Fluorine‐18RadiochemistryBasicConcepts

MichaelR.Kilbourn,Ph.D.UniversityofMichiganMedicalSchool,

AnnArbor,MI

1990

Fluorine‐18:Half‐Life

•  Half‐life:1.8288h(Beetal,2004)

•  Half‐life:1.82871(Garcia‐Toranoetal,ApplRadiatIsot2010:68;1561‐1565).

1990:Exclusive(?)EmphasisonCarbon‐FluorineBondFormaYon

2012:Fluorinebondingtootherelements

OldStandards•  AliphaYcnucleophilicsubsYtuYons

•  AromaYcnucleophilicsubsYtuYons

R X R 18F

18F-

X = halogen, sulfonate ester

nitro

Alipha'cNucleophilicSubs'tu'ons…

Iridiumcatalysis

BzO

O

CCl3

NH

BzO

18F18F/Kryptofix-222

[IrClCOD]2

Topczewski,TewsonandNyugenJACS2011:133;19318

Allylic[18F]FluorinaYon:PdCatalysis

O

O

OR

18F-TBAF

18F

18FX

X = Cl, Br

Pd(dba)2, PPh3

CH3CN, RT

18F-TBAFPd(dba)2, PPh3

R = C6H4NO2, 5-7%R = CH3, 10-52%

20-42%

HollingworthetalAngewChemIEE2011:50;2613

NucleophileassisYngleavinggroups:NALG

SO

OO

OO

( )3

Ar

F

F

Ar18F

ThermalMicrowavew/K‐222w/K‐222noK/222

31 64 1672 75 1211 64 19

LuS…PikeV,JOrgChem2009:74;5290

Making[18F]trifluoromethylgroups

18F-F F

R2R1

F F

R2R1

18F-/K222

DMSO

85o, 5 min

R1 R2 yield

OTs H 93%OTs CH3 52%PhCH2 H 65%

RissandAigbirhioChemComm2011:47;11873

ProYcsolventsfor[18F]fluorinaYon?

O OMs O18F-, Cs+ 18F

t-butanol orisoamyl alcohol

Kimetal,JAmerChemSoc2006:128;16394Chietal,JLabeledCompdsRadiopharm2007:50;S2

OHO N

N

O

O

18F

18F

N N

NO2

OH

N

I

18F OOCH3

Cs18F/alcohol

65%

69%

35%

literature

15%

15%

1%

[18F]FLT

[18F]FMISO

[18F]FP-CIT

Aroma'cNucleophilicSubs'tu'ons…

Pd‐CatalyzedFluorinaYons

OTf

R R

Fphosphine +Pd catalyst

high T, long time

Diarylsulfoxides

S

R R1

O

R R1

18F-/K-22218F 18F

DMF150-200 oC

Worksonlywithstrongelectron‐withdrawinggroupsinpara‐posiYon(NO2,CN,CF3)

Chunetal,JLCR2011:54;S70

IodoniumSaltsfor[18F]FluorinaYon

Coenenpaper

N

SF

CN

I

OMe

N

SF

CN

18F

18F-/K-222DMF, 180 oC, microwave

+-OTf Iodoniumsalt

fluorinaYon

Teluetal,OrgBiomolChem2011:9;6629

Cycloaddi'onReac'ons…

“Click”reacYonsforfluorine‐18labeling

N N NR1

H R2

NN NR1

R2

NN NR1

R2N

N NR1

R2

thermal

Cu(I)

OpYonsforClickRadiolabeling

N N NX

H (CH2)n

NN NX

(CH2)n18F

peptide

18F

peptide

N N N(CH2)n

H X

NN N(CH2)n

Xpeptide

18F18F

peptide

Copper‐FreeClick:StrainedAlkynes

R R

NNN 18F

18FN3

N

18F

+

-OO

O

R

NO

R

O

O

18F

H

H

p-[18F]fluorobenzaldehyde

Nitrone‐based“Click”ReacYon(Zlatopolskiyetal,ARI2012:70;184)

CombinaYonofFluorouschemistryandClickreacYon

ON3S

O

O

C8F17(CH2)2 N318F

18F-

N N

NO2

N N

NO2

N N

N

18FBejotetal,AngewChemIEE2009:48;586

Complexity…

Bi‐FuncYonalReagent

S OO

O SO3K

18F

S OO

O

SOO

O

18F/K-222

r.t., 10 min

CH3CN

83%

18F- amine(biomolecule)

SchmilSetal,ChemComm2011:47;11465.

