse ( lCH gi,r idel ines 52B). This includes a tcst fbl sene lnutat ionin bactcria, an irr t ' i tnt tcst wit lr  cytogcnic cvalrrat ion of chromosornal damagc (c.g. humanlymphocycs) and an irr ui lo tcst for chrornosomal darnage (rodent hcmatopoiet ic cel ls).  Thisbattcry of tests shrruld bc pcrfblrnecl not only bcfbre carr ier-addcd doses of the nclr 'compoundare adnrinistcrcd (rnult i- injcct ion protocols for rcccptor density,asscssurent), but also bcfbrePET studics at the non-carr icr added level arc init iated, sincc gcnotoxicity is not a l incar but astochastic process. A rcal dose-risk assessrncnt lbr humans can ncver be made with the dataf iom the gcnotoxicity tests.To f ind alternativcs tbr S-l ' -1r*Flt luolocarazolol.  f lvc ncw raci iotraccrs with high aff ini t1,lbr the B-adlcnoccptor and nrodcratcly high l ipophil ici ty u,ere synthcsizetl  (chapter V).Evaluation of these radiotracers for i t t  viyo imaging of B-adrcnoceptors in thc blain. together- t r i - - .rvith [ '- ' [] iodocylnopindolol (standard l igand tbr autoradiography), revealed that cerebraluptakc of these ligancls was either too low ol not rclatcd to p-adrenoccptors. even thoughsorre radioligands did display strrccil ic binding in lung and heart. Although a high Kp and(rnodcratcly) high l ipophil icity are oflen uscd as prerequisitcs fbr the suitabil ity of acompound fbr irr l i l ,o irnaging of cercbral receplors, thcsc criteria, combincd with availablephannacokinctic ntbrmation. provccl rrot sufficicnt o select a suitablc p-adrenergic l igand forccrcbral [3-adlenoceptor imaging. Possible reasons include transport by P-glycoprotein,rrrctabolisrr, protein binding ancl unccrtainties in thc K1;1 values, as dctcrminerl in in vitroassays.Anothcr canditlatc fbr celebral B-adrcnoceptor irnaging u,ith favorablc attinity andlipophil icity, (S)-[ 'nF]f ' luorocthylcarazolol c uld be successlirl ly synthesizecl fbr animalstLrdics (chaptcr VI). Evaluation in rats demorrstrated its potency and spccific binding tocerebral B-adrcnoccptors i / /  r , i r?, anrl  i r t  t ' iuo in rats. This novel radiol igand is theretbre of 'potcntial usc fbr B-adrcnoccptor inraging in thc brain with PET. Whcther (S)-I l sF l f luoroc thy lcarazo lo l  i s  gcnotox ic  l i kc  (S) - [ rsF ] t luorocarazo lo l .  remains  to  be  exanr incd .The n.rutagcnic properl ics of carazolol analogucs alc harcl to predict since (S)-f luorocarazololshorved rnutagcnic activi ty in thc Amcs test whelcas (S)-carazolol did not (6).l f  (S)-[ ' tF' ] f luoloethvlcarazolol has proven to be non-toxic, pi lot studies with this l igandcan bc perfbrmcd in voluntecrs. To pt ' t ' rduce suff icicnt anrounts of (S)-IrEFlf luorocthylcarazolol,  the synthctic loute via f luolo-ethvlal ion of (S)-clesisoplopyl u' i l l  beinvestigated. To r lcasurc Bn,^* o tracer kinetic mcldcl (sec chaptcr Vl l)  rnight be applicd.Ho'uvcver. tbr recclt tor quanti f icat ion in the brain binding lrotentials (BP) nray bc sufl lcient.which can be estimatcd using a rcgion with rnainly non-specif ic bindirrg as ref 'ercnce t issue.For p-adrenoceptors this is sl ightly ci i t t icult  bccausc thesc reccptols are widely distr ibutedthroughout the brain. White matter of thc corpus cal losum rnay bc used as a rcference region,since the p-adrenoceptor densitf  in this rcgion is known to bc very low.Subscquently, 1S1-[rEt- l f luoroethylcarazolol can be applicd to quanti ly B-adrcnoccptors inthe brains of patients suffering f iorn rnood disordcrs (e.g. depression), clegcnerative diseases(e.g. Alzhcimer's cl isease). and also in patients suf ' f l r ing f iorn rr.rult iplc sclcrosis (MS). Thislast group of patients displays a lack of astt 'ocyt ic B:-adrenoceptors in Trrrs/ /r , , / /e' l l  t issr. lc.rvhich may be involr. ,ed in thc induction or perl)ctuation of autoirnnrunc rei ict iorts (3). Mult iplein t , i t ,o mcasuremcnts with PET and 15.y-[ ' 'F]f luorocthylcarazolol can probably be used tornonitor discase progrcssion and rrray al lou, dif- lerential diagnosis of MS ancl otherneurodegcnerative discases.Irurthcnnorc, PET and 1S1-[rsF]f lLr.rroetlr ] , lcalazrr lol nra,v prove to be a'"alLrable tcchniqucto assess reccptor occupancy of central ly act ing [3-blockcrs. This rnight rcveal i f  thcmcchanisrns of act ior.r of B-blockers in a variety of brain pathologics not ini t ial ly assctciatcclw i th  B-adrenoccptors ,  inc lud ing  migra ine  (16)  and (1 .8 )  suddcn card iac  dca th  (9 ) .  