New approach to the nucleophilic synthesis
of 6-[18F]fluoro-L-DOPA
F. M. Wagner, J. Ermert, H.H. Coenen
Institut für Neurowissenschaften und Biophysik (INB-4): Nuklearchemie
Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany
Sixth International Symposium on Radiohalogens
September 6 – 10, 2008, Whistler, B.C., Canada
Application of 6-[18F]fluoro-L-DOPA
visualisation of neurodegeneration
Garnett, Firnau, Nahimias Nature 305, 137 (1983)
diagnosis of tumours
Heiss et al. J. Nucl. Med. 37, 1180 (1996)
Syntheses of aromatic [18F]fluoroamino acids
via destannylation reactions
18
F
H
CO2H
L-6-[18F]fluorodopa
NH2
HO
OH
Namavari et al. Appl. Rad. Isot. 43, 989 (1992)
de Vries et al. Appl. Rad. Isot. 51, 389 (1999)
R = formyl
R' = OBoc
R'' = OBoc
18
1. [ F]F2
2. HBr
Sn(CH3)3
18
1. [ F]F2
2. HBr
18
F
H
CO2H
R'
NH2
CO2C2H5
NHR
R''
R = Boc
R' = OBoc
R'' = H
H
18
1. [ F]F2
2. HBr
18
R = Boc
R' = H
R'' = OBoc
HO
F
H
CO2H
NH2
OH
6-[18F]fluoro-L-m-tyrosin
VanBrocklin et al. Appl. Rad. Isot. 61, 1289 (2004)
2-[18F]fluoro-L-tyrosin
Hess et al. Appl Radiat Isot 57, 185 (2002)
Asymmetric synthesis
of n.c.a. 6-[18F]fluoro-L-DOPA
H3CO
CHO
H3CO
N(CH3)3TfO
[K⊂2.2.2.]+ 18F
H3CO
CHO
DMF
H3CO
18
NaBH4
F
18
HBr
H3CO
Br
18
H3CO
F
CH2OH
H3CO
18
O
F
(Ph)2CNCH2COOtBu
PTC, CsOH, H2O, toluene
OtBu
C 6H 5
N
H3CO
OCH3
18
H3CO
C 6H 5
Br
F
HI, 200 °C
NH2
COOH
HO
N
+
N
OH
RCY = 23 %; ee = > 96 %
O
PTC
Lemaire et al. Eur. J. Org. Chem., 2899 (2004)
F
Model reactions as basis for nucleophilic syntheses
of 18F-labelled aromatic amino acids
CHO
OH
CHO
OR
[K⊂2.2.2.]+
18
OR
F
H2O2
OH
KHSO4
18
NO2
18
F
F
Chakraborty and Kilbourn, Appl. Rad. Isot., 42, 673 (1991)
CHO
CHO
OR
[K⊂2.2.2.]+
18
OR
F
OH
Pd/C
or RhCl(P(C6H5)3)3
NO2
18
F
18
F
Chakraborty and Kilbourn, Appl. Rad. Isot., 42, 1209 (1991)
Plenevaux et al. Appl. Rad. Isot. 43, 1035 (1992)
“Direct” nucleophilic synthesis of
[18F]fluoro-m-L-tyrosine from a complex precursor
TfO
+
O
N
18
O
[K⊂2.2.2.]
O
HN
O
F
+ 18
O
F
O
HN
MeCN, 85°C
F3C
O
O
F3C
CF3
O
O
CF3
18
O
F
O
CF3
oxone
18
H2SO4
O
F3C
NaOH
OH
O
HN
O
F
O
O
Mulholland et al., Patent 2001
NH2
OH
ee = ?
