Synthesis of [1-11C]propyl and [1-11C]butyl iodide from [11C]carbon monoxide and their use in alkylation reactions

Article abstract of DOI:10.1002/jlcr.1119

A method to prepare [1-¹¹C]propyl iodide and [1- ¹¹C]butyl iodide from [¹¹C]carbon monoxide via a three step reaction sequence is presented. Palladium mediated formylation of ethene with [¹¹C]carbon monoxide and

Full text of DOI:10.1002/jlcr.1119

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 1105–1116.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1119
Research Article
Synthesis of [1-11C]propyl and [1-11C]butyl iodide from
[11C]carbon monoxide and their use in alkylation
reactions
Jonas Eriksson1, Gunnar Antoni2 and Bengt Langstrom1,2,
*
¨
1 Department of Biochemistry and Organic Chemistry, BMC, Uppsala University,
PO Box 576, S-751 23 Uppsala, Sweden
2 Uppsala Imanet, PO Box 967, S-751 09 Uppsala, Sweden
Summary
A method to prepare [1-11C]propyl iodide and [1-11C]butyl iodide from [11C]carbon
monoxide via a three step reaction sequence is presented. Palladium mediated
formylation of ethene with [11C]carbon monoxide and hydrogen gave [1-11C]propio-
naldehyde and [1-11C]propionic acid. The carbonylation products were reduced and
subsequently converted to [1-11C]propyl iodide. Labelled propyl iodide was obtained
in 58 Æ 4% decay corrected radiochemical yield and with a specific radioactivity of
270 Æ 33 GBq/mmol within 15 min from approximately 12 GBq of [11C]carbon
monoxide. The position of the label was confirmed by 13C-labelling and 13C-NMR
analysis. [1-11C]Butyl iodide was obtained correspondingly from propene and
approximately 8 GBq of [11C]carbon monoxide, in 34 Æ 2% decay corrected radio-
chemical yield and with a specific radioactivity of 146 Æ 20 GBq/mmol. The alkyl
iodides were used in model reactions to synthesize [O-propyl-1-11C]propyl and
[O-butyl-1-11C]butyl benzoate. Propyl and butyl analogues of etomidate,
a
b-11-hydroxylase inhibitor, were also synthesized. Copyright # 2006 John Wiley &
Sons, Ltd.
Key Words: [11C]carbon monoxide; [1-11C]propyl iodide; [1-11C]butyl iodide; carbo-
nylation; formylation; alkylation
*Correspondence to: Bengt Langstrom, Department of Biochemistry and Organic Chemistry, BMC,
¨
Uppsala University, PO Box 576, S-751 23 Uppsala, Sweden. E-mail: Bengt.Langstrom@kemi.uu.se
Copyright # 2006 John Wiley & Sons, Ltd.

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J. ERIKSSON ET AL.
Introduction
The use of positron emission tomography (PET) in medical applications and
drug discovery1–3 has stimulated the development of labelling methods and
tracer molecules labelled with 11C (b+, t1=2=20.3 min) and other positron
emitting radionuclides. The main radiolabelled building blocks for tracer
synthesis, [11C]methyl iodide4–7 and [11C]methyl triflate8 have been used
extensively in alkylation reactions with nitrogen and oxygen nucleophiles.
Alkyl halides with longer alkyl chains prepared from Grignard reagents and
[11C]carbon dioxide, e.g. [1-11C]ethyl iodide, [1-11C]propyl iodide, [1-11C]iso-
propyl iodide and [1-11C]butyl iodide, have also been used but to lesser extent
and are typically obtained with moderate to low specific radioactivity.9–16 The
possibility of fine-tuning tracer characteristics by using different alkyl groups
have been an incentive to explore new synthetic methods for 11C-labelled ethyl,
propyl and butyl iodide that would give products with higher specific
radioactivity. Recently a method to synthesize [1-11C]ethyl iodide from
[11C]carbon monoxide was published which avoids reagents that potentially
lead to isotopic dilution.17 This method which utilized palladium mediated
carbonylation of methyl iodide followed by reduction and iodination has now
been modified in order to synthesize [1-11C]propyl iodide and [1-11C]butyl
iodide. Ethene and propene were considered to be promising starting materials
since carbonylation and formylation of olefins can be utilized in the synthesis
of carboxylic acids, esters and aldehydes.18–20 Carbonylation of olefins with
[11C]carbon monoxide has not been reported previously although various
11C-carbonylation reactions have been explored.21–28
In this paper we describe the synthesis of [1-11C]propyl iodide and
[1-11C]butyl iodide according to the method shown in Scheme 1.
