Preparation of labeled aromatic amino acids: Via late-stage18F-fluorination of chiral nickel and copper complexes

Article abstract of DOI:10.1039/d0cc02223c

A general protocol for the preparation of 18F-labeled AAAs and α-methyl-AAAs applying alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral complexes using Ni/Cu-BPX templates as double protecting groups is reported. The chiral auxiliaries are easily accessible from commercially available starting materials in a few synthetic steps. The versatility of the method was demonstrated by the high-yielding preparation of a series of [18F]F-AAAs and the successful implementation of the protocol into automated radiosynthesis modules. This journal is

Full text of DOI:10.1039/d0cc02223c

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E. A. Urusova, J. Zischler, M. Brugger, H. Endepols, B. Neumaier and B. D. Zlatopolskiy, Chem. Commun.,
2020, DOI: 10.1039/D0CC02223C.
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DOI: 10.1039/D0CC02223C
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Preparation of Labeled Aromatic Amino Acids via Late-Stage
18F-Fluorination of Chiral Nickel and Copper Complexes
Austin Craig,a,b,c† Niklas Kolks,a,b† Elizaveta A. Urusova,a,b Johannes Zischler,a,b Melanie Brugger,a
Received 00th January 20xx,
Accepted 00th January 20xx
Heike Endepols,a,b,d Bernd Neumaier,a,b,c* and Boris D. Zlatopolskiya,b,c
DOI: 10.1039/x0xx00000x
A general protocol for the preparation of 18F-labeled AAAs and α- [18F]fluoro-L-tryptophan (7-[18F]FTrp) have been used as
methyl-AAAs applying alcohol-enhanced Cu-mediated neurotracers for the visualization of the dopaminergic and
radiofluorination of Bpin-substituted chiral complexes using Ni/Cu- serotonergic systems.7,8
BPX templates as double protecting groups is reported. The chiral
Accordingly, a significant amount of research has been
auxiliaries are easily accessible from commercially available devoted to the development of convenient and versatile
starting materials in a few synthetic steps. The versatility of the protocols for the production of 18F-labeled AAAs. Despite the
method was demonstrated by the high-yielding preparation of a substantial effort, the majority of the published protocols lack
series of [18F]F-AAAs and the successful implementation of the efficacy and are too impractical for routine applications.
protocol into automated radiosynthesis modules.
Consequently, the potential of 18F-labeled AAAs has not been
fully explored.
Selected recent preparations of 18F-labeled AAAs (shown in
Scheme 2) highlight challenges including multi-step precursor
syntheses, low RCYs, and regioselectivity issues. The group of
DiMagno reported the use diaryliodonium salts towards 6-
[18F]FDOPA ([18F]7) and 4-[18F]FPhe preparation, although
lengthy precursor synthesis and fair RCYs limited these
approaches (Scheme 2 A).9,10 Liang et al. accessed 18F-labeled
AAAs via spirocyclic iodonium(III) ylides; unfortunately,
demanding precursor synthesis also reduced the practicality of
this method.11 Tsushima and co-workers applied an
electrophilic radiofluorination towards α-[18F]FMePhes despite
giving rise to multiple 18F-labeled products and low specific
activities (As).12
Positron emission tomography (PET) has gained great
importance as a prominent non-invasive imaging modality in
clinical practice. Using tracers containing a suitable β+-emitting
radionuclide, PET may provide real-time visualization of
complex biochemical processes at the molecular level, with high
sensitivity and excellent image quality. Fluorine-18 has been
established as an advantageous β+-emitting radionuclide for
PET, mainly due to its efficient large-scale cyclotron production
in the form of [18F]fluoride, relatively long half-life (109.7 min),
low maximum positron energy of 0.635 MeV, and high β+-decay
branching intensity (97%).1
For decades, 18F-labeled aromatic amino acids (AAA)
including O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET), 3,4-
dihydroxy-6-[18F]fluoro-L-phenylalanine (6-[18F]FDOPA), and 2-
[18F]fluoro-L-tyrosine (2-[18F]FTyr) have played a significant role
in clinical diagnostics of cancer and neurodegenerative
disorders using PET.2-4 In combination with MRI and CT, [18F]F-
AAA-PET has been demonstrated to be a sensitive tool for
effective tumor diagnosis and staging.5,6 In addition, 6-
[18F]FDOPA, 6-[18F]fluoro-meta-L-tyrosine (6-[18F]FMT), and 7-
R2
R2
R2
R2
Bpin-(Het)Ar-CH2-X
2
18F-(Het)Ar
N
N
N
N
O
N
O
O
N
O
B
C
M
M
R1
H
A
R1
R1
H2N
COOH
(Het)Ar-Bpin
O
O
Nine examples
Ph
Ph
1
4
3
M = Ni/Cu
a. Forschungszentrum Jülich GmbH, Institute of Neuroscience and Medicine, INM-5
Nuclear Chemistry, 52425 Jülich, Germany
A
B
C
: Alkylation
: Cu-mediated radiofluorination
. Hydrolysis/Deprotection
R1 = H/CH3
R2 = H/Cl
R2
X = Br/Me3N+I-
b. Institute of Radiochemistry and Experimental Molecular Imaging, University
Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
c. Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931 Cologne,
Germany
Scheme 1 Application of Ni/Cu-BPX templates for the late-stage preparation of 18F-
labeled AAAs.