“Direct” nucleophilic synthesis
of 6-[18F]fluoro-L-DOPA from a complex precursor
OCH3
OHC
BnO
OCH3
F
OHC
[K⊂2.2.2.]+ 18F
N
N
N
BnO
DMF
18
mCPBA
CHCl3
O
OCH3
O
BnO
F
OCH3
OCH3
H
N
N
18
N
HBraq
HO
F
COOH
HO
OCH3
18
F
NH2
RCY = 10 %; ee = 70 %
Tierling et al. J. Label. Compds Radiopharm. 44, 146 (2001)
New concept for the nucleophilic synthesis
of aromatic amino acids from a complex precursor
Boc N
CH3
N
O
F
18
Boc N
N
CH3
Boc N
O
F
N
18
18
F
CH3
HBr
Y
mCPBA
O
O
F
COOH
HO
18
F
NH2
X
O
PTC
O
X
O
X
Boc N
[(C6H5)3P]3RhCl
N
CH3
O
18
F
COOH
HBr
Y
X = H, OBenzyl
PTC = phase transfer catalyst
18
F
Y = H, OH
X
NH2
Synthetic attempts for new precursors
X
X
F
F
Br
BMI
BMI F
X
F
RO´
BMI F
OHC
BMI F
BMI F
X
BMI F
X
RO´
RO´
O
HO
F
BMI
X
Br
O
BMI =
N
N
X
X
X
O
O
, X = H or OR
O
Eleven step synthesis of a new precursor
for 6-[18F]fluoro-L-dopa
F
F
F
Br
Br2
HO
O
O
O
1. s-BuLi
2. DMF
BnO
LDA
F
N
(COCl)2
HO
N
O
N
O
OHC
F
DMSO
O
O
OTHP
BnO
F
PPTS
BnO
OTHP
BnO
OTHP
Br
CBr4
PPh3
OTHP
BnO
(S)-BOC-BMI
OH
F
OH
NaBH4
BnO
OTHP
O
F
CHO
BnO
BnO
O
F
Br
DHP
Br
LiAlH4
BnO
HO
F
TsOH
Br
BnBr
HO
O
F
Br
TMSDAM
HO
HO
F
N
O
TEA
O
N
O
N
O
O
“Direct” nucleophilic synthesis
of 6-[18F]fluoro-L-dopa from the new precursor
Ph
Ph
O
O
OH
O
F
O
TBAHCO3
O
18
F
1. mCPBA
O
18
DMF, 18F
2. HBr
N
N
O
N
NH2
COOH
O
ƒ ~ 22 % radiochemical yield (overall)
ƒ
F
N
O
O
OH
enantiomeric excess > 99 %
Radiochemical yield of the 18F-exchange and a by-product
with different phase transfer catalysts for anion activation
phase transfer catalyst
product
by-product
Cs2CO3
9.5 %
-
[K⊂2.2.2]2CO3
39.8 %
49.9 %
[K⊂2.2.2]2C2O4/CO3
6.25 %
-
TBAOH
2.3 %
41.4 %
TBAHCO3
47.6 %
12.6 %
TBAHCO3
59.5 %
11.5 %
[precursor] = 14.25 mmol/L, DMF, 130 °C (110 °C),10 min, (n = 3)
Enantiomeric purity of c.a. 6-[18F]fluoro-L-DOPA
HPLC: Daicel Crownpak CR(+)5 µ; 150 x 4 mm; 0.02 M HClO4; 1.0 ml/min; 5 – 10 °C
Comparison of different methods for the
synthesis of 6-[18F]fluoro-L-DOPA
Reference
time
[min]
RCY
[%]
ee
[%]
de Vries et al. 1999
< 60 min
33 %
> 99 %
Lemaire et al. 2004
90 min
23 %
> 96 %
Tierling et al. 2001
70 min
16 %
85 %
this work
105 min
22 %
> 99 %
Conclusion and outlook
Using the new precursor, complete preparation and isolation under
present conditions leads to c.a. 6-[18F]fluoro-L-DOPA with > 20 %
radiochemical yield and 99 % of the desired L-isomer.
The maximum amount of carrier obtained is about 3 mg
(the electrophilic methods involve up to 15 mg).
The new method lends itself for easier automation;
first studies are being performed.
Other leaving groups for n.c.a. labeling may be considered.
The synthetic concept can be extended to other aromatic 18F-labelled
amino acids like 6-[18F]fluoro-L-m-tyrosine and 2-[18F]fluoro-L-tyrosine
“Direct” nucleophilic synthesis of [18F]fluoro-m-L-tyrosine
via the new precursor concept
O
F
O
TBAHCO3
O
18
F
1. mCPBA
O
18
DMF, 18F
2. HBr
N
N
O
O
OH
N
F
NH2
N
O
COOH
O
No results reported for the
18F-for-I substitution
O
O
18
I
O
F
Ox.
N
???
hydrolysis
N
O
O
Kuroda et al., Bull. Chem. Soc. Jpn., 73, 417 (2000)