[11C]Carbon monoxide and hydrogen is used in palladium mediated
formylation of ethene and propene to produce the corresponding [1-11C]alde-
hydes and [1-11C]carboxylic acids. The labelled carbonyl compounds were
reduced and subsequently converted to the corresponding [1-11C]alkyl iodides
and then applied in the labelling of esters.
Results and discussion
The first step in the synthesis of [1-11C]propyl iodide and [1-11C]butyl iodide,
i.e. the formation of the corresponding aldehyde and carboxylic acid, was
Scheme 1. Synthesis of [1-11C]propyl iodide and [1-11C]butyl iodide from
[11C]carbon monoxide
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1105–1116
DOI: 10.1002/jlcr

SYNTHESIS OF [1-11C]PROPYL AND [1-11C]BUTYL IODIDE
1107
Figure 1. Schematic drawing of the experimental setup used in the carbonylation
reactions
performed in a Teflon1 coated micro-autoclave using the experimental set-up
shown in Figure 1.29 [11C]Carbon monoxide was prepared via the reduction of
[11C]carbon dioxide over Zn at 4008C. It was concentrated to a small volume
on silica at À1968C and then transferred to a 200 ml cylindrical reaction
chamber, i.e. micro-autoclave, via an inlet at the bottom surface of the
chamber.
A palladium hydride complex was generated in tetrahydrofuran (THF) by
treatment of tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) with tri-
phenylphosphine (PPh3) and p-toluenesulfonic acid monohydrate (p-TsOH).
Pd2(dba)3 was used because of its excellent air stability compared to some
other Pd0-complexes and due to the ability to form hydride complexes with
PPh3 and acid that activates olefins towards insertion into the palladium–
hydride bond. The palladium hydride solution was transferred together with
the olefin and hydrogen into the micro-autoclave via a second inlet at the
bottom surface by use of a high-pressure pump (41 MPa). The high pressure
inside the micro-autoclave secured an efficient trapping of [11C]carbon
monoxide in the reaction mixture due to a very small gas phase volume.
Within the 3 min reaction time 11C-labelled aldehyde was obtained as shown in
Scheme 1. The corresponding labelled carboxylic acid was also obtained in
approximately equal amount, most likely through nucleophilic attack of water
Copyright # 2006 John Wiley & Sons, Ltd.
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DOI: 10.1002/jlcr

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J. ERIKSSON ET AL.
on the acyl palladium intermediate. A change from the monohydrate p-TsOH
to methyl sulfonic acid gave similar results. No desired product was obtained
when hydrogen was used without sulfonic acid present. Acidic conditions
without the addition of hydrogen resulted in the formation of labelled
carboxylic acid but no aldehyde was observed. These observations may
indicate that the aldehyde was formed via the insertion of the olefin into the
palladium hydride, generated by p-TsOH, followed by the insertion of
[11C]carbon monoxide into the palladium carbon bond and finally by the
reductive elimination induced by hydrogen.
The formylation reactions proceeded readily at a broad temperature range
from room temperature to 70 and 60 8C was used throughout the experiments.
Highest radiochemical yield for the formylation of ethene was obtained with
28 mmol of the olefin while the amount for propene was 170 mmol. Olefin and
hydrogen was in used in 1:1 molar ratio. The identity of the labelled aldehydes
were confirmed with analytical HPLC after derivatization with 2,4-dinitro-
phenylhydrazine.30 The radiochemical purity of the propyl and butyl
hydrazine derivatives was 47 and 28%, respectively.
