Carrier free synthesis of N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane

Full text of DOI:10.1002/jlcr.517

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Labelled Cpd Radiopharm 2001; 44: 909–920.
DOI: 10.1002/jlcr.517
Research Article
Synthesis of [4-11C]amino acids via ring-
opening of aziridine-2-carboxylates
N. M. Gillings*1 and A. D. Gee2
1 PET Centre, Aarhus University Hospital, 8000 Aarhus C, Denmark
2 GlaxoSmithKline, Clinical Research Unit, Addenbrookes Hospital,
Cambridge, UK
Summary
Ring-opening of N-(tert-butoxycarbonyl)aziridine-2-isopropyl carboxylate
with no-carrier-added (n.c.a.) [11C]cyanide is reported. Following purification
by HPLC, the protected d,l-[4-11C]b-cyanoalanine was subsequently hydro-
lysed, to yield d,l-[4-11C]asparagine or d,l-[4-11C]aspartic acid, or reduced
followed by hydrolysis to give d,l-2,4-diamino[4-11C]butyric acid. Typical
syntheses starting with 10 GBq hydrogen [11C]cyanide yielded 1–1.4 GBq of
[4-11C]amino acid within 30 min, giving the labelled amino acids in 30–40%
decay corrected radiochemical yield (counted from [11C]cyanide) with radio-
chemical purities of 95%, 98% and 60%, respectively. Copyright # 2001 John
Wiley & Sons, Ltd.
Key Words: carbon-11; cyanide; aziridine; amino acid
Introduction
Positron emission tomography (PET) is a powerful technique for the
in vivo study of biochemical processes and has become a valuable tool
for both basic biomedical research and diagnostic imaging. This
technique relies on the synthesis of tracer molecules labelled with
short-lived positron emitting nuclides such as 11C and 18F. The short
radioactive half-life of 11C (20.4 min) imposes major constraints on
*Correspondence to: N. M. Gillings, PET & Cyclotron Unit, 3982, Copenhagen University
Hospital, Blegdamsvej 9, 2100 Kꢀbenhavn Ø, Denmark. E-mail: nic@pet.rh.dk (N.M. Gillings)
Copyright # 2001 John Wiley & Sons, Ltd.
Received 19 March 2001
Revised 15 June 2001
Accepted 7 August 2001

910
N. M. GILLINGS AND A. D. GEE
the time available for synthesis of compounds labelled with this
radionuclide. Carbon-11 chemistry requires rapid labelling techniques
with the 11C-label incorporated as late as possible in the synthetic
pathway.
Amino acids labelled with short-lived positron emitting radionuclides
are of particular interest when used in conjunction with PET for
measurement of in vivo processes such as protein synthesis rates and
amino acid transport1 and neurotransmitter synthesis2. The use of
11C-labelled methionine for the detection and delineation of malignant
brain tumours has increased markedly over the last few years.3 Other
11C-labelled amino acids such as [11C]DOPA,4,5 [11C]tyrosine6,7 and
[11C]5-hydroxytryptophan8–11 have been utilized in PET oncology
studies in recent years. Furthermore, a recent paper reported a
preliminary investigation of the uptake of 11C-labelled glutamate,
glutamine and aspartate in tumour cell aggregates and in vivo in both
rats and humans.12 Of these three amino acids, 11C-aspartate appeared
most promising, with a high uptake in neuroblastoma aggregates
combined with relatively low organ uptake.
The results presented in this paper were obtained from a study into
the application of aziridine ring-opening reactions in the synthesis of
11C- and 18F-labelled compounds.13,14 Aziridine-2-carboxylates
are known to undergo nucleophilic ring-opening reactions with a range
of nucleophiles, leading to amino acid products.15 Activation of the
aziridine nitrogen has been shown to considerably increase reaction
rates.16 Ring-opening of N-activated aziridine-2-carboxylates with
[11C]cyanide could be useful for the synthesis of the amino acids
[4-11C]aspartic acid, [4-11C]asparagine and 2,4-diamino[4-11C]butyric
acid via a b-[11C]cyanoalanine ester. l-[4-11C]aspartic acid and
l-[4-11C]asparagine have only previously been produced by enzymatic
methods,17–19 whereas d,l-2,4-diamino[4-11C]butyric acid has also been
produced using traditional synthetic methods.20
Results and discussion
2,3-Dibromo-propionic acid isopropyl ester was prepared in three steps
from commercially available acrylic acid as described previously.21
Reaction of this with liquid ammonia followed by reduced pressure
distillation22 gave racemic aziridine-2-isopropyl carboxylate (1). Reac-
%
tion of 1 with di-tert-butyl dicarbonate in the presence of base gave
%
Copyright # 2001 John Wiley & Sons, Ltd.
