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:31.1@3hp.i.Highenoughfortumorimaging

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 ComparedwithtumoruptakeofMBBGandMIBG@3hp.i.

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