The reaction mixture was transferred from the micro-autoclave to a vial
containing lithium aluminium hydride (LAH) where the carbonyl compounds
were reduced. Conversion to 11C-labelled alkyl iodide was carried out using
hydriodic acid similarly to previous procedures.5 In order to obtain the
labelled alkyl halide in good yield it was important to thoroughly remove the
THF from the reaction mixture before the addition of the hydriodic acid. This
was performed by flushing with nitrogen gas while heating the vial. The vial
containing the dry alkoxide salt was cooled down to sub-zero temperature
prior to the addition of the hydriodic acid to control the vigorous exothermic
reaction. The vial was then heated for 5 min at 130 8C during iodination
reaction. A closed reaction vessel was utilized to prevent the volatile alcohol
from escaping. After 5 min the resulting labelled alkyl halide was distilled off
and transferred in a stream of nitrogen gas through a drying tower
(phosphorus pentoxide desiccant) to a vial containing dimethylformamide
(DMF). The labelled alkyl halides were synthesized from [11C]carbon
monoxide within 15 min.
The decay-corrected radiochemical yield of [1-11C]propyl iodide trapped in
DMF was 58 Æ 4% based on the amount [11C]carbon monoxide in the
autoclave at the start of the synthesis. [1-11C]Propyl iodide accounted for
93 Æ 4% of the transferred radioactivity. [1-11C]Butyl iodide was obtained in
34 Æ 2% yield and with a radiochemical purity of 79 Æ 9%. The only labelled
by-product found was [11C]methyl iodide which was assumed to be derived
from the reoxidation of [11C]carbon monoxide to [11C]carbon dioxide in the
micro-autoclave. This may occur through the PdII promoted water–gas shift
reaction18,31 or a heterogeneous reaction with oxygen on the surface of the
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1105–1116
DOI: 10.1002/jlcr

SYNTHESIS OF [1-11C]PROPYL AND [1-11C]BUTYL IODIDE
1109
Scheme 2. Synthesis of [1-11C]propyl iodide from [11C]carbon monoxide, ethene
and water
autoclave.32 Zudin et al has reported inhibition of the water–gas shift reaction
at acidic conditions by the addition of hydrogen.33 Accordingly, when water
was used instead of hydrogen as shown in Scheme 2, the radiochemical purity
of [1-11C]propyl iodide was significantly decreased from 93% to 75%.
The radiochemical yield decreased moderately from 58 to 52%. Contrary to
when hydrogen was used, there was strong temperature dependence with a
maximum radiochemical yield at 708C. In the synthesis of the labelled alkyl
halides, highest radiochemical yield and best reproducibility was achieved by
using the formylation conditions. No labelled branched product was detected
in the formylation of propene when PPh3 was used. The regioselectivity was
reduced when 1,3-bis-(diphenylphosphino)propane was utilized giving labelled
n-butyl iodide and iso-butyl iodide in 10:1 ratio. The position of the
radioactive label on [1-11C]propyl iodide was confirmed with 13C-NMR
analysis after performing the synthesis with an isotope mixture of
[11C]/(11C)carbon monoxide.
The labelled alkyl halides were used in the synthesis of [O-propyl-
1-11C]propyl benzoate 1, [O-butyl-1-11C]butyl benzoate 2, [1-11C]propyl
1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate 3 and [1-11C]butyl 1-[(1R)-
1-phenylethyl]-1H-imidazole-5-carboxylate 4.
The specific radioactivity of the labelled benzoates and the isolated
radiochemical yield of the labelled compounds are presented in Table 1. The
alkylated products were obtained with >98% radiochemical purity after semi-
preparative HPLC purification (Figure 2).
The specific radioactivity of the labelled alkyl halides were estimated by
quantification of the corresponding labelled alkyl benzoates. The lowest
isotopic dilution was achieved when the amount of LAH used in the reduction
step was kept to a minimum without compromising the radiochemical yield.
This was probably due to trace amounts of impurities in the commercially
available stock solutions of LAH.