d. Department of Nuclear Medicine, University Hospital Cologne, Kerpener Str. 62,
50937 Cologne, Germany
† contributed equally
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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COMMUNICATION
Journal Name
Ph
Ph
N
Selected previous works
I = Precursor Synthesis
II = Radiofluorination
III = Deprotection
View Article Online
MEMO
Boc
A)
HO
H
H
N
N
Boc
I
O
N
O
O
O
DOI: 10.1039/D0CC02223C
N
N
N
HO
MEMO
5 steps (28% yield)
Ni
Ni
Pd2(dba)3, XPhos, B2pin2, KOAc
DMSO, 80 oC, 24 h
CO2Me
HO
HO
CO2H
O
O
N
N
II
NH2
I
III
Ph
Ph
18F
Br
B
O
6
CO2H
6-[18F]FDOPA ([18F]
)
H2N
7
O
5
Ref [9]: RCY: 14 ± 4% (n.d.c.)
O
17
3f
, 17%
CO2tBu
18F
B)
Scheme 3. Suzuki-Miyuara borylation upon Ni-BPB-AAA.
O
O
N(Boc)2
I
HO
HO
II
O
5 steps (17% yield)
enantiomeric purity of 6-[18F]FTrp was suboptimal (89% ee).
Moreover, the harsh deprotection conditions (50% H2SO4, 130
°C, 15 min) led to the partial decomposition of the tracer. In our
revised strategy, we were attracted by the possibility of using
Ni-BPX complexes to overcome these limitations.
III
OBoc
CO2H
4d
H2N
I
CO2H
H2N
O
9
6-[18F]FMT ([18F]
)
8
Ref. [11]: RCY: 12 % (n.d.c)
: [18F]CH3COOF
C)
D)
Product ratio:
CO2H
II
CO2H
2-18F = 20
3-18F = 3.5
4-18F = 1
18F
AcOH/TFA, 1:1, 90 oC, 5 min
H3C NH2
2-4-[18F]FAMP ([18F]
H3C NH2
10
4g-i
)
Ref. [12]: RCY: 20-30%
Developed by Belokon et al. as early as the 1980s, the chiral
Ni-BPB-Gly (1a) and Ni-BPA-(RS)-Ala complexes (1b) were
designed to enable the stereoselective synthesis of α-amino
and α-amino-α-methyl acids.22 In particular, the commercial
availability/simplicity of their multi-gram scale preparations,
high crystallinity, moisture stability, facile purification and rapid
decomposition (to yield the free AAA) under rather mild acidic
conditions is advantageous for synthetic as well as
radiosynthetic purposes. Whilst multi-step AAA radiosyntheses
using Belokon complexes have been reported,4,23,24 the
application of late-stage Cu-mediated radiofluorination upon
Ni/Cu-BPB complexes has never been previously disclosed. The
Bpin-substituted precursors (3a–i) were accessed via alkylation
upon (S)-M-BPX (1a–c) (Scheme 1 A) using NaH in DMF/MeCN,
furnishing the desired (S)-M-BPX-AAA complexes 3a–i in good
yields. Three of the requisite alkylating agents used for the
synthesis of six tracer precursors were commercially available
Y
4-6 steps (20-31% yield)
18F
II
I
CO2tBu
(Boc)2N
I
III
CO2H
H2N
CO2tBu
·
HCl H2N
2-4-[18F]FPhe ([18F]
Refs [18,19]: RCYs: 22-56%
)
11
Y = TsO, BF4
12a-d
4a-c
18F
Bpin
E)
CO2H
CO2Et
CO2H
5 steps (26% yield)
II
III
NH2
N(Boc)2
NH2
I
8
6-[18F]FMT ([18F]
)
4d
13
OH
OMe
R2
OH
Ref. [20]:RCY: 8-16%
This work
R2
O
R2
(Het)Ar-Bpin
18F
R1
O
M
R2
O
Bpin-(Het)Ar-CH2-X
R1
N
2a-i
CO2H
R1 NH2
N
H
O
M
R3
II
