Radiopharmaceutical chemistry with short -lived positron emitters...

•1

Radiopharmaceutical chemistry Radiopharmaceutical chemistry

with shortwith short--lived positron emitterslived positron emitters

carboncarbon--11 and fluorine11 and fluorine--1818

General Aspects of Positron Emission Tomography (PET)

Radiopharmaceutical Chemistry with 11C and 18F

�� General aspects for the design and synthesis of PET-radiotracers

�� 11C chemistry

- Radionuclide production, radiosynthesis, examples of 11C- radiotracers

�� 11F chemistry

- Radionuclide production, radiosynthesis (special focus on small secondary

labelling precursors), examples of 18F-radiotracers

OutlineOutline

•2

General aspects of

Positron Emission Tomography (PET)

OHO

HO OH

OH

18Fββββ++++

ββββ−−−− 180°

511 keV

511 keV

• Today approx. 350 PET centres with a cyclotron worldwide• approx. 150 in the U.S.A., approx. 25 in Germany• PET cameras 3-4 times more present than “full“ PET centres• approx. 85% [18F]FDG, [18F]F-Dopa, [15O]H2O, [13N]NH3

• Satellite concept with 18F-radiotracers possible (2 x t1/2 = 4 h)

Positron Emission Tomography (PET):

A Multidisciplinary Approach

•3

The first clinical PET imaging 1953

Brownell et al., Localization of brain tumors with positron emitters. Nucleonics 1953, 11:40-45.

DesignSynthesis (automation if possible)Quality control

Nuclear medicineDrug research

Radionuclideproduction

Radionuclide Half-life 11C 20.4 min13N 9.96 min15O 2.03 min18F 109.8 min64Cu 762 min68Ga 68.3 min76Br 966 min120I 88 min124I 4.15 d

TimeTime00 max. 3 max. 3 xx tt1/21/2

S

N

NH2

CN

11CH3

H3C

“Smart”radiotracers

•4

Isotopic labelling with 11C, 13N, 15O 18F: Substitute for H or OH

Short half-lifes enable

• Minimum radiation dose• Repeated studies in the same subject

Tracer kinetics principle

• No perturbation of biological processes• Estimation of absolute values of pysiological

parameters and fate of the labelled molecule�� Quantification (Bq/voxel)

Spacial resolution of human PET scanners

• At present: 100 mm3; Future: 10 mm3 ?

Spacial resolution of small animal PET scanners

• 10 mm3 commercially available

BUT: Expensive technique, “Running against time“

StructureStructure

PhysiologyPhysiology

MetabolismMetabolism

BiodistributionBiodistribution

MolecularMolecular

TargetsTargetsReceptorsReceptors, ,

EnzymesEnzymes etc.etc.

SensitivitySensitivity

&&

SpecificitySpecificity

XX--rayray –– CTCT

MRIMRI

UltraUltra--soundsoundSPECTSPECT

PETPET

PETPETSPECTSPECT

PETPET

MolecularMolecular ImagingImagingPET PET characteristicscharacteristics

11C 18F 123I Metal chelates (99mTc)

rvdW 1.7 Å 1,6 Å 2,1 Å

Identical -H -OH, CH3 unpredictableproperties -OH - Ph- physical- chemical- biological- pharmacological

SubstanceSubstance alterationalteration

BiocompatibilityBiocompatibility of of LabelledLabelled CompoundsCompounds

•5

General Aspects for the

Design and Synthesis of PET-Radiotracers

Design and Synthesis of Design and Synthesis of PETPET--RadiotracersRadiotracers: : ChoiceChoice of of radionuclideradionuclide

Suitable physical half-life; long enough for monitoring the physiological organ functions to be studied, but not too long to avoid long term radiation effects

The physical half-life of the radionuclide has to be adjusted to the biological equivalence

Fast physiological processes vs. Slower physiological processes

Protein synthesis

Receptor or enzyme binding

Blood flow

Oxygen extraction

15O (t1/2 = 2.03 min) 18F (t1/2 = 109.6 min)

•6

Design and Synthesis of Design and Synthesis of PETPET--RadiotracersRadiotracers: : LabellingLabelling positionposition

* = 11C

CO2H

NH2

HO

HO

**

CO2H

NH2

HO

HO

** NH2HO

HO

* aromatic amino acid-decarboxylase

11CO2

11CO2

BBB

X

* = 11C

No storage

in neurons

Trapping

in neurons

Design and Synthesis of Design and Synthesis of PETPET--RadiotracersRadiotracers: : Time Time aspectaspect

• Optimum between chemical yield and radioactive decay

• Rule of thumb: Production time less than three half lives

•7

Design and Synthesis of Design and Synthesis of PETPET--RadiotracersRadiotracers: : SpecificSpecific radioactivityradioactivity

Specific radioactivity = activity / amount of substance ( GBq/µmol )

18F : 19F 1 : 106

18F : 19F 1 : 100 ... 1000

Does the biosystem noticethe presence of the compound?

c.a.(carrier-added)

n.c.a.(no-carrier-added)

Yes!

No! radiotracer concept;

submicromolar amounts of substance

Design and Synthesis of Design and Synthesis of PETPET--RadiotracersRadiotracers: :

Synthesis Synthesis usingusing submicromolarsubmicromolar amountsamounts of of substancesubstance

Extraordinary stoichiometry between labelling precursor and

radioactive labelling reagent (up to 104 to 1)

�� pseudo-first order kinetics

Classical example:

�� N-, O- or S-heteroatom methylation reactions with [11C]methyl iodide

NH

O11CH 3Cl

ClOH O

NNH

OHCl

ClOH O

N

11CH 3I

Small amounts enable simple technical handling

�� Purification, miniaturization, automation

•8


UtilisationUtilisation of of kinetickinetic isotopeisotope effectseffects ((KIEsKIEs))

11C/12C, 11C/13C and 18F/19F KIEs negligible in PET studies

1H/2H KIE significantly larger (ranging 1-12)

�� In principle observable in PET studies: example 11C-deprenyl

CH 3

N

H311C

DD

CH 3

N

H311C

HH

MAO B

CH 3

N

H311C

+

N

N

NH

NH

O

O -

H3C

EnzS

[11C]MAO B

In vivo assessment of brain monoamineoxidase-B (MAO-B) activity by means of PET

More adequate representation of brain MAO-B distribution through reduction of 11C-deprenyl to MAO-B by using deuterium-substituted 11C-deprenyl


Automation and Automation and radiationradiation safetysafety

•9


PurificationPurification and and identificationidentification

• Purification by semi-preparative HPLC and/or solid phase extraction (SPE)

• Chromatographic methods (TLC, GC, HPLC) for analysis

• Identification:

- Radioactivity detection AND mass detection (e.g. UV) by co-elution of thesample with a characterised reference

- Assessment of labelling position by 13C-NMR spectroscopy

(Performance of a combined 11C/13C synthesis, record 13C-NMR after decay)

11C chemistry

•10

Outline

• Introduction Key references, Production of carbon-11, Advantages of carbon-11

• 11C-RadiochemistrySynthesis of important labelling precursors ([11C]MeI, [11C]CO, [11C]HCN)

• 11C-RadiochemistryHeteroatom methylation reactions with [11C]MeI and [11C]MeOTf11C-C bond formations with [11C]MeI, [11C]CO and [11C]HCN

• Summary and outlook

G. Antoni, T. Kihlberg, B. Langström. 11C: Labelling Chemistry and Labeled Compounds. In: A. Vertes, S. Nagy, Z. Klencsar (eds.) Handbook of Nuclear Chemistry, Volume 4, Radiochemistry and Radiopharmaceutical Chemistry in Life Science. 2003 Kluwer Academic Publishers, 119-165.

