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SynthesisandBiologicalEvalua4onsofRadiobrominatedCompoundsforTumorImaging
ShigekiWatanabeQuantumBeamScienceDirectorateJapanAtomicEnergyAgency(JAEA)
7thInterna4onalSymposiumonRadiohalogen,on18th,Sep.,2012
TableofContents
Advantagesofradiobromines,especiallyBr‐76
ProducConofradiobromines
SynthesisandbiologicalevaluaConsofradiobrominated
compoundsfortumorimaging
76Br‐MBBG:MIBGanalog
76Br‐BAMT
76Br‐BAMP
ConclusionsandFutureplans
:Aminoacidtracer
AdvantagesofRadiobromine
RadiobromineshaveaNrac4venuclidesforbothimagingand
therapy.
Labelingstrategiesofradioiodineareapplicable.‐ Electrophilicornucleophilicreac4on⇒ Radiobrominatedcompoundcanbesynthesizedconveniently.
C‐BrbondisstrongerthanthecorrespondingC‐Ibond.⇒ Easytoobtainmorestablecompoundinvivothaniodine.
Promisingradiobrominesforclinicalapplica4ons
Applica4on Nuclides
Imaging 75Br(PET),76Br(PET)
Therapy 77Br(Auger),82Br(β‐)
AdvantagesofBr‐76
Longerhalf‐lifethanconven4onalPETnuclides(18F,11C)Longenoughtoequilibrateofbiomoleculeinvivo Produc4onbycyclotronwithhighyield
Wehaveno4ced76Brbecause…
Wehaveused76Brand77Brasfollows;
Half‐life Advantages Purposesinthisstudy
76Br 16.1h Highβ+raCo ForonlyPETstudies
77Br 57.0h Longhalf‐lifeDetectableγ‐ray
Forbasicinves4ga4onsOpCmizaConofsyntheCccondiCon,cellularuptake,biodistribCon,…
⇒Synthesisandevalua4onof76Brcompoundssince5yearsago.
Produc4onofRadiobromine‐Irradia4on
76Br 77BrNuclearreacCon
76Se(p,n)76Br natSe(p,xn)77Br
TargetCu276Se
(Enrich:99.67%)Cu2natSe
Ionbeam H+(20MeV,5μA)
IrradiaCon 6hours
SeparaCon Drydis4lla4on
AcCvity@EOB 1040MBq 100MBq
Radionuclidepurity >99%
AVFcyclotron
76Brand77BrwereproducedusingAVFcyclotroninJAEA
Cu2Setarget
Produc4onofRadiobromine–Drydis4lla4on
Teflontube
Cu2Setargetembeddedintungstenplate
Quartztube
Argas30mL/min.
1stElectricfurnace Temp;1120℃
2ndElectricfurnaceNotcontrolled
Yield:77% CollectedBrwasrou4nelyprovidedforsynthesisa_erevapora4on.
Separatedbyconven4onaldrydis4lla4on*
TrapH2O(15mL)
*Tolmachevetal.,Appl.Radiat.Isot.,49,1537‐1540(1998)
Synthesisandbiologicalevalua4onsof76Br‐MBBGforNET‐expressingtumorimaging
Background–76Br‐MBBG
Meta‐iodobenzylguanidine(MIBG):FuncConalanalogofnorepinephrineHighaffinitytonorepinephrinetransporters(NET)
131I‐MIBG:RadionuclidetherapyforNET‐expressingtumors (Pheochromocytomas,Neuroblastomas,…)
123/131I‐MIBG:DiagnosisbySPECT DetecConoflesionsormetastasisMonitoringaccumulaConlevelofMIBG
PET:Higherresolu4onthanSPECT
PETnuclidelabeledMIBGispromisingtoimprovediagnos4cability
SPECT
Objec4ve
[76Br]‐meta‐bromobenzylguanidine(76Br‐MBBG) 123I‐MIBG
76Br Similarchemicalproper4estoiodineSuitablehalf‐life(16.1h)fortracingMIBG
AlreadyreportedbyFrenchgroupinthe1990s*(BiodistribuCon,…) PETstudieshavenotbeendoneyet.
*J.Clercetal.,J.Nucl.Med.,36,859‐866(1995)
⇒ Weconductedbiologicalevalua4onsincludingPETstudies.