The temperature used in the evaporation of the THF prior to the addition of
hydriodic acid influenced the specific radioactivity for [1-11C]butyl iodide but
not for [1-11C]propyl iodide. Heating the vial at 120 8C rather than 60 8C
during the evaporation resulted in a significant increase of the amount butyl
iodide while there was a small change in the radiochemical yield. There is no
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1105–1116
DOI: 10.1002/jlcr

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J. ERIKSSON ET AL.
Table 1. Radiochemical yield, radiochemical purity and specific radioactivity
Entry
RCYa
(%)
RCPb
(%)
Product
amount
(nmol)
Specific
Initial
radioactivityc radioactivity
(GBq/mmol)
11CO (GBq)
[1-11C]Propyl iodide 58 Æ 4d (14)e 93 Æ 4%
}
}
270 Æ 33f (3)
146 Æ 20f (3)
162 Æ 20 (3)
}
}
[1-11C]Butyl iodide
34 Æ 2d (13) 79 Æ 9%
1
52 Æ 2h (6)
26 Æ 1h (4)
29 Æ 2h (4)
37 Æ 2h (2)
27 Æ 2h (2)
>98%
>98%
>98%
>98%
>98%
14 Æ 1 (3)
7.8 Æ 0.7 (3) 88 Æ 12 (3)
18 Æ 5 (3)
}
}
12.2 Æ 0.7 (3)
8.1 Æ 0.3 (3)
4.6 Æ 0.6 (3)
}
2g
2I
3
26 Æ 11 (3)
}
}
4
}
a Decay-corrected radiochemical yield based on the initial amount of radioactivity at the start of the
synthesis and the radioactivity of the isolated product. When the reaction mixture was transferred from the
micro-autoclave to the evacuated 2 ml vial containing LAH, the radioactivity in the vial was measured. The
radioactive residues left in the micro-autoclave were estimated to be less than 1%. Hence, the amount of
initial radioactivity could be determined.
b Radiochemical purity assessed with analytical HPLC, defined as the percentage of the total radioactivity
present in the specified chemical form.
c Specific radioactivity of the isolated product.
d Decay-corrected radiochemical yield of the alkyl halide transferred to the alkylation reaction.
e Number of experiments in brackets.
f Approximate value that was derived from the analysis of the corresponding labelled benzoic ester.
g Evaporation of THF at 608C prior to the addition of the hydriodic acid.
h Decay-corrected radiochemical yield of the isolated product.
i Evaporation of THF at 1208C prior to the addition of the hydriodic acid.
Figure 2. Products obtained via alkylation with [1-11C]propyl iodide and
[1-11C]butyl iodide
clear explanation for this observation. However, it may indicate that excessive
heating of minute amounts of THF in the presence of the lithium/aluminium
salt may have resulted in ring opening of THF and formation of butoxide. The
treatment of the alkoxide with hydriodic acid would then give butyl iodide.
Conventional ether cleavage of THF with hydriodic acid may be a less likely
source of isotopic dilution since is should result in the formation of
1,4-diiodobutane.34
Conclusion
Ethene and propene are feasible starting material for the synthesis of
[1-11C]propyl iodide and [1-11C]butyl iodide from [11C]carbon monoxide.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1105–1116
DOI: 10.1002/jlcr

SYNTHESIS OF [1-11C]PROPYL AND [1-11C]BUTYL IODIDE
1111
Formylation compared to hydroxycarbonylation gave higher radiochemical
yield, increased the radiochemical purity and decreased the temperature
dependence of the reaction. The syntheses performed using formylation
conditions resulted in labelled aldehydes and carboxylic acids which were
reduced and converted to alkyl iodides. [1-11C]Propyl iodide and [1-11C]butyl
iodide, obtained in 58 Æ 4% and 34 Æ 2% yield, respectively, were used in the
alkylation of benzoic acid. [O-propyl-1-11C]propyl benzoate was isolated in
30 min with a specific radioactivity of 162 GBq/mmol from 12.2 GBq of
[11C]carbon monoxide. The decay-corrected radiochemical yield was 52%.