G. Antoni, T. Kihlberg, B. Langström. Aspects on the synthesis of 11C-Labelled Compounds. In: M. J. Welch, C. S. Redvanly (eds.) Handbook of radiopharmaceuticals. 2003 John Wiley & Sons, New York, 141-194.

G. Antoni, B. Langström. Progress in 11C Radiochemistry. In: P. E. Valk et al. (eds.) Positron Emission Tomography: Basic Science and Clinical Practice. 2003 Springer-Verlag London, 237-250.

Langström B, Kihlberg T, Bergstrom M, Antoni G, Bjorkman M, Forngren BH, Forngren T, Hartvig P, Markides K, Yngve U, Ogren M (1999) Compounds labelled with short-lived beta(+)-emitting

radionuclides and some applications in life sciences. The importance of time as a parameter. Acta. Chem. Scand. 53:651-669.

Elsinga PH (2002) Radiopharmaceutical chemistry for positron emission tomography. Methods.

27:208-127.

Fowler JS, Wolf AP (1997) Working against time: Rapid radiotracer synthesis and imaging the human brain. Acc. Chem. Res. 30:181-188.

Key references

•11

RadionuclideRadionuclide productionproduction 1111CC

14N(p,αααα)11CEnergy range : 13 �� 3 MeVTarget yield: 3820 MBq/µAh

11B(p,n)11CEnergy range: 10 �� 0 MeV

Target yield: 3400 MBq/µAh(highly enriched target material necessary)

10B(d,n)11CEnergy range : 10 �� 0 MeVTarget yield: 2480 MBq/µAh(highly enriched target material necessary)

Half-life: 20.4 min

ββββ+ (99.8), EC (0.2)

Eββββ+ + + + = 0.96 MeV

Theoretical specific radioactivity: 3.4 x 105 GBq/µmol

Practical specific radioactivity: 50-5000 GBq/µmol

14N(p,αααα)11CN2/O2 11CO2

N2/H2

14N(p,αααα)11C11CH4

Th

ick

targ

et

yie

ld(M

Bq

/µA

h

Hot atom chemistry!!!

11C: Radionuclide production

•12

11C 18F 123I Metal chelates (99mTc)

rvdW 1.7 Å 1,6 Å 2,1 Å

-H -OH, CH3 unpredictable-OH - Ph

Substance alteration

Why 11C: Biocompatibility of Labelled Compounds

Identical properties

- physical- chemical- biological- pharmacological

• 1934: First production of 11C and study of physical propertiesCrane et al., Phys. Rev. 1934, 45, 497.

• 1939: First biological applicationInvestigation of photosynthesis in plants using 11CO2

Ruben et al., J. Am. Chem. Soc. 1939, 61, 661.

• 1945: First experiments on humansFixation of 11CO by red blood cellsTobias et al., Am. J. Physiol. 1945, 145, 253.

Carbon-11 in life sciences

11C: t1/2 = 20.4 min, ββββ+(99.8), Eββββ+ = 960 keV

•13

11C-Radiochemistry: Important labelling precursors

11CH411CHCl3

11CH2N211CCl4 11COCl2

11CNBr

11CH3OH11CH3Li

R11CH3CuLi 11CH3NO2

Ph3P11CH2

Ph3As11CH2

R11COCl R11COPdL2 R11COR

11CH3I11CO2

H11CN

11CO

1. “Wet“ chemistry route 2. Gas phase reaction

• 11CO2 is transferred into a LiAlH4-solution• Evaporation of the solvent (THF, Et2O)• Addition of HI (57%)• Destillation of [11C]MeI through NaOH and P2O5

• Alternative: Conversion of [11C]MeOH into [11C]MeI bymeans of PPh3

.I2 or P2I4

�� Specific radioactivity usually lowercompared with gas phase reaction

11CO2

LiAlH4 HI11CH3OH 11CH3I

• Conversion of 11CO2 into 11CH4 on Ni-catalyst• 11CH4 is converted into [11C]MeI in a quartz tube

(partly filled with I2, radical reaction) employinga closed loop process

11CO2

H2 I211CH411CH3I

Ni, 400°C 720°C

11C-Radiochemistry: 11C-labelling precursor [11C]MeI

�� Specific radioactivity usually higher

compared with “wet“ chemistry route

•14

11C-Radiochemistry: 11C-labelling precursor [11C]MeI

Ni catalyst

Poropak

Iodine

11CH3I

11CH3Li

11CH3OTf

n-BuLi

AgOTf11

CH3NO2

AgNO2

N

Sn

H311

C

PPh311

CH3

+I

-

AsPh311

CH2

PPh3/AsPh3

n-BuLi

S CuLi

CN

Li11

CH3(2-Th)Cu(LiCN)

NSn

Cln-BuLi

Electrophiles

Nucleophiles

11C: Labelling precursors derived from [11C]MeI

•15

11C-Radiochemistry: 11C-labelling precursor [11C]CO

• [11C]CO is a versatile 11C-labelling precursor

• Syntheses of radiotracers at high specific radioactivity possible

• Automation possible

• Problem: Poor solubility of CO in organic solvents

�� Microautoklave or High Pressure Reactor or use of BH3 . THF

11CO BH3.11CO

carbonylative couplings

BH3.THF

11C-Radiochemistry: 11C-labelling precursor [11C]CO

Furnace

Carbonylative couplings

Reactor

11C-labelled

carbonyl compounds

11CO2

11CO

Zn

400°C

11CO

Mo

850°C

•16

11C-Radiochemistry: 11C-labelling precursor [11C]HCN

14N(p,αααα)11C

N2/O2

11CO2

N2/H2

14N(p,αααα)11C11CH4

Ni/H2, 400°C35-40 ml/min

H11CN

Pt, 1000°CNH3, 2ml/min

Pyridiniumtribromide,

Sb

11CNBr

Ph-O11

CN

R-NH11

CN

S11

CN-

R-NH2

Na2S

Ph-OH

Cyanations

11C-labelled

nitriles

11C-Radiochemistry: General types of reactions

1.) Heteroatom methylation reactions with [11C]MeI and

related alkylating reagents (e.g. [11C]MeOTf)

2.) Ring-closure reactions to form ring-11C-labelled aromatic

compounds and aromatic heterocycles

3.) 11C-C bond forming reactions with [11C]MeI, [11C]CO and

[11C]HCN

4.) Enzyme-catalysed reactions

•17

N-, O- und S-methylation reactions

11C-Radiochemistry: 11C-methylation reactions

GH11

CH3X

R

R = alkyl, arylGH = OH, SH, NH2, NHR, NR2 CO2H, CONH2, CONHR

polar solvent base

X = I, OTf

GR 11

CH3

Extraordinary stoichiometic relationship between the desmethyl

precursor and [11C]methyl iodide or [11C]methyl triflate (factor 104 to 1)