SynthesisofMBBG
PurificaCon:Solid‐phaseextracCon,HPLC
RCY:23‐44%RCP:>97%SA:>18GBq/umol
Radiobromina4on:Halogenexchange*
*C.Lochetal.,Nucl.Med.Biol.,21,49‐55(1998)
Precursor
HPLCprofile
76/77Br‐MBBG
Non‐radioac4veMBBG
76Br‐MBBG Ra
dioa
c4vity
UV(2
20nm)
Cellularuptakestudies
0
20
40
60
80
100
1 2
Tumorcell:PC‐12(ratpheochromocytoma)Amixtureof77Br‐MBBG(3kBq)and125I‐MIBG(2kBq)wasadded.
Cellularuptake Inhibi4onassay
77Br‐MBBG 125I‐MIBG
■ Control■ Nisoxe4n■ Desipramin
● 77Br‐MBBG■ 125I‐MIBG
Uptake:77Br‐MBBG<125I‐MIBGMBBGwastakenupviaNET,justlikeMIBG
Biodistribu4onintumor‐bearingmice Mice:PC‐12(Ratpheochromocytoma)bearingmice
Amixtureof77Br‐MBBG(30kBq)and125I‐MIBG(20kBq)wasinjectedintraveniously.
● Tumor ■ Adrenal ▲ Heart◆ Liver ◆ Stomach ■ Muscle ◆ Blood
UptakeofMBBG
Rapidclearancefromblood
Tumor‐to‐normal4ssuera4osT/B:54.4,T/M:[email protected]
IncomparisontoMIBGTumor:MBBG>MIBGHighcorrela4on(r=0.997)
32.0%dose/g Tumor Adrenal
HeartNormal>> >
%ID/g
Invivostabilitystudies
● MBBG■MIBG
70%ofMIBGwasdecomposed@5min.
55%ofMBBGremainedintact@60min.
MBBGwasmuchmorestablethanMIBGinvivo⇒ AlargeramountofMBBGwouldbeabletoreachtotumors,andconsequently,theuptakewashigherthanMIBGinvivo.
Comparisonoftumoruptakeinvitroandinvivo
Invitro(Cellular)
MBBG<MIBG⇒ lowerlipophilicityofMBBG*
Invivo(Mice)
MBBG>MIBG⇒ Differenceofinvivostability?
TimeauerinjecCon(min.)
*P.K.Gargetal.,Nucl.Med.Biol.,21,97‐103(1997)
RadioacCvityinblooddrawnfrommice
%ofradioacCvity
Photo 76Br‐MBBG@6h 18F‐FDG@1h
PETImaging
• 76Br‐MBBGclearlyvisualizedthetumorlesion.• MBBGuptakeinthelowertumorwashigherthantheupperone.• FDGvisualizedonlytheuppertumor.• Uptakeoftracerswasdifferentfromlesionstolesions
inthesameanimal.
HistologicStainingofTumors
Uptake:76Br‐MBBG:Weak 18F‐FDG:Strong
Poorlydifferen4ated
TumorswereextractedandstainedwithH&E
Uptake:76Br‐MBBG:Strong 18F‐FDG:None
Welldifferen4ated
Alotofnecrosis Highcellularity
Thezellballenpayern,prevalentinpheochromocytoma
Tumordifferen4a4oncontributedtoaccumula4onlevelofMBBGandFDG
Summary–76Br‐MBBG
76Br‐MBBGwaspreparedbyhalogen‐exchangereacCon.
Showedthehighestuptakeintumor,whichwaswellcorrelatedtoMIBG.
MorestablethanMIBGinvivo
Clearlydepictedtumorlesions76Br‐MBBGhasagreatpoten4alasPETtracerforNET‐
expressingtumors,andwillprovideusefulinforma4on
forMIBGtherapy.
S.Watanabeetal.,J.Nucl.Med.,51,1472‐1479(2010)
76Br‐BAMT,brominatedaminoacidtracer
fortumorimaging
Background
GoldstandardfortumorPETimaging
Accumulatesinnotonlymalignantbutbetweenbenignorinflamma4on
18F‐FAMT(18F‐fluoro‐α‐methyl‐L‐tyrosine):aminoacidtracerMorespecifictomalignantthanFDGClinicallyavailableinGunmaUniv.,Japan.staging,detecConofmalignancyandmetastasisforvarioustumors
(braintumor,lungcancer,…)
18F‐FAMT
Malignant Benign FDGFAMTFDGFAMT
18F‐FDG
Brominatedaminoacidtracer–76Br‐BAMT
[76Br]‐3‐bromo‐α‐methyl‐L‐tyrosine76Br‐BAMT 18F‐FAMT
76Br Longerhalf‐life(16.1h)than18F EasilylabeledtotyrosinebyelectrophilicreacCon
18F‐FAMTisusefulforvarioustumorimaging,butshorthalf‐lifeof18Frestrictswidespreaduses.