N
N
N
R3
I
III
18
R4
4a-i
[
F]
O
40-85%
N
RCYs: 25-60%
3a-i
(52-86%)
1a c
-
M-BPX
O
R2
R2
Scheme 2. Selected examples of 18F-labeled AAA preparations. Conditions for
radiolabeling steps (II): A): 1) azeotropic drying of [18F]KF/K2.2.2 (×3), 2) diglyme, 140 °C,
5 min; B) 1) azeotropic drying of [18F]Et4NF (×3), 2) DMF, 120 °C, 20 min; C): [18F]AcOF,
AcOH/TFA 1:1, 90 °C, 5 min; D: [18F]Et4NF, Cu(MeCN)4OTf, DMF or MeOH/DMF, 85–95 °C,
20 min, air or Ar; E): 1) azeotropic drying of [18F]KF/K2.2.2 (×5), 2) Cu(py)4(OTf)2, DMF,
120 °C, 20 min, air; this work: [18F]Et4NF, Cu(py)4(OTf)2, nBuOH/DMA, 110 °C, 15 min, air.
Procedures D and the novel procedure (this work) avoid any azeotropic drying steps.
O
O
(Het)Ar-18
F
Ph
R1
Ph
(Het)Ar-Bpin
R1
O
Ni
N
O
Ni
N
N
N
O
[
18F]F-,Cu(py)4(OTf)2
N
N
R2
nBuOH/DMA, 110 oC, 15 min
R2
3a-f
18
O
18a-f
, [ F]
: R1 = H, R2 = Ph
: R1 = Me, R2 = H
18
3g-i
18g-i
, [ F]
18
18a-i
F]
[
18
3a-i
3a-e, g-i
18a-e, g-i
: (Het)Ar = Ph-R3
; [ F]
18
3f
18f
, [ F] : (Het)Ar = 3-indolyl
In recent years, Cu-mediated radiofluorination strategies
have received much attention, owing to high RCYs, the wide
substrate scope and their facile implementations.13-15 More
recently, additives including alcoholic co-solvents and
pyridinium salts have been demonstrated to further enhance
the efficiency of Cu-mediated radiofluorination reactions.16,17
Cu-mediated radiolabeling of (aryl)(mesityl) iodonium salts
proved a promising method, although possible epimerization
and multistep precursor synthesis remained significant
drawbacks (Scheme 2 D).18,19 Gouverneur and coworkers
Ent
ry
1
Precursor
Product (RCY %)
3a, R3 =H, 2-Bpin
[18F]18a (92±5)
[18F]18b (90±2)
[18F]18c (86±4)
[18F]18d (90±3)
[18F]18e (90±6)
[18F]18f (94±2)
[18F]18g (84±6)
[18F]18h (89±7)
[18F]18i (92±4)
2
3b, R3 =H, 3-Bpin
3
3c, R3 =H, 4-Bpin
4
3d, R3= 5-OMOM, 2-Bpin
3e, R3= 4-OMOM, 2-Bpin
3f, R3 = H, 4-Bpin
3g, R3 = H, 2-Bpin
3h, R3 = H, 3-Bpin
3i, R3 = H, 4-Bpin
5
prepared
6-[18F]FMT
([18F]4d)
via
Cu-mediated
6
radiofluorination of the corresponding pinacol arylboronate
(Bpin) in 15±1% RCY (Scheme 2 E); however, the five-step
precursor synthesis was low-yielding and required HPLC
purification.20 In our previous work, we have successfully
employed a chiral Schöllkopf auxiliary towards 6-[18F]fluoro-L-
tryptophan (6-[18F]FTrp, [18F]16); however, we encountered
several challenges.21 The laborious six-step precursor synthesis
(overall yield 37%) was expensive and time-consuming, the
7
8
9
Table 1. 18F-Labeling: Ni-BPX-AAA (3a–i, 10 µmol), Cu(py)4(OTf)2 (20 µmol), [18F]F–
/Et4NHCO3 (50–1500 MBq), 250 μL nBuOH/750 μL DMA, air, 110 °C, 15 min. All
experiments were carried out at least six times. Radio-HPLC was used to determine RCYs,
given in the form of mean ± standard deviation.