Pseudo-first order kinetics

• Very rapid consumption of the radioactive labelling

reagent �� short reaction times of 1-10 min

• No problems with polyalkylation

AgOTf11CH3I

11CH3OTf200°C


Rxn-conditions [11C]Methyltriflate [11C]Methyliodide

Temperature (°C) 20 – 60 80 -120

Time (min) 1 2 - 10

Amount of precursor (mg) < 1 1 - 10

•18

1. 11C-methylation reactions in solution- Desmethyl precursor (0.5 mg to 5 mg) dissolved in an

appropriate polar solvent (DMSO, DMF, acetone etc.) in the

presence of a base (e.g. NaOH, TBAOH)

- Transfer of [11C]MeI or [11C]MeOTf into the precursor solution

- Heating for 1-10 min, subjection on HPLC

2. 11C-methylation reactions on solid support- Fixation of desmethyl precursor onto a solid support (HPLC-

loop, SPE-cartridge)

- Transfer of [11C]MeI or [11C]MeOTf and elution of the product

with appropriate solvent (e.g. EtOH) or subjection onto HPLC

3. 11C-methylation reactions using micro-reactors- Radiolabelling with microfluidic technology (hydrodynamically-

driven micro-reactor)

11C-methylation reactions: Technical aspects

[11C]MeI

N

N

N

O

F

O

O

11CH3

NS11CH3

H

[11C]McN-5652

NH

O11CH3Cl

ClOH O

N

[O-methyl-11C]raclopride [N-methyl-11C]flumazenil [11C]WAY 100635

L-[S-methyl-11C]methionine

O

NN

N

N

O

11CH3

[N-methyl-11C]choline

H311C N

CH3

CH3

OH H311C

S CO2H

NH2

+

[11C]SCH23390

N

HO

Cl11CH3

NN

O OO

11CH3

[11C]carfentanil

SNH2

CNHN

11CH3

[11C]DASB


•19

• Carbonation of organometallic compounds with [11C]CO2

• 11C-Alkylation of stabilised carbanions (e.g. malonic esters)

• Reaction of 11C nucleophiles (e.g. [11C]CN-, [11C]MeLi) at electrophilic C-atoms

• 11C-C bond forming reactions

Cu-mediated reactions with [11C]CH3I and other 11C-alkyl halides

Pd-mediated 11C-C bond forming reactions with [11C]CH3I

Pd-mediated 11C-C bond formations with [11C]HCN (cyanations)

Pd- and Se-mediated and photoinitiated 11C-C bond formations with [11C]CO (carbonylations)

Important synthetic method to expand the arsenal of 11C-labelled compounds

Position-specific 11C labelling

11C-Radiochemistry: 11C-C bond forming reactions

R-Pd(II)-X

R-Pd(II)-R´

R-Pd(II)

R´

R-XPd(0)

Oxidative addition

Transmetalation

Reduktive elimination

R-R´

Isomerisation

R´-G

G-X

11CO

11CH3I

11CN-

CHALLENGE: Rapid and selective reactions under mild conditions

CATALYSTS

Transition metal complexes

11C-Radiochemistry: 11C-C bond forming reactions

•20

R3-Pd(II)Ln-R1

R3-Pd(II)Ln-X

R3-X

Oxidative addition

Transmetalation

Reductive elimination R1Sn(R2)3

R1-R3

XSn(R2)3

Pd(0)Ln

11C-Radiochemistry: Stille reaction with [11C]MeI

Advantages: �� mild method

�� broad tolerance towards functional groups

�� reagents are not sensitive towards moisture or oxygen

�� easy access to stannanes

NH

O

ON

OHO

OH

Me3Sn

Pd2(dba)3/P(o-tolyl)3

F

NH

O

ON

OHO

OH

H311C

F[11C]MeI

DMF, 130 °C, 5 minAs = 0.7 GBq/µmol


Sn

CH3

CH3

H3C

Sn1.3 1.0

10.0

1.0

Selectivity problems during the transfer of a 11CH3-group

1.3 Times faster transfer of a Ph-group in Ph-SnMe3 compared to Ph-SnBu3

BUT: a methyl group is transferred 10 times faster than a butyl group

�� Better selectivity with SnBu3 groups

•21

Sn

N

11CH3

N

SnCl

11CH3Sn

(TMS)2N

(TMS)2N F

F

11CH3Li

11CH3

SnI

(TMS)2N

(TMS)2N

Sn[N(TMS)2]2

11CH3I

TBAF

R-XR-

11CH3

5-[11C]methyl-1-aza-5-stanna-bicyclo[3.3.3]undecane

mono-[11C]methylstannate

Pd-complex

R-SnR'3

11CH3-IPd-complex


Two complementary synthesis routes

Typical reaction conditions

Pd-complex: Pd2(dba)3, Pd(PPh3)4

Co-ligand: P(o-tolyl)3, P(2-furyl)3, AsPh3

Additive: Cu(I)-saltsSolvent: DMF, NMP, DMSOTemperature: 90-130 °C

ONH

11CH3

N

N NCF3

H311

C

SH2N

O

O

SNH2

NMe2

HO

HO

HO

OCH(CH3)2

O

ON

F

H311C

S

NCN

11CH3

11CH3

H311C


•22

11C-Radiochemistry: Suzuki reaction with [11C]MeI

R

B(OH)2

R

B O

O

R

11CH3

11CH3I, Pd(dppf)Cl2, K3PO4,

DMF, 60-120 °C, MW (50 W),

49-92 % (d.c.)

R = m-CHO, o-Br, o-NO2o-NO2, p-CO2H, p-OH, p-CO2Me, p-NH-COCH3

or

S

N

CN

(HO)2B

S

N

CN

H311C

11CH3I, Pd(dppf)Cl2, K3PO4,

DMF, MW, 28.5±2 % (n.d.c.)

t-BuO

OB

12HO

O11

CH3

1) 11CH3I, Pd(PPh3)4,

NaOH, 90 °C, 4 min

2) TFA, 70 °C, 1 min

1275 % (d.c.)

R1-Pd(II)Ln-OR2

R1-Pd(II)Ln-X

R1-XR1-R3Pd(0)Ln

NaOR2

NaIR3-BY2

R2O-BY2

R1-Pd(II)Ln-R3

Advantages:�� Reactions proceed under mild conditions

� Broad tolerance towards fuctional

groups

� Reproducible yields

� Cross-coupling of highly functionalised

compounds possible

� No toxic by-products

LnPd(II)

R-XLnPd(0)

RĆ

X

R

LnPd(II)

C

R

CR`

CH

base, CuI

RĆ CCuCuX

RĆ CR

11C-Radiochemistry: Sonogashira reaction with [11C]MeI

Classical Sonogashira conditions do not workwith [11C]MeI due to rapid quarternisation of the amine base (e.g. NEt3)

Modified procedure for the palladium-catalysed cross-coupling of terminal alkynes with [11C]MeI in the presence of TBAF as activator

HR 11CH3R

[11C]MeI, Pd(0),

AsPh3, TBAF

•23

OH

HO

11CH3

OH

O

11CH3HO

NN

F

OH 11CH3

OH

MeO

11CH3

11C-Radiochemistry: Sonogashira reaction with [11C]MeI

Radiochemical yields (based upon [11C]MeI): 49-69%

Important Note

Destilling [11C]methyl iodide directly into a solution containing the Pd complexand all other components for the cross-coupling reaction may give erratic yields, usually low, and sometimes zero.