⇒ Weconductedsynthesisandbiologicalevalua4onsofBAMT.
Precursor 76/77Br‐MBBG
SynthesisofBAMT Radibromina4on:Electrophilicsubs4tu4onwithNCS
Reten4on4me(min)0 5 10 15 20
Radioa
c4vity 77Br‐BAMT
UV‐Absorba
nce
Reten4on4me(min)0 5 10 15 20
Standard
PurifiedwithHPLC HPLCanalysis
RCY:20‐30%RCP:>99%SA:>10GBq/μmol
tR=14.7min. tR=14.7min.
InvitroandinvivostabilityofBAMT
0
20
40
60
80
100
0 2 4 6
Time (h)
Invitro(Serum)
%ofradioacCvity
of7
7 Br‐BA
MT
0
20
40
60
80
100
0 20 40 60
Time (min)
Invivo(Normalmice)
%ofradioacCvity
of7
7 Br‐BA
MT
BAMTisstableinvitro,butnotstableinvivo.
>80%ofBAMTwasdecomposed.
>95%ofBAMTremainedintact.
Biodistribu4onintumor‐bearingmice
• HighandrapidaccumulaConinkidney,pancreas,andtumor.• Rapidclearancefromblood• T/B(2.3@3h)andT/M(5.2@3h)washighenoughforimaging.• SimilardistribuCon,butloweraccumulaConlevelthanFAMT
Mice:LS‐180(Humancolonadenocarcinoma)bearingmiceAmixtureof77Br‐BAMT(15kBq)and18F‐FAMT(20kBq)wasinjectedintraveniously.
PETimaging 76Br‐BAMT(6h) 18F‐FAMT(2h)Photo
• 76Br‐BAMTvisualizedthetumorlesionwithPET.• Whole‐bodyimagewassimilartoFAMT,nottoFDG.• ThebackgroundishigherthanthatofFAMT.
18F‐FDG(1h)
Y.Ohshimaetal.,Nucl.Med.Biol.,38,857‐865(2011)
76Br‐BAMTcanbeusedfortumorimaginglike18F‐FAMT
Summary–76Br‐BAMT
76Br‐BAMTwasdesignedandpreparedfortumorimaging.
ShowedsimilardistribuContoFAMT. VisualizedtumorlesionwithPET,andwholebodyimagewassimilartoFAMT,nottoFDG.76Br‐BAMTcouldpoten4allyserveasPETtracerforvarioustumorimaginglikeFAMT.
However,thebackgroundwashigherthanFAMT.⇒ Slowexcre4onoffreeBrdecomposedfromBAMT‐lowstability.
Y.Ohshimaetal.,Nucl.Med.Biol.,38,857‐865(2011)
76Br‐BAMP,aminoacidtracertoimprove
invivostability
76Br‐BAMP–Improveinvivodistribu4on
[76Br]‐4‐bromo‐α‐methyl‐phenylalanine76Br‐BAMP
SlowexcreConofradiobromineinwholebodywillcauseundesirableproblems(Declineofimagequality,increaseofradiaCondose)
⇒ Itisnecessarytoimproveinvivostability
Wecameupwithalterna4onoflabelingposi4on
⇒ Weconductedsynthesisandbiologicalevalua4onsofBAMP.
[76Br]‐4‐bromo‐α‐methyl‐tyrosine
76Br‐BAMT
SynthesisofBr‐BAMP Radiobromina4on:Electrophilicdestannyla4on
4(RCY:75%)
6(RCY:38%from3)
1(Yield:82%)
2(Yield:quant)
3(Yield:42%)
5(RCY:quant)
Charactariza4on
TLC,HPLCanalysiscorrespondingtocoldstandard
Invitroandinvivostability
76Br‐BAMT
BAMP
h
InvivostabilityofBAMPwasdrama4callyimproved
0
20
40
60
80
100
0 2 4 6
Time (h)
Invitro(serum)
%ofradioacCvity
of7
7 Br‐BA
MP
Invivo(Normalmice)
>95%ofBAMPremainedintact
>95%ofBAMPremainedintact
%ofradioacCvity
of7
7 Br‐tracer
60
40
20
0
80
100
Biodistribu4onintumor‐bearingmice
0
5
10
15
20
25
30
35
40
45
Bld Liv Kid Int Spl Pan Lng Hrt Sto Mus Tum
%dose/g
30min1h3h6h24h
LS‐180(Humancoloncarcinoma)bearingmice
• HighandrapidaccumulaConinkidney,pancreas,andtumor.• T/B(4.0@3h)andT/M(4.0@3h)raCowashighenoughto
visualizetumor.• RetenConofradioacCvitywasobservedinallorgans.