a rc  le la tcdto p-adrerroccptor binding, scrotonin reccptor binding, non-spccif ic nrembrane stahi l izingprol.rcrt ies or pcripheral ly mediatcd activi ty (17). Morcorer, (S)-[r*F]f luoroethylcarazolol-PET could elucidate the rclat ionship betwccn p-adrenoceptor occupancy and side cffects,such as hal lucination, depression, insolnnia. fat iguc. dizziness. impairccl shofi- ternr merloryand a le f tncss  ( rcv iewcd in  (8 ,1  l ) ) .Myocardial and pulmonary B-adrenoceptor imagingChapter VII deals with the imaging of p-adrenoceptors in hutnan heart.  Thc radiol iganci["C]CGp 12388 produced excel lcnt irnages of B-adrenoccptors in thc heart,  lung and spleenof healthy voluntecrs. Bccausc of i ts favorable phannacokinetic (e.g. low rnctabolisrn) anclpharmacot lynar r ic  (e .g .  spec i l i c  b ind ing  w i th  h igh  assoc ia t ion  ra tcs )  p roper t i cs .  {S t - [ r 'C lCC;e12388 appears sr"r i table tbr quanti tat ivc PET studics using a rnult i- inject ion protocol.Traccr-kinetic modeling allowed the estimation of all ntodel parameters of (S)-["C]CGPl238ii (chapter VIII). 8,,,,,. and K11 w€r€ rcliably calculated in the rvhole left ventricle andregional dit lcrences could be plotted in a pararnetric polar map (120 differcnt segments). Weconclude that (S)-[r 'C1CCe 12388 in combination with a tracer-kinetic model is useful forcalcrrlating rcgional B,,,,,. values in hunran lefl ventricle in vivo.Data fiom various injection protocols appeared to allow calculation of reliable B,no^ valucs.The flt procedure appearecl to bc equally scnsitive to changes in thc value of thc parameters.The ideal protocol horvever, should bc most sensitive to tl ie paranreter B,,,,,,, while thescnsitivity to thc other paralneters i lcss essential. Simulation of different injection protocols(various injected masses and injcction intervals). based on the acquircd data, should reveal thcoptinral injection protocol and rvhethcr thlee injcctions are cssential or not. Obviously. aprotocol with a rninimal number of injections is prefcrred becausc it is morc convenient in aclinical sctting.The protocol may be turther sinrpli l icd by using tlre bloodpool (endocardium) as inputfunction in stcad of the arterial sarnples, which reduces thc inconvenienccs for the patient.(S)- [ r rC]CGP 12388,  howu,cr  shows substant ia I  b inding to rcc l  b looc]  ce l ls  (chapter  VI I ) .Thelefbre, using the whole blood as input f iurction to accurately rlodcl the kinetics of theligand, is probably only fbasible when the bloodpool data is (dynamically) correctcd lor redblood cel l  b inding.When the optimal plotocol is tbund, the 8,,,.* can be assessed in patients suffering l iomHCIM, DCM or other myocardial deficicncies and compared to those found in healthyvolunteers. Since traccr kinetic modcling in principle allorvs the identif ication of all modelpararncters vr'hilc requil ing only standard u priori assunrptions, it could scrl 'c as a goldstandard to validatc simplif icd procedurcs including graphical models, which are based onrnany additional hypothcses and oftcn allow only the idcntif ication of conrpositcs ofparameters (c.g. B,,,,,,/ Kp, r 'ather than B,,,,,").f ' ]-Adrenoccptors were also visualizcd with (S)-[ ' C]CGP 12388 in thc lungs of healthyvolunteers. This technique however is probably not suitable to detect diffcrences in p-adrerrcrccptors in  COPD, as was a l ready c lemonstrated wi th (St- [ r 'C]CCR l2 l ]7  in  asthmat icsub.jects vcrsus age-matched healthy controls (13). Intravctously achninistered radioligandmainly binds to alveolar rcceptors (> 900,6). and much less (< 10%) to rcccptors on smoothmuscle cclls in the uppcr airways (see also (15)). which are involved in the regulation ofairway calibcr and thus contributes to the pathophysiology of COPD. Thercfore, it would belal rnore intcresting to image exclusively B-adrcnoceptors in the upper airways. This rnight bepossib le by adnr in is ter ing (S)- [  C]CGP 12388 r ' ia  inhalat ion.  (S)- [ '  C]CGP 12388 inhalat ionrnay also be usccl to assess B-adrenoccptor occupancy of B-mimetics and to deterrnine thepat tern ofdeposi t ion ofvar ious inhalers and ncbul izers.

Beta-adrenergic receptor imaging with positron emission tomography

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Beta-adrenergic receptor imaging with positron emission tomography

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