• Oxidative addition of [11C]methyl iodide to the Pd complex must occur firstwhen reacting tracer levels

• Oxidative addition of [11C]methyl iodide to the Pd complex is adequately facile

First addition [11C]methyl iodide into the solution containing the Pd-complex, then transfer to the reaction mixture containing all othercomponents

11C-Radiochemistry: 11C-C bond formations with [11C]MeI

•24

X

R

11CN

R

X = Br, I, OTfR = Br, CH3, H, NH2, NO2, OMe, OH

K222/K+, Pd0, 11CN-

THF, 90 °C, 5 min

RCY: 50-95 %

11CONH2

R

Pd0, 11CN-, KOH

THF, 90°C

4 minH3C

HN

I H3C

HN

11CN

[11C]cyano-MK-801

40 %

11C-Radiochemistry: Cyanation reactions with [11C]HCN

11C-Radiochemistry: Carbonylation reactions with [11C]CO

Benefits

• Easy access to [11C]CO • Usually one step radiosynthesis• Great tolerance towards most functional groups• Radiotracers are obtained at high specific radioactivity• Large number of compounds containing a carbonyl group

Challenges

• Poor solubility of CO in organic solvents• Usually drastic reactions conditions (high pressure) required

•25

11CO

R-C-OHO

Carboxylic acids

R-C-ORÒ

Esters

R-C-RÒ

KetonesR-C-HO

Aldehydes

RR`N-C-NR``R```

O

Ureas

R-C-NR`R``

O

Amides

RR`N-C-OR``

O

Carbamates

RO-C-OR`

O

Carbonates

RR`N-C-SR``

O

Thiocarbamates

R-C-SRÒ

Thioesters

Pd-mediated 11C-C

bond formations

with [11C]CO

Se-mediated 11C-C

bond formations

with [11C]CO

Photoinitiated radical

carbonylations with

[11C]CO



Pd(0)

R-Pd(II)-X

R-11C-Pd(II)-X

R-C-Pd(II)Nu

Oxidative addition

R-X

11CO insertion

Reductive elimination

Nucleophilic attack

11COO

Nu-

X-

O

R-C-NuO

NH

N

I

O

*

N

O

*

NH

OO

N*

S

O

*

OH

O

*R

Amides Esters

Thioesters KetonesCarboxylic acids

Pd-mediated 11C-C bond formations with [11C]CO

Nucleophiles: • amins (reactivity important!)• alcohols (usually low yields)• thiols• hydroxide• stannanes

* = 11C

•26

Selenium-mediated synthesis of 11C-labelled carbamoyl compounds

Cl NH

OONH

HN O

* *

O

OO*

Ureas

Carbonates

Carbamates


RXHBu4NF . Se

R11COYR' (XY = R"N, NH, O)

R'YH11CO

+

Alternative to phosgen (COCl2 ) chemistry

Se11CO

Se11COR-XH

SeO

O

*R

-

XR`O

O

*R

R`-XH

X = O

R-NCO

*

NHR`NHR

O

*

X = O, NH, NR`

X = NH X = NR`

Se`RRN

O

*

2

XR```RRN

O

*

R``-XH

SeX

O

*R

R`-NH

-

* = 11C

* = 11C


Photoinitiated radical carbonylations with [11C]CO

R-I11COh . ν

.R R O.

R-I R O

I

Nu-R O

Nu

*

* *

1 2

3 4

NH

O

*

OO

*

OH

O

*

Amides

Esters

Carboxylic acids

1. Generation of alkyl radical via homolysisof an alkyl iodide

2. Carbonylation with [11C]CO (acyl radicalformation)

3. Formation of acyl iodide4. Trapping of acyl iodide by a nucleophile

* = 11C

Overcome the limitation of

ββββ-hydride elimination

�� Use of alkyl halides possible

•27

Summary and outlook

• Radiochemistry with the short-lived positron emitter 11C (t1/2 = 20.38 min) represents special challenges in terms of synthesis time and labelling techniques.

• Radiochemistry is mainly based on the readily labelling precursors [11C]MeI and [11C]CO

• Developments in 11C radiochemistry have steadily expanded the number of 11C-labelled compounds

• Recent developments in 11C radiochemistry are an important prerequisite to further stimulate the progress of positron emission tomography (PET) as powerful imaging technique in clinical routine and research, and drug research and development.

Selected 11C-Radiopharmaceuticals: [1-11C]acetate

14N(p,αααα)11CN2/O2 11CO2

1. MeMgCl

2. Hydrolysis[1-11C]acetate

Radiochemistry: - Use of Grignard-solution (0.2 – 0.4 M in THF)- Hydrolysis (water or phosphorous acid)- Purification via Ag2O-cartritdge ans cation exchange cartridge- Sterile filtration (0.22 µm sterile filter)

Pharmaceuticalquality: - pH = 7.0 ± 1.0

- sterile and pyrogen-free

•28

Selected 11C-Radiopharmaceuticals: [1-11C]acetate

Rezidiv

Lymph nodemetastases

ONa

O

*

Exact accumulation mechanism still uncertain

Radiochemistry: L-[1-11C]methionine

S11CO 2H

NH 2

S NC

1. BuLi

2. 11CO2

3. Separation of enantiomers

S O S11CO 2H

NH 2

1. Strecker synthesis with11CN -

2. Seperation of enantiomers

Selected 11C-Radiopharmaceuticals: [11C]methionine

L-[S-Methyl-11C]methionine vs.L-[1-11C]methionine

•29

Radiochemistry: L-[S-methyl-11C]methionine

S CO 2H

NH 2

1. Na/NH3

2. 11CH3I

S

H311C

S CO 2H

NH 2

1. NaOH/Aceton

2. 11CH3I

H311C

S CO 2H

NH 2O

NH 2


FDG [11C]methionine


•30

11CH3I

N

N

N

O

F

O

O

11CH 3

NH

N

N

O

F

O

O

Selected 11C-Radiopharmaceuticals: [N-methyl-11C]flumazenil

Benzodiazepine receptor antagonist Clinical relevance: Epilepsy

Selected 11C-Radiopharmaceuticals: [O-methyl-11C]raclopride

NH

O11CH 3Cl

ClOH O

NNH

OHCl

ClOH O

N

11CH 3I

Selective D2-receptor antagonist

•31

Selected 11C-Radiopharmaceuticals: [O-Methyl-11C]raclopride

Clinical relevance: Parkinson disease

18F chemistry

•32

RadionuclideRadionuclide productionproduction 1818FF

2020Ne(d,Ne(d,αααααααα))1818FF

EnergyEnergy rangerange: 14 : 14 �� 0 MeV0 MeV

TargetTarget yieldyield: 1110 MBq/: 1110 MBq/µµAhAh

1818O(p,n) O(p,n) 1818FF


TargetTarget yieldyield: 2960 MBq/: 2960 MBq/µµAhAhEnrichedEnriched targettarget material material necessarynecessary