PETimaging 76Br‐BAMP(6h) 18F‐FDG(2.5h) 18F‐FAMT(2.5h) 76Br‐BAMP(24h)
• 76Br‐BAMPvisualizedthetumorlesionwithPETat3hp.i.• ThebackgroundissCllhigherthanthatofFAMT.• HighacCvitywasretainedaroundabdomenat24hourp.i.
BAMPcouldbeapplicablefortumorimaging,buthighbackgroundremainedunchanged.
LipophilicityofFAMT,BAMT,andBAMP
ParCConcoefficientsof1‐octanol/water(LogPC)
Compound LogPC
18F‐FAMT ‐1.75
77Br‐BAMT ‐1.09
77Br‐BAMP ‐0.22
BAMPwasmuchmorelipophilicthanFAMTandBAMT
⇒ Reten4onofradioac4vityinwholebodyisduetohigh
lipophilicityofBAMP.
Summary–76Br‐BAMP
BAMPwasdesignedandpreparedtoimproveinvivostability
InvivostabilitywasimproveddramaCcally.
AlsovisualizedtumorlesionwithPET.
76Br‐BAMPcouldbeapplicablefortumorimaging
However,highbackgroundwassCllunsolved. ⇒ Thismighthavebeenconsideredtohighlipophlilicity
Itisnecessarytodesignmorehydrophilictracer.
ObtainedgoodPETimagesbyusing76Br‐tracer
whichhashighT/BorT/Mra4olike76Br‐MBBG.
Conclusions
Rou4nelyproduced76/77Brandinves4gatedpossibilityofradiobrominatedcompoundsfortumorimaging.
Chemicalfindings(labelingposi4onof76Br,
lipophilicityofcompounds,…)isextremely
importantfordevelopmentofusefultracers.
Elabora4ngbrominatedaminoacidtracersbasedonthe
chemicalfindingsobtainedinthisstudy. Expandingsmallcompoundstobiomolecules
Futureplans
Pep4des An4body
⇒ Talkaboutourstudyinthenextsession
Challengefornovel76Brlabeledtracerfortumorimaging
Acknowledgement
JAEAYasuhiroOhshima,Ph.D.SatoshiWatanabe,Ph.D.LiangJixin(ChinaInsCtuteofAtomicEnergy)YumiSugo,Ph.D.NorikoS.Ishioka,Ph.D.
TheseworkswereconductedwithGunmaUniversity
FUJIFILMRIPharmaKindlyprovidingof125I‐MIBG
GunmaUniversityHirofumiHanaoka,M.D.ShinjiYamamoto,Ph.D.HideyukiTominaga,Ph.D.NoboruOriuchi,M.D.YasuhikoIida,Ph.D.KeigoEndo,M.D.
Funding• 21stCOEProgram• YoungScienCst(A)(22689035)• YoungScienCst(B)(21791227)
fromMinistryofEducaCon,Sports,andCultureofJapan
Thankyouverymuchforyoura9en:on
MatsumotoCastle,Nagano,Japan
PETstudiesinGunmaUniv.
MicroPET,Inveon(Siemens)
Tumoruptake:MBBG>MIBGUptakeofotherCssues:Similar
ComparisontoMIBG
32.0%dose/g
MBBG MIBG
32.0%dose/g
25.1%dose/g
● Tumor ■ Adrenal ▲ Heart◆ Liver ◆ Stomach ■ Muscle ◆ Blood
ComparisonofTumorUptake [email protected].
0
10
20
30
0 10 20 30 40
%dose/g(77Br‐MBBG)
%do
se/g(1
25I‐M
IBG)
In131I‐MIBGradiotherapy…
TheaccumulaConlevelofMIBGisimportantfactorstoselectgoodresponder
DifferentfrompaCenttopaCent,evenlesionstolesions.