2 | J. Name., 2012, 00, 1-3
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18F
CO2H
NH2
18F
(Scheme 1 A & B, 2a–c). The synthetic routes towards 6-
[18F]FMT ([18F]4d), 2-[18F]FTyr ([18F]4e), 4-[18F]FTrp ([18F]4f)
precursors using alkylating agents (2d–f) are outlined in the
Supporting Information. We also investigated the use of the
bromomethyl substituted arylboronic acids as alkylating agents;
however, problems with the purification of the corresponding
Ni-BPX complexes prevented us from pursuing this pathway.
We considered various protecting groups, bearing in mind
that rapid and high yielding deprotection would be most
practical for radiosynthesis and selected O-methoxymethyl
(MOM) groups, which could be introduced in near quantitative
yields and rapidly cleaved. Suzuki-Miyuara borylation was used
to incorporate the Bpin leaving groups at the desired aryl
positions.
View Article O
C
n
Olin2
H
e
18F
DOI: 10.1039/D0CC022N2H3C
CO2H
2
Me
H2N
18
HO
18
4g:
[
F]
50±3%
18
[
4d:
[
F]
26±5%
18F
4a:
F]
52±6%
3.2 GBq/µmol (0.14 GBq)
CO2H
NH2
Ph
N
18F
18F
O
N
O
R3
CO2H
CO2H
Me
Ni
R2
HO
18
H2N
58±2%
252.1 GBq/µmol (1.9 GBq)
H2N
4e:
25±5%
O
N
18
18
4h
F] : 56±4%
[
4b:
[
F]
[
F]
18F
33.1 GBq/µmol (1.4 GBq)
R1
18F
CO2H
NH2
CO2H
18
18a-i
F]
[
CO2H
18F
NH2
Me
H2N
4c:
56±4%
N
18
18F 18
[
F]
H
4i:
F] 53±4%
[
18
29.1 GBq/µmol (0.18 GBq)
4f:
25±4%
[
F]
2.0 GBq/µmol (0.33 GBq)
Figure 1. 18F-Labeled AAAs ([18F]4a-i) prepared using the novel method. All RCYs are
isolated yields corrected for decay and determined at least in triplicate. All tracers were
enantiomerically pure (ee > 95%). Furthermore, for [18F]4b,c and [18F]4g–i molar
activities (Am) are provided. For [18F]4b and [18F]4h Am values at different activity
amounts were additionally determined: 4.6 GBq/µmol (0.13 GBq), 76.3 GBq/µmol (1.1
GBq) ([18F]4b) and 61.2 GBq/µmol (0.5 GBq) ([18F]4h), respectively.
An alternative synthetic approach via the direct Suzuki-
Miyuara borylation upon Ni-BPB-AAA (18) also proved to be
feasible, affording the desired precursor 3f in an unoptimized
yield of 17% (Scheme 3). Radiosynthesis commenced with the
loading of [18F]fluoride onto an anion exchange resin followed
by its subsequent elution with Et4NHCO3 in MeOH. The amount
of Et4NHCO3 required for successful elution was minimized
considering the base-sensitivity of Cu(py)4(OTf)2. The low
boiling point of MeOH (65 °C) facilitated its subsequent rapid
removal within 2–3 min, which was followed by the addition of
the corresponding Ni-BPX-AAA precursor and Cu(py)4(OTf)2 in
nBuOH/DMA (1:2). The elution of 18F- using Et4NHCO3 in
nBuOH/DMA avoiding any evaporation steps was also
evaluated. However, in this case, 18F– recovery was slightly
lower (90–95%) and higher amounts of precursor (30 instead of
10 µmol) were necessary for the subsequent radiolabeling step.
The precursor/Cu-complex ratio of 1:2 provided the highest 18F-
incorporation rates (Scheme 4).25 The removal of volatiles after
radiolabeling required to achieve efficient decomposition of the
radiolabeled complexes and simultaneous cleavage of
protecting groups. The latter was carried out using 37% HCl at
110 °C for 15 min.26 Complete hydrolysis was pleasantly
indicated by a sharp color change from deep red to pale yellow.