1 g (1 g (1818O)HO)H22O ca. 150O ca. 150€€

1616O(O(33He,p)He,p)1818FF


TargetTarget yieldyield: 480 MBq/: 480 MBq/µµAhAh

Gas target

Gas target (Ni):

Ne (25 bar) containing 0.1 to 0.2% F2

Water target: [[1818O]HO]H22O, O, enrichmentenrichment: 98% [: 98% [1818O]O]

Material Material targettarget chamberchamber: : silversilver, , titaniumtitanium, , niobiumniobium

Up to 150 GBq (3.8 Ci) [18F]fluoride

Energy density 500 W/cm3, 30 bar, T ≈≈≈≈ 250°C - Hydrothermale conditions

- Consumption, radionuclide impurities

Pressure

sensor

Target

water

20Ne(d,αααα)18F 18O(p,n)18F


•33

18O(p,n)18FH2

18O [18F]F-

Ne/F2

20Ne(d,αααα)18F[18F]F2

Theoretical specific activity: 6.3 x 104 GBq/µmol(Carrier-free 18F)

Practical specific activity(No-carrier-added 18F)

50 - 400 GBq/µmol

Half-life: 109.8 min.

Practical specific activity(Carrier-added 18F)

0.4 GBq/µmol

[18F]F2[18F]Fluoride

18F : 19F 1 : 100 ... 1000 18F : 19F 1 : 106


1818FF--Radiochemistry: Radiochemistry: Advantages of Advantages of 1818FF

Radionuclide Max. ββββ+ energy (MeV) Max. range in water (mm)

• Half-life = 109.8 min. (Synthesis, shipping)

• Radiotracers at high specific radioactivity

• Low ββββ+ energy � good spacial resolution

11C 0.96 4.1213N 1.19 5.3915O 1.72 8.2018F 0.64 2.39

•34

18F-

18F-F

18F-(CH2 )n-X Br-18F

18F-Xe-FO

18F

O

G

18F

1818FF--Radiochemistry: Radiochemistry: ImportantImportant 1818F F labellinglabelling precursorsprecursors

Electrophilic vs. nucleophilic radiofluorinations with 18F

1818FF--Radiochemistry: Radiochemistry: ElectrophilicElectrophilic radiofluorinationsradiofluorinations withwith 1818FF

[18F]F2 [18F]AcOF + [18F]HF AcOH/AcOK

Triacetylglucal

OHO

HO18F

OH

OH

O

OAc

AcO

AcO

OHO

HO

18F

OH

OH

A: 1. [18F]F2; 2. HCl

B : 1. [18F]AcOF; 2. HCl

[18F]FDG [18F]FDM

A 3 (RCY: 10 %) 1

B 7 (RCY: 20 %) 1

Electrophilic radiofluorinations: RCY max. 50 % and low specific radioactivity

•35


[2-18F]FDOPA

NH 2

CO 2H

OHOH

NH 2

CO 2H

OHOH

NH 2

CO 2H

OHOH

NH 2

CO 2H

OHOH

18F

18F

18F

[5-18F]FDOPA [6-18F]FDOPA

[18F]F 2

solvent

Hydrogen substitution: e.g. 6-18F-Dopa synthesis

Solvent RCY % 2-18F-Dopa 5-18F-Dopa 6-18F-Dopa

HF/BF3 40 35 5 60

HF 30 35 5 60

TFA 9 90 10 050% TFA in HOAc 5.3 56 44 0

10% TFA, 2% Ac2O in HOAc 7.6 57 43 0

HOAc 0 0 0 0


Fluorodemetallations

NHBoc

CO 2Me

OBocOBoc

NH 2

CO 2H

OHOH

18F

[6-18F]FDOPA

[18F]F 2Me 3Sn

NHAc

CO 2Me

OMeOMe

F3COCOHg

HBr

NH 2

CO 2H

OHOH

18F

[6-18F]FDOPA

[18F]AcOF

HI

26-33% RCY45-50 min.

12% RCY50 min.

•36

• N-18F compounds

• [18F]XeF2

• [18F]fluorine gas from [18F]fluoride

CH 3I[18F]fluoride

[18F]CH 3FF2/Ne 150 nmol-1.5 µmol

Electrical discharge[18F]F 2

10 - 20 GBq/µmol

1818FF--Radiochemistry: Radiochemistry: Other eOther electrophiliclectrophilic radiofluorinationradiofluorination reagentsreagents

Radiofluorination reactions at high specific radioactivity

Soluble in organic solvents

“naked“, reactive nucleophilic fluoride

Highly hydrated fluoride

Little reaktive

HO

H

HO

H

H

OH

HO

H

HOH

H

OH

N

O

O

N

O

O

O

OK+

F-K2CO 3,K222

F -

Alternative reagents for [18F]fluoride activation

Cs2CO3 � [18F]CsFRb2CO3 � [18F]RbFTBAOH � [18F]TBAF

1818FF--Radiochemistry: Radiochemistry: NucleophilicNucleophilic radiofluorinationsradiofluorinations withwith 1818FF

•37

• Nucleophilic aromatic substitution reactions (incl. heteroaromats)

• Nucleophilic aliphatic substitution reactions

• Nucleophilic ring-opening reactions

• Reactions with [18F]BrF

• Pd-mediated cross-coupling reactions with [18F]fluoroaryl halides


18F-radiochemistry at high specific radioactivity:

Classification of general types of reactions


Nucleophilic aliphatic and aromatic substitutions with 18F

Alkylfluorides

Arylfluorides

Fluoroalkyl-amides

Fluoroalkyl-amines

Fluoroalkyl-ethers

R 18F

X18

F

(CH2)nO18

F

18F

-

18F

-

18F

-

18F -(CH2)n-X

18F

NNHN

S

O

O

CO 2H

NH 2O18

F

HO

O

OH

18F

OF

CR

O

N(CH2)nN 18F (CH2)n

18F

18F-

18F- (CH2)n -X

•38

1818FF--Radiochemistry: Radiochemistry: NucleophilicNucleophilic aromaticaromatic radiofluorinationsradiofluorinations withwith 1818FF

CorrelationCorrelation

RCY vs. RCY vs. δδδδδδδδ((1313CC--NMR)NMR)

1818FF--Radiochemistry: Radiochemistry: NucleophilicNucleophilic aromaticaromatic radiofluorinationsradiofluorinations withwith 1818FF

•39

1818FF--Radiochemistry: Radiochemistry: ReactionsReactions withwith [[1818F]BrFF]BrF

S NN

N18

F

N

18F

HO

OH18

F

OOX

I

X

+

BrCHO

O2N

X

18F

X = Br, I

Stillereaction

Buchwald N -arylation

Sonogashira reaction

18F-Radiochemistry: Pd-mediated cross-coupling reactions with [18F]fluoroaryl halides

•40

Fluorine-18 Labelling of Small Molecules

• Introduction to 18F-labelling of small monomeric compounds

� Importance of small monomeric compounds as PET radiotracers

� Direct vs. indirect labelling procedures with 18F

• Secondary labelling precursors derived from n.c.a [18F]fluoride

� 18F-labelled aryl fluorides (aldehydes, aryl halides, benzyl halides etc.)