76Br‐MBBG:Powerfultooltoes4matetheMIBGaccumula4onlevel
r=0.997
UptakeofMBBGandMIBG
→ Highcorrela4on
PETStudieswith76Br‐MBBGand18F‐FDG Photo 76Br‐MBBG@3h
size:2mm weight:5mgUndetectedbeforePET
18F‐FDG@1h
76Br‐MBBGnotonlydepictthetumorclearly,butalsodetectanextremelysmalltumorswithPET
S.Watanabeetal.,J.Nucl.Med.,51,1472‐1479(2010)
Evalua4onwithTBRandDifferen4a4on
TBR(Tumor‐to‐backgroundraCo)DeterminedfromPETimages
Differen4a4onClassifiedasfollows;● WelldifferenCated (WD)▲ ModeratelydifferenCated
(MD)■ PoorlydifferenCated (PD)
WD MBBG: Strong FDG: Weak
PD MBBG Weak FDG Strong
S.Watanabeetal.,J.Nucl.Med.,51,1472‐1479(2010)
Tumordifferen4a4oncontributesuptakeleveloftracers
SynthesisofFAMT
Supplemental slide 1 Fluorination of α-methyltyrosine
[18F]Fluorine(18F2)
②
α-methyl-L-tyrosine or
α-methyl-D-tyrosine
F2 18F/F2
18F/F2
+
+ CH3COOK/CH3COOH
CH3COO18F
CH3COO18F
L-[18F]FAMT or
D-[18F]FAMT +
①
③
Ref., Tomiyoshi K, et al. Nucl Med Commun. 1997;18:169-75. Synthesis of isomers of 18F-labelled amino acid radiopharmaceutical: position 2- and 3-L-18F-alpha-methyltyrosine using a separation and purification system.
Fluorination step of α-methyltyrosine
2‐5.BiodistribuCon(LS180bearingmice) (indetail)
0
5
10
15
20
Blood Liver Kidney Intestine Pancreas Stomach Muscle Tumor
%ID
/g o
f tis
sue
18F-FAMT (1h) 18F-FAMT (3h) 18F-FAMT (6h)
77Br-BAMT (1h) 77Br-BAMT (3h) 77Br-BAMT (6h)
18F-FAMT (30 min) 18F-FAMT (10 min)
77Br-BAMT (30 min) 77Br-BAMT (10 min)
77Br‐BAMTHigheruptakethan18F‐FAMT(Red)RetenConinBloodandStomach(Blue)⇒ HigherretenConthan18F‐FAMT(Dueto77Br‐ decomposedfromBAMTauerinjecCon)
Time after administration 10 min 30 min 1 h 3 h 6 h
77Br-BAMT
Tumor-to-blood ratio 1.01 ± 0.11 1.79 ± 0.27 3.15 ± 0.63 2.31 ± 0.36 1.38 ± 0.29 Tumor-to-muscle ratio 2.84 ± 0.48 3.15 ± 0.77 3.92 ± 0.76 5.20 ± 1.62 4.94 ± 2.17
18F-FAMT
Tumor-to-blood ratio 1.41 ± 0.15 2.37 ± 0.51 4.80 ± 0.97 9.54 ± 4.70 7.17 ± 0.91
Tumor-to-muscle ratio 3.90 ± 0.44 3.61 ± 1.06 3.59 ± 0.35 2.40 ± 0.33 2.20 ± 2.16
T/BandT/Mra4oofBAMTandFAMT
T/B:77Br‐BAMT<18F‐FAMTT/M:77Br‐BAMT>18F‐FAMT
Highenoughtovisualizetumorlesion
2‐5.BiodistribuCon(LS180bearingmice)
UrinaryexcreConof77Br‐BAMT
>90%ofBAMTwasmetabolizedviaurine85%ofradioacCvitywasintactinurine
TimeaueradministraCon
30min 1h 3h
29.99±12.21 84.29±5.67 93.34±5.67 Urine
DistribuConof77Br‐
0
5
10
15
20
%ID
/g o
f tis
sue
AccumulaConinbloodandstomach Retainedineachorgan T/Bwas<1unCl3hours.⇒Differentfrom18F‐FAMTand77Br‐BAMT
77Br(30min)77Br(1h)77Br(3h)
Tumoruptakeof77Br⇒ accumulaConofintact:77Br‐BAMTRetenConof77Brinwholebody⇒ RetenConoffree77BrdecomposedfromBAMT