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SYNTHESIS OF [4-11C]AMINO ACIDS
911
racemic N-(tert-butoxycarbonyl)aziridine-2-isopropyl carboxylate (2)
%
(Scheme 1).
Scheme 1. Reagents: i, di-tert-butyl dicarbonate, triethylamine; ii, tetrabuty-
lammonium [11C]cyanide, DMF; iii, HCl (0.1 M); i*, HCl (4 M); *, NaBH4/
CoCl2, MeOH; *i, HCl (conc.)
Reaction of 2 with tetrabutylammonium [11C]cyanide was achieved
%
by heating in DMF. In the absence of the tetrabutylammonium counter
ion, 50% of the radioactivity remained unreacted after heating at 1208C
for 60 min. This is attributed to the insolubility of hydrogen
[11C]cyanide in DMF. The rate of [11C]cyanide incorporation was
followed by HPLC analysis of samples taken from the reaction mixture
at regular intervals. Total incorporation of [11C]cyanide was achieved
within 4 min by reaction with 5mg of aziridine precursor ( 2) in 300 ml
%
DMF. The reaction rate was dependent on both temperature and
aziridine precursor concentration. Reducing the amount of precursor to
1 mg (in 300 ml solvent) halved the rate of reaction at 1208C with
complete reaction of [11C]cyanide in 8 min. Temperatures above 1208C
did not lead to a significant reduction in reaction time but led to a
reduction in the yield of the labelled intermediate, probably due to
hydrolysis of the ester function. Experiments using the unactivated
aziridine (1) demonstrated a marked reduction in reactivity, with 55%
%
of the radioactivity remaining as [11C]cyanide after 30 min heating at
1208C (Figure 1).
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912
N. M. GILLINGS AND A. D. GEE
Figure 1. Time dependence of [11C]cyanide consumption on reaction with
activated and unactivated aziridine precursors
Purification of the crude reaction mixture was achieved using reversed
phase HPLC (Figure 2). Following evaporation of the solvent in vacuo,
the labelled intermediate (Figure 2, b) was reduced and/or hydrolysed
to give the [4-11C]amino acids (426) (Scheme 1). The identity of
%
%
the labelled intermediate (d,l-[4-11C]b-cyanoalanine isopropyl ester
(3) was inferred based on the identity of the final products. There
%
was no evidence for the isolation of the N-Boc intermediate of (3),
%
which is assumed to be hydrolysed during the reaction. This
intermediate would be expected to be more strongly retained on
the preparative HPLC column. A 11C-labelled by-product (ca. 25%
of the total radioactivity, as determined by HPLC) which eluted after
(3) was, however, consistently observed (Figure 2, c). Collect-
%
ion and hydrolysis of this fraction gave unidentified labelled products
which did not correspond to a-amino acids. This by-product is proposed
to be the product of [11C]cyanide attack at the a-carbon of the aziridine
ring to give 3-amino-3-cyanopropionic acid isopropyl ester. The relat-
ive amounts of b and c (Figure 2) decreased with prolonged reaction
time or increased temperature, resulting in increased amounts of
more polar products (Figure 2, a). Optimization of these factors
gave a maximum yield (as a percentage of the total crude labelled
product) of 48% of d,l-[4-11C]b-cyanoalanine isopropyl ester (3).
%
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Copyright # 2001 John Wiley & Sons, Ltd.