MulY‐componentAssembly

O

N

NC

NH2

18F N

N

HN

18Fisoamyl alcohol170 oC, 15 min

Sc(OTf)3

Lietal,ChemSci2011:2;123

ElectrophilicFluorina'ons…

Electrophilic[18F]FluorinaYon

•  HighlyusefulbutapplicaYonsremainlimitedduetolowspecificacYvityof[18F]F2andany[18F]fluorinaYngagentderivedfrom[18F]F2– Bestachievedabout55GBq/micromole(Solin,1997)

Palladiumreagent:electrophilic[18F]fluorinaYonfrom[18F]fluorideion

LeeE….HookerJMandRilerTScience2011:334;639

NewConcepts

Carbon‐fluorinebond:isthatallthereis…

Sulfonyl[18F]fluoridesCHO

SO2Cl

CHO

SO218F

18FCs /Cs2CO3

H2O/tBuOH97%

R

SO218F

R = CHO, maleimido, O

Inksteretal,Chemistry2011:18;11079

Aluminum‐fluoridecomplexes

NN

N

OH

O

O

OHO

R

NN

N

O

O

O

O

O

R

Al OH

NN

N

O

O

O

OO

R

Al18F

18F-fluoride

McBrideetal,ARI2012:70;200(andothers)

Boron‐fluoridecomplexes

N N

Ar

BPh OH

+- N N

Ar

BPh

+-

18F

18F/KHF2

H2O/CH3OH

carrier added 25 mCi/micromole

Lietal,ChemComm2011:47;9324

Silicon‐fluoridecompounds

O

HSi 19F

O

HSi 18F

18F-/K-222

CH3CN,RT, 10 min

Schirmacheretal,BioconjugateChem2007:18;2085

Si19F NCS Si18F NCS

18F/K-222

DMSO, RT, 10 min95%

Schirmacher et al 2009

Silicon‐fluoride:HypoxiaImagingagents

NN Si

O2N

R1R1

OR2

NN Si

O2N

R1R1

OR2

18F-/K-222

CH3CN/HOAc

R1=Me,iPr,Ph,NaphtR2=Et,iPr

BOHNETAL,NUCLMEDBIOL2009:36;895

NewApplicaYons

Fluorine‐labeledsmallmolecules…isthatallthereare…

DiamondNanoparYcles:F‐18labeling

From:Rojasetal,ACSNano2011:7;5552‐5559.

“Thesecarbonnanocompositesarecommerciallyavailable,astheycanbeobtainedinlargequanYYesbyexplosivedetonaYon”

From:Guerreroetal,BioconjugateChem2012:23;399

GoldNanoparYcles

CellandLiposomeMembraneLabeling

•  Celllabeling:Maetal,NuclMedBiol2005:32;701‐705

•  Liposomelabeling:Urakamietal,ArYficialOrgans2009:33;164‐168

N

O

(C16H33)-OTf

+O

(C16H33)

18F

(C17H34)O

OOTs

(C17H34)O

O

18F

NewMethods

Reac'onvessels,loops,isthatallthereare…

Solid‐phasesupported[18F]FDGsynthesis

O

O

EOMO

OMe

Ph

SO

O(CH2)2O(CF2)2

O

NH

O

HO

OH

HO

HO

18F-/K-222

18F

CH3CN

BROWNETAL,ORGBIOMOLCHEM2009:7;564.

Solid‐phasesupported[18F]fluorinaYons

O

I

I

NH

HN O

O

NH

HN O

O

18F-/K-22218F

18F

S

O

O

O

NN

R

R

18F

-

+

CH3CN, 85 oC

18F-/K-222

CH3CN, 85 oC

[18F]CsF

120 oC, 30 min

23%RCY

+

+

Solid‐phasesupportedpepYdelabelingwithfluorine‐18

NH

O

O

HNpeptide

Lys NH2

PEPTIDE LysHN

R

O

O

OH

18F

O

OH18F

or

Solid‐phasesupportedfluoroDOPAsyn:electrophilicfluorinaYon

O Sn

OtBOC

OtBOC

NH

OO

OtBOC

OtBOC

NH

OO

18F-F2

18F

CFCl3, rt

HO

HO

NH2

O

OH

18F

H+ heat

Alilleofeverything…

N

NN

(X)S

O

O

O R N

NN

(X)S

O

O

O R

H3C

+

OTf-

N

NN

(X)S

O

O

O R

H3C

+

-18F

Cu(I)

click

MeOTf

18F-/H2O

t-amylalcohol

heatelute

CH3CN

18F R

DYChiandcoworkers,JLCR2011:54;S68

Microfluidics

•  “ConvenYonal”(Manyusers,commercial)– Smallvolumesofsolvents,smallamountsofprecursors

– Needs[18F]fluoridetrapping/concentraYonmethodssuchaselectrochemicalorresin

– Numerouscompoundsnowsynthesized•  MicrodropletgeneraYon(UCLA)– DMDG–digitalmicrofluidicdropletgeneraYon– EWOD–electrowetng‐on‐dielectric

Microfluidics

•  NotyetintroducinganynewchemicalreacYons,butenhancingyieldsofconvenYonalmethods

•  BUT–veryhardtodetermineformostpublicaYonstheAMOUNTSof[18F]fluorideionused,andtheAMOUNTSoffinalproductsisolated

SoWhat’sChanged?

•  DON’Tneedanhydrous[18F]fluorideion•  DON’TneedapolaraproYcsolvent•  DON’Tneedspecialglassware•  DON’TneedK+/Krypofix•  DON’TneedtobelimitedtoC‐Fbonds

WhereisFluorine‐18going….?

•  Numerousfluorine‐18labeledradiotracersinclinicaltrials,orrecentlyapprovedbyFDA:moreverylikelytobedeveloped

•  Chemistrygetngsimplerandmorereliable•  WillF‐18+PETbecometheworkhorseoffutureNuclearMedicineclinics?