[O-butyl-1-11C]Butyl benzoate was isolated in 30 min with a specific radio-
activity of 88 GBq/mmol from 8.1 GBq [11C]carbon monoxide and with an
decay corrected radiochemical yield of 26%. [1-11C]Propyl and [1-11C]butyl
1-(1-phenylethyl)-1H-imidazole-5-carboxylate were synthesized and purified
within 30 min from [11C]carbon monoxide with a decay-corrected radio-
chemical yield of 30 and 27%, respectively. The labelled imidazole derivates
are currently being investigated in preclinical experiments to evaluate their
potential usefulness as tracers.
Experimental
General
11C was prepared by the 14N(p,a)11C nuclear reaction using 17 MeV protons
produced by a Scanditronix MC-17 Cyclotron at Uppsala Imanet AB and
obtained as [11C]carbon dioxide. The target gas used was nitrogen
(AGA Nitrogen 6.0) containing 0.05% oxygen (AGA Oxygen 4.8). The
carbonylation reactions were carried out in a 200 ml Teflon1 coated micro-
autoclave using the experimental set-up described in Figure 1 and the
following procedure.29
[11C]Carbon dioxide (approximately 1–10 nmol) was carried in a stream of
nitrogen gas from the cyclotron to the CO2-trap containing Alltech silica gel
100/120 at À1968C. The CO2-trap was then flushed with helium gas at
20 ml minÀ1 for 1 min before it was warmed up and the [11C]carbon dioxide
was transferred in the gas stream through a quartz tube heated at 400 8C
containing zinc granules (Merck 14–50 mesh). [11C]Carbon dioxide was
reduced to [11C]carbon monoxide in the quartz tube. Any remaining trace of
[11C]carbon dioxide was subsequently removed by a column containing
Ascarite1. [11C]Carbon monoxide was transferred to the CO-trap where it was
trapped on Alltech 100/120 silica gel (1 mg) at À1968C. The V3-valve
connecting the CO-trap to the micro-autoclave was then switched to stop,
giving rise to a pressure build-up of approximately 400–500 kPa by the helium
carrier gas. The V4-valve was switched, connecting the autoclave to the
injection valves. The CO-trap was heated to release the [11C]carbon monoxide
Copyright # 2006 John Wiley & Sons, Ltd.
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J. ERIKSSON ET AL.
from the silica. By switching the V3-valve to the CO-trap, [11C]carbon
monoxide was transferred to the micro-autoclave by the pressure difference
over the valve. After the transfer, the V3-valve was switched to stop. The
reagents were then transferred from the reagent loops to the 200 ml micro-
autoclave by the pressure of THF pumped at 41 MPa. After 3 min reaction
time the mixture was transferred from the micro-autoclave to the product vial
by the switching of the V3-valve.
THF was freshly distilled over sodium and benzophenone in a nitrogen
atmosphere before use. The hydride palladium complex was generated in situ
from Pd2(dba)3, p-TsOH and PPh3. All chemicals were purchased from
Aldrich/Fluka and used as received. The 13C-NMR spectra were recorded
using a Varian 400 MHz spectrometer. The identities of compounds 3 and 4
were assessed using a Waters Quattro Premier triple quadrupole mass
spectrometer (Waters, Milford, MA, USA) with electrospray ionisation
operated in positive mode. The identities of the remaining labelled compounds
were determined with analytical HPLC using authentic samples as reference.
The concentrations of compounds 1 and 2 were assessed with analytical
HPLC. Analytical HPLC was performed on a Beckman system, equipped with
a Beckman 126 pump, a Beckman 166 UV detector in series with a Bioscan
b+-flow count detector and a Beckman Ultrasphere ODS dp 5 m column
(250 Â 4.6 mm). A Gilson 231 was used as auto injector. Purification with
semi-preparative HPLC was performed on a similar Beckman system
equipped with a Beckman Ultrasphere ODS dp 5 m column (250 Â 10 mm).
Mobile phase: A) 0.05 M ammonium formate pH 3.5 B) acetonitrile.