SYNTHESIS OF [4-11C]AMINO ACIDS
913
Figure 2. Preparative HPLC purification of crude product using column A
(linear ordinates). a, hydrolysed products; b, d,l-[4-11C]b-cyanoalanine isopropyl
ester; c, unidentified 11C-labelled product. Chromatographic conditions are
described in the text
Typical syntheses starting with 10 GBq hydrogen [11C]cyanide yielded
1–1.4 GBq of [4-11C]amino acid within 30 min in 30–40% decay
corrected radiochemical yield. The final products were analysed using
chiral HPLC (Figure 3(a)–(c)). Product identities were confirmed by
co-injection of authentic reference solutions. Radiochemical purities
were 95% for 4, 98% for 5 and 60% for 6. The low radiochemical purity
%
%
%
of 6 was due to unidentified 11C-labelled products (possibly due to
%
over-reduction to 2,4-diamino-butan-1-ol). Amino acid concentrations
in the final products could not be measured due to their low UV
absorbance. The specific activities of the final products were, however,
estimated to be ca. 10–50 GBq/mmol at the end of synthesis, based on
the specific activity of hydrogen [11C]cyanide routinely produced in our
laboratory.
Chiral aziridines have, in many cases, been shown to undergo
ring-opening reactions without loss of stereochemical integrity.23–25
In order to examine the stereochemistry of this reaction, the racemic
aziridine precursor 2 was resolved by chiral HPLC. This gave a highly
%
enantiomerically enriched sample (96.5% e.e.) which was labelled
with [11C]cyanide, purified and hydrolysed to [11C]aspartate as
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N. M. GILLINGS AND A. D. GEE
Figure 3. Analytical chromatograms of product solutions of 4, 5 and 6 with added
reference. a – d-[4-11C]asparagine, b – l-[4-11C]asparagine, c – d-[4-11C]aspartic
acid, d – l-[4-11C]aspartic acid, e – d-[4-11C]-2,4-diaminobutyric acid, f – l-
[4-11C]-2,4-diaminobutyric acid (radioactivity is decay corrected and on a linear
scale). Chromatographic conditions are described in the text
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 909–920

SYNTHESIS OF [4-11C]AMINO ACIDS
915
before. Analysis by chiral HPLC, however, revealed a racemic
product. Chiral HPLC analysis of the initially formed 11C-labelled
product (3) before hydrolysis suggested that racemization occurred
%
during the ring-opening reaction. This racemization has been
noted previously25 and is attributed to the acidity of the b-
hydrogen. Attempts to avoid racemization by using the less polar
solvent, dibutyl ether, again produced a racemic product. There
exist, however, a number of chiral HPLC columns (see for
example Diacel Chiral HPLC catalogue) which could be utilized
for resolution of the produced racemic amino acids prior to in vivo
PET experiments.
Experimental
Materials and methods
All chemicals were obtained from Aldrich or Sigma Chemical
Companies unless otherwise stated. Anhydrous solvents for labelling
and other reactions (where anhydrous is stated) were supplied by
Aldrich in Sure/SealTM containers. HPLC grade solvents were supplied
by Aldrich Chemical Co. Ltd. or Merck. References samples of
aspartate, asparagine and 2,4-diaminobutyric acid (both l and d,l)
were obtained from Sigma. WatersTM Sep-Pak solid phase extraction
cartridges were obtained from Millipore Corporation. NMR data were
obtained using
a
Bruker 300 spectrometer (1H : 300.075MHz;
13C : 75.462 MHz). Chemical shifts are reported in ppm (d) relative to
TMS internal standard (d=0.00 ppm) for H and 13C. Mass spectra
1
were recorded using a Micromass 7070F spectrometer (EI+ve mode).
Preparative HPLC was performed using a Perkin-Elmer model 200
isocratic pump with a 1 ml injection loop connected in series with a
Phenomenex Nucleosil 5C18, 205 ꢀ 10 mm column (column A),
an Applied Biosystems 759A variable UV detector and a GM
tube radiodetector of in-house design. Analytical HPLC was per-
formed using a Perkin-Elmer model 250 pump with a 20 ml inject-
ion loop connected in series with either a Phenomenex Selectosil
SCX, 250 ꢀ 4.6 mm column (column B), a Daicel–Crownpak Cr+,
150 ꢀ 4 mm chiral column (column C) or a Daicel OD-H 250 ꢀ 4.6 mm
chiral column (column D), a Perkin-Elmer LC295variable wavelength
UV detector and a sodium iodide radiodetector of in-house design.