- Reductive amination reactions

- Carbonyl-olefination reactions (Wittig reaction, Knoevenagel reaction etc.)

- Alkylation reactions

- Pd-mediated C-C and C-N bond formation processes

- Miscellaneous ([18F]benzylamides, [18F]anilines, [18F]phenol)

� 18F-labelled alkyl halides and sulfonates- Alkylation reactions

• Summary and conclusion

•41

• Most of the known several hundred 18F-labelled PET tracers aresmall monomeric compounds

OHOHO OH

OH

18F HO

HO

18FO

18F

HO N

NH

O

O

H3C

CO2H

NH2

NN

NO2

18FOH

• Increasing number of small monomeric fluorine-containing drugs

OHN

F3CN

N

MeO

HN

F

ClN

ONH

O

Cl O

F

CH3

Why 18F labelling of small monomeric compounds?

Primary

labelling

precursors

18O(p,n)18F

20Ne(d,αααα)18F

[18F]fluoride

(n.c.a., SA ↑)

[18F]F2

(c.a., SA ↓)

Secondary labelling

precursors

SN2 or

SNAr

SEAr

Direct labelling

Indirect

labelling

PET

radiotracer

Direct labelling

Indirect

labelling

X

18F

18F(CH2)n X

X = CHO, COR, Hal, CH2Hal, CH2NH2 NH2, OH

X = Hal, NH2 OTs, OMs, OTf

[18F]AcOF

[18F]XeF2

PET

radiotracer

General aspects of 18F radiochemistry

•42

18F-labelled aryl fluorides

CHO18F X

18FX = I, Br

18FX = I, Br, NH2

X

18F

R

O

R = CH3, phenylX

18FX = OH, NH2

Secondary labelling precursors derived from n.c.a. [18F]fluoride

18F-labelled fluoroalkyl halides and fluoroalkyl sulfonates

18F

n = 0,1X = I, Br

Br 18F

X XX = H, D

18F

n = 0,1R = CH3, Tolyl, F3C

X

RO2SO

n

n

18F-labelled aryl fluorides: Benzaldehydes

18F-labelled benzaldehydes: Reductive amination reactions

Two-steps/one-pot reaction

HN

18F

18F

NaBH3CN, AcOH, solvent

R NH2

R1 NH

R2

CHO

R

N

18F

R2R1

primary amines

secondary amines solvent: DMSO, DMF, MeOH

secondary amines

tertiary amines

•43

N

OO

Cl NH

O NH2

N

18F

N

OO

Cl NH

O NH2

NH

CHO

18F

NaBH3CN, AcOH, DMF 120°C, 10 min.

18F-labelled benzaldehydes: Reductive amination reactions

Results:Radiochemical yield 5 - 13 % (not decay-corrected)Total synthesis time 90 - 95 minRadiochemical purity > 95 %Specific radioactivity 59 - 184 GBq/µmol

P. Mäding et al. J. Label. Compds. Radiopharm. 2004, 47, 1053.

Two-steps/one-pot procedure �� DMF as the solvent is necessary

18F-labelled aryl fluorides: Benzaldehydes

18F-labelled benzaldehydes: Carbonyl-olefination reactions

18FCHO

C-H acidic

compounds

R1, R

2 = EWG

organo-phosphorus compounds

R1 CH2

R2 R1 C

R2

18F

PPh3

+

R P(OEt)2R

O 18F

R

Knoevenagel reaction

Wittig reactionHorner-Wadsworth-Emmons (HWE) reaction

•44

PPh3

propylene oxide,o-dichlorobenzene, 160°C, 10 min.

CHO

18F

18F

+R

R

18FR +

NN O Ph

Ph

R RCY (%) Z/E

H 90 -

Et 40 37/63

(CH3)2CH 41 40/60

CO2CH3 85 2/98 25 40/60

A. Piarraud et al. J. Label. Compds. Radiopharm. 1993, 32, 253.

Z isomer E isomer

Carbonyl-olefination reactions: Wittig reaction

Two-steps/two-pots procedure

�� Drawback: E and Z isomer formation

S. Gester et al. Amino acids. In press

MOMO

OMOM

OMOM

MOMO

18F

DMF, KOtBu

15 min, 60°C

CHO

18F

OH

HO

18F

3N HCl

15 min, 60°C

P(OEt)2

O

� Synthesis time: 120 - 130 min� Radiochemical yield: 8-13 %

(based upon [18F]fluoride)

Two-steps/one-pot procedure

�� DMF as the solvent required

Exclusive formation of E isomer

Carbonyl-olefination reactions: HWE reaction

18F

HO18F

H2N

18F

Me2N

•45

DABCO, EtOH140°C, 10 min.

O

N

O

O

N

O

18F18F

CHO

AcOH, HI, P(red) 220°C, 10 min

CO2H

18FNH2

CO2H

18FNH2

+

L-[4-18F]fluorophenylalanineC. Lemaire et al. Appl. Radiat. Isot., 1987, 38, 1033.

• Hydrolysis �� racemate

• Chiral HPLC �� 5 % RCY

(L-amino acid)

Carbonyl-olefination reactions: Knoevenagel reaction

18F-labelled aryl fluorides: Benzyl halides

18F-labelled benzyl halides: Alkylation reactions

ClNH

MeHN OMe

NH

CH3

BrCl

NH

MeHNOMe

N

CH3

ortho: 36%para: 88%

18F

18F

K. Hatano et al. J. Label. Compds. Radiopharm. 1991, 29, 373.

CHO

18F 18F

X

X = Br, I

First heteroatom benzylation reaction in 18F chemistry

• Convenient access to [18F]fluorobenzyl halides as useful alkylating agents

• Most prominent: [18F]fluorobenzyl iodide and [18F]fluorobenzyl bromide.

•46


RX

N

18FX = CH, N

S18F

R

HN18F

R

NH

R

18F

O

Secondary amines (piperidines, piperazines)Rapid reactions at ambient temperature without auxiliary base Solvents: DMF, DMSO, CH3CN

ThiolsRapid reactions at ambient temperatureAuxiliary base: TEA; Solvents: DMF, DMSO

AnilinesVigorous reaction conditions required (100°C) without auxiliary baseSolvents: DMF:CH3CN

AmidesAmbient temperature and TEOH as auxiliary baseSolvents: CH3CN

R. H. Mach et al. Nucl. Med. Biol. 1993, 20, 777.

Cl

HONMe

S18F

NO N

NO

F

18F

R. H. Mach et al. Nucl. Med. Biol. 1993, 20, 777.

R. Iwata et al. J. Label. Compds. Radiopharm. 2000, 43, 873.

HN N

O

18F

NH

N

18FOMe

OMe

O

R. H. Mach et al. J. Med. Chem. 1993, 36, 3707.


☺ Applicable for O-, S-, and N-alkylation reactions with 4-[18F]fluorobenzyl halides� Multi-pot & multi-step reaction sequence

•47

Enantioselective synthesis of 6-[18F]fluoro-L-dopa via asymmetric phase-transfer-catalysis (PTC)

18F

OMeMeO

Br

NO

N

+

N CO2tBu

18F

OMeMeO

N CO2tBu

CO2H

NH2

HO

HO 18F

CsOH, PTC 4, 0°C

HI, 200°C

6-[18F]fluoro-L-dopa

5

4� Total synthesis time: 100 min. (incl. HPLC)

� Radiochemical yield: 25-30 % (decay-corrected, based upon [18F]fluoride)

� Enatiomeric purity: >95 % C. Lemaire et al. Eur. J. Org. Chem. 2004, 2899.