It was also found that higher temperatures caused a partial
decomposition of 6-[18F]FMT ([18F]4d), 2-[18F]FTyr ([18F]4e) and
4-[18F]FTrp ([18F]4f). Purification of the resulting AAA tracers
([18F]4a–i) was achieved by semi-preparative HPLC applying
aqueous EtOH as a mobile phase yielded AAA tracers ([18F]4a–i)
in decay-corrected radiochemical yields (RCYs) of 25–60%
within approximately 90 min with a radiochemical purity (RCP)
and enantiomeric excess (ee) of > 95% as ready-to-use
solutions.
Molar activities (Am) of [18F]AAAs prepared using the novel
method were comparable to or better than those for [18F]AAAs
produced using published protocols (Figure 1).
The implementation of the protocol into automated
modules was straightforward owing to the simplicity of the
radiosynthesis. The procedure allowed the rapid preparation of
a series of 18F-labeled AAAs shown in Scheme 1 C under general
conditions without the need for further optimization.
Additionally, the applicability of a Cu complex 19 as an
alternative to Ni-BPX radiolabelling precursors was investigated
(Scheme 4).27 The use of Cu- instead of Ni-containing precursors
would mean that only a single trace metal determination
required for quality control in cGMP production. The test
radiosynthesis furnished 3-[18F]FPhe in a good RCY of 42% and
confirmed the applicability of the appropriate Cu-complexes for
radiolabeling. The Ni & Cu content amounted to 0.001–0.37
mg/preparation (determined by ICP-MS) and was significantly
below any level of concern according to the ICH Guideline of
Elemental Impurities (Q3D).28
The AAA PET-tracers were compared to clinically
established [18F]FET, which provides information on the LAT1
transporter expression. As the majority of malignant tumor cells
overexpress such transporters, [18F]FET can afford invaluable
information on the location and size of tumors.2,29 The uptake
of 3-[18F]FPhe ([18F]4b) in PC3 and MCF7 cells was significantly
higher than of [18F]FET (Chart S1; Supp. Information).
Uptake of
3-[18F]FPhe and [18F]FET in MDA-MB-231 cells was comparable.
One of the most important applications of radiolabeled
AAAs is the detection of cerebral tumors. Consequently, high
tracer uptake in the brain is a necessary property of a successful
candidate probe. Brain accumulation of 3-[18F]FPhe ([18F]4b) in
healthy rats was higher than that of [18F]FET with a mean value
of 57.7±2.9 SUVbw during the first 30 min p. i. A distinct pattern
was visible with high uptake in the olfactory bulb, frontal cortex,
occipital cortex, thalamus, inferior colliculus, cerebellum, and in
the areas around the 4th ventricle (Figure 2). This brain
distribution pattern was similar to that of [18F]FET.
Cl
Cl
1) [18F]F-,[Cu(OTf)2(py)4]
N
N
O
N
O
18F
CO2H
NH2
Cu
2) nBuOH/DMA, 110 °C, 15 min
O
3) 12 M HCl, 110 °C, 15 min
Bpin
Ph
RCY: 42 ± 2%
ee: >95%
Cl
Scheme 4. Preparation of [18F]4b via alcohol-enhanced Cu-mediated radiofluorination
of (S)-Cu-BPB-AAA complex 19.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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In
summary,
alcohol-enhanced
Cu-mediated
radiofluorination of Bpin-substituted Ni-BPX-AAA complexes is
a simple, yet powerful method for the fast production of
structurally diverse radiolabeled AAAs. The attractiveness of the
procedure is highlighted by an efficient precursor synthesis,
high RCYs, and amenability to automation. The utilization of M-
BPX complexes facilitates precursor synthesis and allows a
series of AAA tracers to be accessed in a short time and practical
manner. In addition, the use of chiral Cu(II) complexes towards
radiofluorinated AAAs has been described for the first time. The
proposed protocol could be easily implemented also for the
preparation of radiofluorinated D-AAAs owing to accessibility of
the corresponding BPX-AA complexes. Notably, 3-[18F]FPhe
showed higher or similar uptake in tumor cells, and higher brain
uptake in healthy rats compared to the clinically-established
PET-tracer [18F]FET.
This work was supported by the DFG grants ZL 65/1-1, ZL
65/3-1 and EN 439/6-1. The authors thank Dr. H. Frauendorf
and G. Udvarnoki, Prof. M. Schäfer and M. Neihs for the
measurement of mass spectra, and Prof. A. Berkessel and C.
Schmitz for the measurement of elementary analyses.
Conflicts of interest
There are no conflicts to declare.
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4 | J. Name., 2012, 00, 1-3
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