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916
N. M. GILLINGS AND A. D. GEE
Chiral analytical HPLC using the Crownpak column was performed at
a temperature of approximately 08C with the aid of a column cooler/
heater of in-house design. Column D was also used for preparative
chiral HPLC of the aziridine precursor. Labelling reactions were
performed using a fully automated synthesis unit described elsewhere.26
N-(tert-butoxycarbonyl)aziridine-2-isopropyl carboxylate (2)
%
To a solution of di-tert-butyl dicarbonate (1.69 g, 7.75mmol)
and triethylamine (0.78 g, 7.75mmol) in anhydrous DMF (5ml) a
solution of aziridine-2-isopropyl carboxylate (1.0 g, 7.75mmol) in
anhydrous DMF (2 ml) was added, dropwise with stirring. The resulting
solution was stirred at room temperature for 48 h. After addition of
dichloromethane (25ml), the mixture was extracted with saturated
aqueous sodium hydrogen carbonate (2 ꢀ 25ml), saturated aqueous
sodium chloride (25ml) and distilled water (25ml). The remaining
organic phase was dried over magnesium sulphate and evaporated in
vacuo to give N-(tert-butoxycarbonyl)aziridine-2-isopropyl carboxylate
1
as a clear oil (600 mg, 34%). d H (CDCl3) 1.28 (t, J=6.0 Hz, 6H,
(CH3)2), 1.45(s, 9H, (CH ) ), 2.37 (dd, J=1.6, 5.5 Hz, 1H, CH), 2.50
3 3
(dd, J=1.6, 3.3 Hz, 1H, CH), 2.97 (dd, J=3.3, 5.5 Hz, 1H, CH), 5.07
(sept, J=6.0 Hz, 1H, CH); d 13C (CDCl3) 21.7, 21.8 (2 ꢀ CH), 27.9
(CðCH3Þ3), 31.2 (CH), 35.1 (CH), 69.5 (CH2), 82.0 (C(CH3)3), 159.6
%
(C=O), 168.0 (C=O); m/z (super saturated) 230 (M+1) 186 (M-
CH(CH3)2), 174, 170 (M-OCH(CH3)2), 142 (M-CO2CH(CH3)2), 130
(M-Boc).
Production of hydrogen [11C]cyanide
[11C]carbon dioxide was produced via the 14N(p,a)11C reaction in a
nitrogen gas target (2% oxygen) with 16.5MeV proton bombardment,
using a General Electric Medical Systems PETtrace 200 cyclotron. On-
line conversion to hydrogen [11C]cyanide was achieved according to
previously reported procedures.27,28 Briefly, this process involves
reduction of [11C]carbon dioxide with hydrogen gas over a nickel
catalyst at 4008C to produce [11C]CH4, followed by reaction with
ammonia over a platinum catalyst at 10008C to produce hydrogen
[11C]cyanide which is delivered in a mixture of hydrogen and ammonia
at 50 ml/min.
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SYNTHESIS OF [4-11C]AMINO ACIDS
917
Synthesis of d,l-[4-11C]b-cyanoalanine isopropyl ester (3)
%
No-carrier-added (n.c.a.) hydrogen [11C]cyanide, produced as described
above, was bubbled through a solution of N-(tert-butoxycarbonyl)azir-
idine-2-isopropyl carboxylate (5mg, 21.9 nmol) in a 100 mM solution of
tetrabutylammonium hydrogen carbonate in anhydrous DMF (300 ml)
in a septum sealed 0.9 ml pear-shaped vial at room temperature. The
reaction vial was then placed in a heated aluminium block (1208C) for
4 min. The solution was subsequently diluted with 50 mM phosphoric
acid (500 ml) and the mixture injected onto a HPLC column (column A)
eluted with water:acetonitrile (85: 15) at 8 ml/min. The fraction
corresponding to the radioactive product was collected (rt=11 min)
and transferred to a rotary evaporator, where the solvent was removed
in vacuo.
