Preparation of 4-[11C]methylmetaraminol, a potential PET tracer for assessment of myocardial sympathetic innervation

Article abstract of DOI:10.1002/jlcr.642

The false adrenergic neurotransmitter [¹¹C]meta-hydroxyephedrine ([¹¹C]HED) is currently the PET tracer of choice for assessment of myocardial sympathetic innervation. The molecule is metabolised in the 4-position of the aromatic rin

Full text of DOI:10.1002/jlcr.642

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 55–65.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.642
Research Article
Preparation of 4-[11C]methylmetaraminol, a
potential PET tracer for assessment of
myocardial sympathetic innervation
2
1
3
Oliver Langer1,5,*, Tobias Forngren , Johan Sandell , Frederic Dolle ,
! !
!
2
Bengt Langstrom , Kjell Nagren and Christer Halldin
1 Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet,
4
1
(
.
(
Karolinska Hospital, S-17176 Stockholm, Sweden
2 PET Centre, Uppsala University, S-751 85 Uppsala, Sweden
3
! ! ! !
Service Hospitalier Frederic Joliot, CEA/DSV, 4 Place du General Leclerc,
F-91406 Orsay, France
4 Radiopharmaceutical Chemistry Laboratory, Turku PET Center,
Porthaninkatu 3, FIN-20500 Turku, Finland
5 Department of Clinical Pharmacology, Vienna University Medical School,
. .
Wahringergurtel 18-20, 1090 Vienna, Austria
Summary
The false adrenergic neurotransmitter [11C]meta-hydroxyephedrine ([11C]HED)
is currently the PET tracer of choice for assessment of myocardial sympathetic
innervation. The molecule is metabolised in the 4-position of the aromatic ring.
The resulting radiolabelled metabolites need to be measured in order to obtain
an arterial input function. Our aim was the development of a PET tracer with
an increased metabolic stability relative to [11C]HED. We selected 4-
methylmetaraminol as a candidate molecule for radiolabelling with 11C (t1/2
20.4 min). Our radiosynthetic approach towards 4-[11C]methylmetaraminol
involved a palladium-catalyzed cross-coupling reaction of a protected 4-
trimethylstannyl derivative of metaraminol with [11C]methyl iodide followed
by removal of the protective groups. 4-[11C]methylmetaraminol was obtained
in a final decay-corrected radiochemical yield of 20–25% within a synthesis
*Correspondence to: O. Langer, Department of Clinical Pharmacology, Vienna University Medical
.
School, Wahringergurtel 18-20, 1090 Vienna, Austria. E-mail: Claus.Oliver.Langer@univie.ac.at
.
Copyright # 2002 John Wiley & Sons, Ltd.
Received 10 May 2002
Revised 9 July 2002
Accepted 24 July 2002