2‐5.BiodistribuCon(LS180bearingmice)
76Br-BAMT (3 h) 18F-FAMT (2 h) 18F-FDG (1 h) Photo
76Br‐BAMTdepictedtumorlesionwithPETBackground: 76Br‐BAMT>18F‐FAMT
2‐6.PETimaging
Y.Ohshimaetal.NuclearMedicineandBiology(2011 inpress)
18F-FDG-PET 76Br-BAMT-PET 18F-FAMT-PET 24 h 24 h
Start End
<Schedule>
Cellularuptakeandreten4on Tumorcell:LS180(humancolonadenocarcinoma)
0
10
20
30
40
50
60
70
0 20 40 60 80 100 120 140
% d
ose/
mg
of p
rote
in
Time (min)
FAMT BAMT
*****
***
*****
***18F‐FAMT77Br‐BAMT
***
0
20
40
60
80
100
120
0 20 40 60 80 100 %
rele
ased
radi
oact
ivity
Time (min)
FAMT BAMT 18F‐FAMT77Br‐BAMT
*****
***
******
******
Cellularuptakeandreten4on:77Br‐BAMT>18F‐FAMT
*(P<0.05)**(P<0.01)***(P<0.001)
77Br‐BAMT>18F‐FAMT 77Br‐BAMT<18F‐FAMT
Cellularuptake Release
0 5 10 15 20 25
Retention time (min) 0 5 10 15 20 25
Retention time (min)
ColdstandardColdstandard
3h
6h
24h
1h
6h
24hSaline Serum
Invitrostability
RadioacCvity
RadioacCvity
BAMPwasstableinvitro
Biodistribu4oninnormalmice
0
1
2
3
4
10min 30min 1h 3h 6h
% d
ose/
g
Blood Br-α-Me-Phe
FAMT
0
10
20
30
40
50
60
70
80
10min 30min 1h 3h 6h
Kidney
0
10
20
30
40
10min 30min 1h 3h 6h
Pancreas
0
10
20
30
40
50
60
70
80
0 2 4 6 Time(h)
FAMT
0
10
20
30
40
50
60
70
80
0 2 4 6
%do
se/g
Time(h)
Br-α-Me-Phe
Pancreas
Kidney
Pancreas
Kidney
ClearanceofBr‐α‐Me‐PhewasslowerthanFAMT
ComparisonwithFAMT
Br‐α‐Me‐Phe%dose/g FAMT%dose/g
30min 1h 3h 30min 1h 3h
Blood 4.00± 0.24 3.18±0.17 3.23±0.28 1.80±0.76 0.42±0.03 0.10±0.04
Muscle 3.28± 0.20 3.18±0.16 3.25±0.34 1.08±0.21 0.71±0.02 0.40±0.12
Tumor 9.62± 1.02 9.25±0.91 13.3±3.05 5.73±0.82 2.81±0.34 0.85±0.42
Tum/Bld 2.43± 0.40 2.91±0.22 3.94±0.66 3.58±1.28 6.72±0.65 8.87±2.33
Tum/Mus 2.96± 0.48 2.91±0.22 3.95±0.51 5.37±0.56 3.94±0.47 1.97±0.32
BiodistribuConintumorbearingmice
Br-α-Me-Phe %dose/g 1h 3h 1h 3h
Bld 4.34 ± 1.07 4.10 ± 0.44 2.98 ± 0.21 2.75 ± 0.16
Mus 4.56 ± 1.17 3.97 ± 0.35 2.81 ± 0.35 2.67 ± 0.12
Tum 6.64 ± 1.79 6.53 ± 0.73 6.18 ± 1.64 4.66 ± 0.54
T/B 1.53 ± 0.14 1.59 ± 0.04 2.10 ± 0.64 1.70 ± 0.14
T/M 1.46 ± 0.16 1.64 ± 0.10 2.23 ± 0.69 1.75 ± 0.23
FAMT %dose/g 1h 3h 1h 3h
Bld 0.99 ± 0.38 0.15 ± 0.02 0.40 ± 0.01 0.14 ± 0.04
Mus 1.05 ± 0.40 0.58 ± 0.08 0.58 ± 0.10 0.35 ± 0.11
Tum 3.12 ± 1.12 0.59 ± 0.07 1.77 ± 0.58 0.42 ± 0.23
T/B 3.17 ± 0.20 4.07 ± 0.22 4.39 ± 1.32 3.58 ± 2.53
T/M 3.02 ± 0.54 1.04 ± 0.18 3.07 ± 0.76 1.10 ± 0.42
Ovariancancer(SK‐OV‐3) Glioblastoma (U87MG)
TumoruptakeofBr‐α‐Me‐PhewashigherthanthatofFAMT.T/BandT/MraCoofBAMPwasnothighduetoitsretenCon
WebelievedthatthisisaNributedtohighlipophilicityofBAMP