Synthesis of d,l-[4-11C]asparagine (4)
%
d,l-[4-11C]b-cyanoalanine isopropyl ester (3) was dissolved in 100 mM
HCl (3 ml) and transferred to a glass tube, which was subsequently
%
heated at 1108C for 8 min. The solution was neutralized by passage
through a column of Dowex AG11 A8 ion exchange resin (5ml), which
was then flushed with a further 7 ml of distilled water to give a 10 ml
solution of d,l-[4-11C]asparagine (4). HPLC analysis was performed on
%
column C at ca. 08C eluting with perchloric acid (113.6 mM, pH 1.0) at
0.4 ml/min with on-line UV absorbance and radioactivity detection. The
two enantiomers (d and l) eluted at 4.3 and 6.1 min, respectively
(k0d=0.66; k0l =1.30; a=1.97; Rs=2.78), and the two radioactive peaks
were found to be of equal magnitude after decay correction of the data.
The radiochemical purity was found to be 95%. Product identities were
confirmed by co-injection of reference samples of racemic and l-
asparagine.
Synthesis of d,l-[4-11C]aspartic acid (5)
%
d,l-[4-11C]b-cyanoalanine isopropyl ester (3) was dissolved in 4 M HCl
(3 ml) and transferred to a glass tube, which was subsequently heated at
%
1108C for 10 min. The solution was neutralised by passage through a
column of Dowex AG11 A8 ion exchange resin (15ml), which was then
flushed with a further 7 ml of distilled water to give a 10 ml solution of
d,l-[4-11C]aspartic acid (5). HPLC analysis was performed on column C
%
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N. M. GILLINGS AND A. D. GEE
at ca. 08C eluting with perchloric acid (113.6 mM, pH 1.0) at 0.4 ml/min.
The two enantiomers (d and l) eluted at 5.6 and 10.4 min, respectively
(k0d=1.19; k0l=2.91; a=2.44; Rs=5.11), and the two radioactive peaks
were found to be of equal magnitude after decay correction of the data.
The radiochemical purity was found to be 98%. Product identities were
confirmed by co-injection of reference samples of racemic and l-aspartic
acid.
Synthesis of d,l-2,4-diamino-[4-11C]butyric acid (6)
%
d,l-[4-11C]b-cyanoalanine isopropyl ester (3) was dissolved in methanol
(2 ml) and transferred to a pressure tube containing cobalt chloride
%
(10 mg, 0.077 mmol) and sodium borohydride (30 mg, 0.793 mmol). The
mixture was shaken, then heated at 908C for 5min. The mixture was
subsequently quenched with concentrated HCl (1 ml) followed by
passage through a C18 WatersTM Sep-Pak (solid phase extraction
cartridge) to remove particulates and lipophilic impurities. The product
solution was diluted with distilled water and analysed without further
purification. HPLC analysis was performed on column C at ca. 08C
eluting with perchloric acid (113.6 mM, pH 1.0) at 0.4 ml/min. The two
enantiomers (d and l) eluted at 9.5and 16.3 min, respectively
(k0d=2.31; k0l=4.75; a=2.04; Rs=3.71), and the two radioactive peaks
were found to be of equal magnitude after decay correction of the data.
The radiochemical purity was ca. 60%. Product identities were
confirmed by co-injection of reference samples of racemic and l-2,4-
diaminobutyric acid.
Chiral HPLC purification
A solution of the aziridine carboxylate (ca. 50 mg/ml) was dissolved
in hexane:IPA (98 : 2) and injected onto column d, eluted with
hexane : IPA (98 : 2) at 0.75ml/min. The two enantiomers were well
separated (baseline separation, UV absorption, 200 nm) and fractions
were collected using a Gilson FC 203B fraction collector. This
procedure was repeated until sufficient quantities of enantiomerically
enriched aziridine were collected. Enantiomeric purity was determined
on dilute samples of the aziridine using the same HPLC column and
conditions.
Copyright # 2001 John Wiley & Sons, Ltd.
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SYNTHESIS OF [4-11C]AMINO ACIDS
919
Conclusion
We have reported here in full the first application of aziridine ring-
opening for the synthesis of 11C-labelled compounds. This method was
successful for the synthesis of three [4-11C]amino acids. Stereospecific
synthesis using a highly enantiomerically enriched aziridine-2-carbox-
ylate precursor was not achieved and only racemic amino acid products
were obtained.
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