[18F]benzyl halides: Asymmetric [18F]-dopa syntheses

18F-labelled aryl fluorides: Miscellaneous

18F-labelled benzylamineAmidation reactions

NH2

18F

CH3CN, r.t.,

O NO O

O

O

NH

O O

18F

15 min

T.Haradahira et al.

Appl. Radiat. Isot., 1998, 49, 1551.

2-propanol120°C, 15 min

N

N

ClR1O

R2O

N

NRO

RO

NH2

HN

18F

Cl

18F

Cl

OH

18F

RN

Br O

BH3 . THF

RN

O

18F

R = H, CH3

[Cu(CN)4]PF6,Cs2CO3, toluene, 110°C

18F-labelled anilinesAlkylation reactions

18F-labelled phenolsArylether syntheses

Y. Seimbille et al.

J. Label. Compds. Radiopharm. 2005, 48, 829.T. Stoll et al.

J. Label. Compds. Radiopharm. 2004, 47, 443.

•48

R-Pd(II)-X

R-Pd(II)-R´

R-Pd(II)

R´

R-XPd(0)

Oxidative addition

Transmetalation

Reductive elimination

R-R´

Isomerisation

R´-G

G-X

X

18FX = Br, I

18F-labelled aryl fluorides:Pd-mediated C-C and C-N bond forming reactions

18F-labelled aryl fluorides: Aryl halides

Stillereaction

Sonogashirareaction

Buchwald reaction

R3-Pd(II)Ln-R1

R3-Pd(II)Ln-X

R3-X

Oxidative addition

Transmetalation

Reductive eliminationR1Sn(R2)3

R1-R3

XSn(R2)3

Pd(0)Ln

18F-labelled aryl halides: Stille reaction

J. K. Stille: (1985)Very versatile and effective palladium-mediated C-C bond forming method between organic halides or triflates with organostannanes

- Stille reaction proceeds in high yields under mild reaction conditions while tolerating a broad variety of functional groups (e.g. CO2R, CN, OH) on either coupling partner

- Organostannanes can easily be synthesised and isolated (they are typically air- and moisture-stable compounds allowing trouble-free storage)

•49

272065DMF / Toluene (1:1)Pd(PPh3)4 / P(o-tolyl)3 / CuI

402065DMF / Toluene (1:1)Pd(PPh3)4 / AsPh3 / CuI

982065DMF / Toluene (1:1)Pd2(dba)3 / P(2-furyl)3 / CuI

932065DMF / Toluene (1:1)Pd2(dba)3 / P(o-tolyl)3 / CuI

852065DMF / Toluene (1:1)Pd2(dba)3 / AsPh3 / CuI

0.23090DMF / Dioxan (1:1)Pd2(dba)3 / AsPh3 / CuI

82065DMF / Dioxan (1:1)Pd2(dba)3 / AsPh3 / CuI

330115DMF / THF (1:1)Pd2(dba)3 / AsPh3 / CuI

502065DMF / THF (1:1)Pd2(dba)3 / AsPh3 / CuI

420100ToluenePd2(dba)3 / AsPh3 / CuI

930115THFPd2(dba)3 / AsPh3 / CuI

202065THFPd2(dba)3 / AsPh3 / CuI

1030115DMFPd2(dba)3 / AsPh3 / CuI

72065DMFPd2(dba)3 / AsPh3 / CuI

RCY [%]

Time [min]

Temp. [°C]

SolventCatalyst systemMeO2S

O

SnBu3

O

18F

I

MeO2S

O

O

18F



NHN

O

18F

NH

O

ON

OHO

OH

18F

RR = OHR = H

N

18F

OH OH

ONa

O

MeO2S

18F

T. Forngren et al. Acta Chem. Scand. 1998, 52, 475.

F. Wüst et al. Org. Biomol. Chem. 2005, 3, 503.

E. Marriére et al. Organic Lett. 2000, 2, 1121.

F. Wüst et al. J. Label. Compds. Radiopharm. 2004, 47, 457.

•50

LnPd

R-XLnPd(0)

RĆ

X

RLnPd

CR

CR`

CH

base, CuI

RĆ CCuCuX

RĆ CR

Kenkichi Sonogashira: (1975)Cu-Pd catalysed coupling of aryl- and vinylhalides or triflates with terminal alkynes

Proposed reaction mechanism

+

X = I, Br, OTf

Pd(0)

X

R'HR

R R'

CuI, amine

Enhanced C-H acidity

due to Cu-ππππ complexationHR

CuI

18F-labelled aryl halides: Sonogashira reaction

Pd-

complexSolvent Temp. Time RCY in %

Pd[PPh 3]4 THF/TEA 60 °C 20 min 5

Pd[PPh 3]4 THF/TEA 80 °C 20 min 19-33



Pd[PPh 3]4 THF/TEA 80 W 5 min 15

Pd(PPh3)2Cl2 THF/TEA 120 °C 20 min 0


Pd[PPh 3]4 THF/TEA 120 °C 40 min 53

I

18F

MeO

OH18F

MeO

OH

Pd[PPh3]4, CuI

THF, TEA

Typical procedure

50-150 MBq 4-[18F]fluoroiodobenzene in THF (1 ml)

TEA (0.5 ml) as amine base

3 mg mestranol , 3 mg CuI

3 mg Pd(0)-complex (Pd[PPh3]4, Pd2(dba)3)

Heating at 120 °C for 20 min in a sealed vial

Total synthesis time (incl. HPLC): 120 min after EOB

Radiochemical yield: 51-64 %

Radiochemical purity: >95 %


•51

OH

HO

OH

O

HO

NN

F

OH

18F18F

18F

RCY : 40-88 %



Sonogashira reactions proceed under mild conditions and moderate to high

radiochemical yields while tolerating functional groups (e.g. OH)

18F-labelled aryl halides: N-arylation

S NN

N18F

OOBr

18FS NN

NHOO

Pd2(dba)3/P(o-tolyl)3

NaOBut, toluene

[18F]RP 62203

(5-HT2A antagonist)

60% based upon [18F]bromofluorobenzene

E. Marriére et al. J. Label. Compds. Radiopharm. 1999, 42, S69.

First N-arylation reaction in 18F chemistry

• Importance of aromatic amines in medicinal chemistry

�� significant number of pharmaceuticals containing aromatic C-N bonds

Need for methods for aromatic C-N bond formation in PET chemistry

•52

NH

I

18F

N

18F

catalyst system

18F-labelled aryl halides: N-arylation of indoles

N-aryl indols: Central structural motif in many drugs and other biologically active compounds