Synthesis of [1-11C]propyl iodide
Pd2(dba)3 (0.70 mg, 1.2 mmol), PPh3 (2.7 mg, 10 mmol, 8.6 eq.) and p-TsOH
(5.6 mg, 29 mmol, 24 Eq.) were placed in a 0.8 ml vial equipped with rubber
septum. THF (600 ml) was added and the resulting solution was degassed with
argon. The solution was loaded into an injection loop (200 ml). A second
injection loop was loaded with ethene (0.7 ml, 100 kPa, 28 mmol). A third
injection loop was loaded with hydrogen gas (0.7 ml, 100 kPa, 28 mmol). THF
was pumped through all three injection loops and the reagents were pumped
into a 200 ml Teflon1 coated stainless steel micro-autoclave containing
[11C]carbon monoxide. The reagents were kept in the autoclave for 3 min at
60 8C. The reaction mixture was then transferred to a 2 ml septum-equipped
evacuated glass vial containing LAH (100 ml, 1 M). The vial was heated at
1208C for 2–3 min during the removal of THF under a stream of nitrogen gas.
Then the vial was cooled down to sub-zero temperature using liquid nitrogen.
Hydriodic acid (1.0 ml, 57 wt% in water) was added and then the vial was
heated for 5 min at 1308C. The vial was removed from the heat source and
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1105–1116
DOI: 10.1002/jlcr

SYNTHESIS OF [1-11C]PROPYL AND [1-11C]BUTYL IODIDE
1113
while it was still warm [1-11C]propyl iodide was transferred in a stream of
nitrogen (30 ml minÀ1) through a drying tower (phosphorus pentoxide
desiccant) to a vessel containing DMF (300 ml). Analytical HPLC was used
to assess the identity and radiochemical purity. Mobile phase A:B (50:50).
Flow 1.5 ml minÀ1. [1-11C]Propyl iodide: Rt 7.3 min; [11C]methyl iodide:
Rt 4.2 min
Synthesis of [1-11C]propyl iodide utilizing water
The synthesis was performed as above with the following modifications. Water
(1.0 ml) was added to the carbonylation reaction instead of using hydrogen gas.
The micro-autoclave was heated for 3 min at 70 8C.
Synthesis of [1-11C]butyl iodide
The synthesis was performed as for [1-11C]propyl iodide with the following
modifications. The second injection loop was loaded with propene (0.7 ml,
600 kPa, 170 mmol). The third injection loop was loaded with hydrogen gas
(0.7 ml, 600 kPa, 170 mmol). The vial was heated at 60 8C for 3–4 min
alternatively 120 8C for 2–3 min during the removal of THF under a stream
of nitrogen gas. Analytical HPLC was used to assess the identity and radio-
chemical purity. Mobile phase A:B (35:65). Flow 1.5 ml minÀ1. [1-11C]Butyl
iodide: Rt 7.1 min; [11C]Methyl iodide: Rt 3.1 min.
Synthesis of (1-13C)propyl iodide
Pd2(dba)3 (0.70 mg, 1.2 mmol), PPh3 (2.7 mg, 10 mmol, 8.6 eq.) and p-TsOH
(3.9 mg, 20.5 mmol, 17 eq.) were placed in a 0.8 ml vial equipped with a rubber
septum. THF (450 ml) was added and the resulting solution was degassed with
argon. The solution (200 ml) was loaded into an injection loop. A second
injection loop was loaded with ethene (1.0 ml, 100 kPa). A third injection loop
was loaded with hydrogen gas (0.7 ml, 100 kPa). A fourth injection loop was
loaded with (13C)carbon monoxide (0.7 ml, 100 kPa). The reagents were
pumped with THF into a 200 ml Teflon1 coated micro-autoclave containing
[13C]carbon monoxide. The micro-autoclave was heated for 15 min at 70 8C.
The reaction mixture was then transferred to a 5 ml septa-equipped evacuated
glass vial containing LAH (150 ml, 1 M). The vial was heated at 120 8C for 2–
3 min during the removal of THF under a stream of nitrogen gas. Then the vial
was cooled down to sub-zero temperature. Hydriodic acid (1.0 ml, 57 wt% in
water) was added and then the vial was heated for 10 min at 130 8C. The vial
was removed from the heating and while it was still warm the labelled propyl
iodide was transferred in a stream of nitrogen (30 ml minÀ1) through a drying
tower (phosphorus pentoxide desiccant) and trapped in chloroform-d (0.8 ml)
at À408C. 13C-NMR was used to assess the position of the 13C-labelling.
Copyright # 2006 John Wiley & Sons, Ltd.
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1114
J. ERIKSSON ET AL.
(1-13C)Propyl iodide 13C-NMR MHz (CDCl3) d: 9.87; (13C)methyl iodide
13C-NMR MHz (CDCl3) d: À23.2.
Characterization of [1-11C]propionaldehyde and [1-11C]butyraldehyde via
derivatization with 2,4-dinitrophenylhydrazine
To a solution of 2,4-dinitrophenylhydrazine (1.2 mg, 6.2 mmol) and perchloric
acid (10 ml) in acetonitrile (1 ml) was added a sample (10 ml) from the
formylation reaction. Analytical HPLC was used to assess the identity and
radiochemical purity. Propyl derivate: Mobile phase A:B (40:60). Flow
1.5 ml minÀ1, Rt 8.68 min; Butyl derivate: Mobile phase A:B (30:70). Flow
1.5 ml minÀ1, Rt 7.44 min.
[O-propyl/butyl-1-11C]Propyl/Butyl benzoate (1/2)
In a 0.8 ml glass vial equipped with a rubber septum, benzoic acid (1.2 mg,
9.8 mmol) was dissolved in dichloromethane (200 ml) at room temperature.
Tetrabutylammonium hydroxide in methanol (4.8 ml, 1 M, 4.8 mmol) was
added. The solvent was removed under a stream of nitrogen. DMF (300 ml)
was added. The labelled alkyl iodide was transferred to the DMF solution in a
stream of nitrogen gas (30 ml minÀ1) through a drying tower (phosphorus
pentoxide desiccant. The vial was then heated for 5 min at 120 8C.
1. Semi-preparative HPLC mobile phase A:B (35:65). Flow 4 ml minÀ1, Rt
9.4 min. Analytical HPLC was used to assess identity and radiochemical
purity. Mobile phase A:B (40:60). Flow 1.0 ml minÀ1, Rt 9.7 min.
2. Semi-preparative HPLC mobile phase A:B (25:75). Flow 4 ml minÀ1, Rt
8.5 min. Analytical HPLC was used to assess the identity and radiochemical
purity. Mobile phase A:B (35:65). Flow 1.0 ml minÀ1, Rt 10.6 min.
[1-11C]propyl/butyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (3/4)
The synthesis was carried out by following the same procedure as for the
labelling of the benzoates 1 and 2. 1-(1-phenylethyl)-1H-imidazole-5-
carboxylic acid (1.2 mg, 5.5 mmol) was treated with tetrabutylammonium
hydroxide in methanol (5.6 ml, 1 M, 5.6 mmol). The labelled alkyl iodide was
transferred in a stream of nitrogen gas (30 ml minÀ1) to the glass vial and
bubbled through the solution. The vial was then heated for 5 min at 1208C.
3. Semi-preparative HPLC mobile phase A:B (34:66). Flow 4 ml minÀ1, Rt
7.2 min. Analytical HPLC was used to assess the radiochemical purity. Mobile
phase A:B (35:65). Flow 1.0 ml minÀ1, Rt 5.8 min. LC-MS(ES+): m/z = 259.
4. Semi-preparative HPLC. Mobile phase A:B (28:72). Flow 4 ml minÀ1, Rt
7.9 min. Analytical HPLC was used to assess the radiochemical purity.
Mobile phase A:B (30:70). Flow 1.0 ml minÀ1, Rt 6.1 min, LC-MS(ES+):
m/z = 273.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1105–1116
DOI: 10.1002/jlcr

SYNTHESIS OF [1-11C]PROPYL AND [1-11C]BUTYL IODIDE
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