N

Cl

F

N NNH

O

N

HNOMe

O

N

N

O

O

36tolueneK3PO4CuI/ethylendiamine

7THF/ tolueneK3PO4CuI/ethylendiamine

0tolueneK3PO4CuI/trans 1,2-

diaminocyclohexane

0THF/tolueneK3PO4CuI/trans 1,2-

diaminocyclohexane

RCY (%)SolventBaseCat.-system

Catalyst system 1:

CuI/1,2-diamines

H2N NH2

NH2

NH2


Pd(0)/Xantphos


28tolueneNaOButPd2(dba)3/Xantphos

16THF/tolueneK3PO4Pd2(dba)3/Xantphos

0THF/tolueneCs2CO3Pd2(dba)3/Xantphos

13THF/tolueneNaOButPd2(dba)3/Xantphos

6THFKOButPd2(dba)3/Xantphos

5THFNaOButPd2(dba)3/Xantphos

Catalyst system 2:

OPPh2PPh2

•53

2-(Dicyclohexyl-phosphino)-2'-(N,N-dimethylamino)-biphenyl


70% (140 °C)tolueneNaOButPd2(dba)3/2-(dicyclohexyl-phosphino)-2'-(N,N-dimethylamino)-biphenyl

3% (65 °C)tolueneNaOButPd2(dba)3/2-(dicyclohexyl-phosphino)-2'-(N,N-dimethylamino)-biphenyl

25 (10 min)69 (20 min)71 (30 min)70 (60 min)

tolueneNaOButPd2(dba)3/2-(dicyclohexyl-phosphino)-2'-(N,N-dimethylamino)-biphenyl

0 %DMFNaOButPd2(dba)3/2-(dicyclohexyl-phosphino)-2'-(N,N-dimethylamino)-biphenyl

22THF/tolueneNaOButPd2(dba)3/2-(dicyclohexyl-phosphino)-2'-(N,N-dimethylamino)-biphenyl

Catalyst system 3:

Cy2P

NMe2


18F-labelled sigma-2 receptor ligands

NH

N

N

NH

N

O

N

N

N

N

N

O

18F

18F

Cat.-system

NaOBut, toluene

20 min, 100 °C

Cat.-system

NaOBut, toluene

20 min, 100 °C

91 %

84 %

18F

I

18F

I



Cat.-system: Pd2(dba)3 /2-(dicyclohexyl-phosphino)-2'-(N,N-dimethylamino)-biphenyl

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N

SAc

HN

S

HN

S

H

TBAOH

18F-

Br18F

H H

15-20%

(based upon [18F]F-)

18F-labelled fluoroalkyl halides/sulfonates

[18F]Bromofluoromethane: Alkylation reactions

NH

NHNN N

N

CF3HO

NH

NHNN N

N

CF3O18F

X X

X = H, D

Br18F

X X

[18F]SPARQ

base

O18F

X X

X = H, D

R

S18F

X X R

HN18F

X X R N18F

R

RR

+BUT

Scope and limitations

T. G. Hamill et al. J. Label. Compds. Radiopharm. 2005, 48, 31.

J. Zessin et al. Nucl. Med. Biol. 2001, 28, 857.

18F-labelled fluoroalkyl halides/sulfonates

Scope and limitations

O18F

S18F

N18F

n

n

n

R

R

R

n = 2, 3

R = aryl, alkyl

R1 = R2 = H

R1 = H, R2 = alkyl, aryl

R1 = R2 = alkyl, aryl

R1R2

O18Fn

R

O

HN18F

n

R

O

Fluoroethyl and fluoropropyl halides/sulfonates: Alkylation reactions (SN2)

GH

18F X

18FR

n

R

n

R = alkyl, arylGH = OH, SH, NH2, NHR, NR2 CO2H, CONH2

n = 2,3

polar solvent base

X = I, Br, OMs, OTs, OTf, ONs

Fluoroethyl chain� fluoroethyl sulfonates as preferred alkylating agents� [18F]FETos works well in DMF and DMSO, not in CH3CN

Fluoropropyl chain� fluoropropyl halides (Br, I) as preferred alkylating agents

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CO2H

ONH2

18F

N18F

CH3

CH3OH

+

CO2HS

NH2

18F

N

CO2Me

I

18F

NO

O 18FnN O

n = 2, 3

NC CN

NH

18F

Fluoroethyl and fluoropropyl halides/sulfonates: Alkylation reactions (SN2)

Summary

Broad arsenal of 18F-labelling techniques for the synthesis of small monomeric compounds available�� More complex structures:

Multi-step built-up syntheses involving 18F-labelling precursors

� Impact of recent advances in modern organic chemistry

(e.g. Pd-mediated C-C and C-N bond formations)

CHO18F

18FX = I, Br, NH2

X

X

18F

X = OH, NH2

X

18FX = I, Br

Reductive aminations

Carbonyl-olefination reactions

Nucleophilic 1,2-additions

Heteroatom alkylations

Amidations

Pd-mediated C-C and C-N bond formations

Aryl ether synthesis

Aniline alkylations

18F

n = 0,1X = I, Br

Br 18F

X X

X = H, D

18F

n = 0,1R = CH3, Tolyl, F3C

X RO2SOn n

Heteroatom alkylation reactions

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Remotely controlled synthesis apparatus enabling

(1) preparation of the labelling precursors

AND

(2) performance of complex built-up syntheses

Outlook

Control Decarboxylation disturbanceDopa to dopamine

HO

HO 18F

H2N CO2H

HONH2

HO2C

HONH2

HO2CHO

HONH2

HO

Tyrosine Dopa Dopamine

Selected 18F-Radiopharmaceuticals: [18F]FDopa

Decarboxylation

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MRT: Surgery defect OMFD-PETTarget/Non-Target

0

5000

10000

15000

20000

25000

0 1000 2000 3000 4000 5000

Frame Midpoint Time [sec]

ac

tiv

ity

(B

q/c

cm

)

0

0,5

1

1,5

2

2,5

3

3,5

4

tum

ou

r /

no

n t

um

ou

r

Tumour Reference region Tumour / Brain

2.2

Blood-brain-barrier

Amino acid

transporter

Tumour

MeO

HO 18F

H2N CO2H

Selected 18F-Radiopharmaceuticals: [18F]OMFD

Selected 18F-Radiopharmaceuticals: [18F]FDG

OHO

HO18F

OH

OH

O

AcO

AcO

AcO

[18F]FDG

OAc

OTf 1. [18F]fluoride

2. Saponification

Mannose-triflate

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Primary tumour in the neck with lung metastesis

R L R L R L


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bonemetastasis

Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf

OP

O

OO

OP

O

OO

OP

O

OO

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

OH-

PO43-

PO43-

OH-

F-

Selected 18F-Radiopharmaceuticals: [18F]fluoride

Selected 18F-Radiopharmaceuticals: [18F]FLT

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CO 2H

NH 2O18

F

TsOOTs [K+/2.2.2]18F -

AcCN, 90°CTsO

18F

Di-Na-salt tyrosine

DMSO, 90°C

Selected 18F-Radiopharmaceuticals: [18F]FET

Selected 18F-Radiopharmaceuticals: [18F]FET

Radiopharmaceutical chemistry with short -lived positron emitters...

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