56
O. LANGER ET AL.
time of 60–80 min. The specific radioactivity at the end of the synthesis ranged
from 18–37 to GBq/mmol. The unlabelled reference molecule, 4-methylmetar-
aminol, was prepared in a 5-step synthesis starting from metaraminol. A
biological evaluation of 4-[11C]methylmetaraminol is in progress and the
results will be reported elsewhere. Copyright # 2002 John Wiley & Sons, Ltd.
Key Words: 4-[11C]methylmetaraminol; sympathetic nervous system; heart;
positron emission tomography; stille coupling
Introduction
Metaraminol ((1R,2S)-2-amino-1-(3-hydroxyphenyl)-1-propanol, 1,
Figure 1) is a structural analogue of norepinephrine, the endogenous
neurotransmitter of the sympathetic nervous system. Due to a high
affinity towards presynaptic uptake mechanisms (Michaelis–Menten
constant, Km, for uptake into rabbit heart slices: 1.0 mM1) and its
metabolic stability 1 has served as a lead structure for developing PET
tracers to assess cardiac sympathetic innervation.2,3 The molecule was
initially labelled with 18F in an electrophilic radiolabelling approach.4,5
However, this approach suffered from low specific radioactivity of the
radiotracer (0.04–0.56 GBq/mmol4), which consequently did not permit
a safe use in human applications. More recently, labelling approaches
with 11C or no-carrier-added 18F have been elaborated6–9; however,
these approaches are rather complex as they involve multi-step reactions
and enantiomeric resolution. The N-methyl analogue of 1, [11C]meta-
hydroxyephedrine ([11C]HED, Figure 1), can be synthesized by simple
methylation of 1 with [11C]methyl iodide and has therefore become the
PET tracer of choice for cardiac neuronal imaging.10,11
The lack of the catechol function and the presence of an a-methyl
group render both 1 and [11C]HED resistant against metabolism by
OH
OH
OH
HO
NH2 HO
NHCH3
HO
NH2
H3C
Metaraminol (1)
Meta-hydroxyephedrine (HED)
4-Methylmetaraminol (2)
-
-
Figure 1. Chemical structures of metaraminol (1), meta-hydroxyephedrine
(HED) and 4-methylmetaraminol (2)
Copyright # 2002 John Wiley & Sons, Ltd.
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PREPARATION OF 4-[11C]METHYLMETARAMINOL
57
catechol-O-methyl transferase and monoamine oxidase, the two main
enzymes responsible for metabolic degradation of catecholamines.12
Nevertheless, a considerable number of radiolabelled metabolites occur
in human plasma following intravenous administration of [11C]HED
(about 48% of total radioactivity in human plasma at 20 min after
injection of [11C]HED represents radiolabelled metabolites11), thus
making the routine determination of plasma metabolites necessary.10
The metabolic degradation of [11C]HED is assumed to occur by
hydroxylation in the 4-position of the aromatic ring.12–14 From this
perspective we considered the introduction of a substituent in the 4-
position of compound 1 as a promising strategy for obtaining a PET
tracer with improved metabolic stability. We selected the 4-methyl
derivative of 1, 4-methylmetaraminol (2, Figure 1), as a candidate
molecule for labelling with carbon-11 (t1/2 20.4 min).
In this work, we report the carbon-11 radiolabelling of 2 via a
palladium-catalyzed cross-coupling reaction of a stannylated derivative
of 1 with [11C]methyl iodide.
Results and discussion
Compound 2 was synthesized as shown in Figure 2. Commercially
available 1 was first iodinated with I2 in NH4OH/EtOH/H2O according
to a literature procedure to obtain 4-iodometaraminol (3) in an yield
of 85% (5). Compound 3 was then treated with benzyl chloride to
afford tribenzyl derivative 4 in 18% non-optimized yield. The benzyl
protective group was chosen because of its stability and fast and easy
removal by catalytic hydrogenation.15 In order to determine the
position of the benzyl protective groups, nuclear overhauser effect
spectroscopy experiments were run in CDCl3. These experiments
showed a correlation peak between the region for the methylene
protons (d=4.7–4.9 ppm) and the proton in the 2-position of the
aromatic ring (d=6.67 ppm), thus indicating the benzyl protective
group to be located on the phenolic hydroxyl group and not on the
benzyl alcohol. The proton attached to the benzyl alcohol
(d=4.66 ppm) showed correlation between protons in both the 2- and
6-positions (d=6.67 and 6.58 ppm, respectively) of the aromatic ring.
Derivative 4 was converted into the trimethylstannyl compound 5 by
reaction with hexamethyldistannane (Sn2Me6) and tetrakis(triphenyl-
phosphine)palladium(0) [(Ph3P)4Pd] in 61% yield (9). Compound 5 was
Copyright # 2002 John Wiley & Sons, Ltd.
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O. LANGER ET AL.
OH
OH
BnCl
HO
NH2
HO
NH2
I2, NH4OH
K2CO3
EtOH/H2O, RT
DMF, 110˚C
I
3
1
-
-
85%
18%
OH
OH
Sn2Me6
(Ph3P)4Pd
BnO
NBn2
BnO
Sn
NBn2
Dioxane, 110˚C
I
5
4
-
-
61%
CH3I, Pd2(dba)3, (o-Tol)3P,
(CH3)4Sn, Pd2(dba)3,
DMF, 100˚C
B
A
CuCl, K2CO3, DMF, 80˚C
12%
21%
OH
OH
Pd / C
HO
NH2
BnO
H3C
NBn2
NH4HCOO
MeOH, reflux
H3C
6
2
-
-
67%
Figure 2. Synthesis of labelling precursor 5 and unlabelled reference molecule
4-methylmetaraminol (2)
then reacted with methyl iodide catalyzed by tris(dibenzylideneacetone)-
dipalladium(0) [Pd2(dba)3] and tri(o-tolyl)phosphine [(o-Tol)3P] to-
gether with copper(I) chloride (CuCl) and potassium carbonate
(K2CO3) in DMF, which afforded the 4-methyl-substituted compound
6 in 21% yield.16 Alternatively, 4 was reacted with tetramethyltin
[(CH3)4Sn] and Pd2(dba)3 to give 6 in a yield of 12% (Figure 2). The
removal of the benzyl protective groups was accomplished by refluxing
6 in CH3OH with ammonium formate and palladium on charcoal to
give 2 in a yield of 67%.
For the radiolabelling, a pathway was pursued that involves a
palladium-catalyzed reaction between an organic stannane and a halide
resulting in 11C–C bond formation (Stille coupling, Figure 3).16 This
pathway has previously been used for the synthesis of various other
PET radiotracers.17–20 Derivative 5 was reacted for 10 min at 1108C
with [11C]CH3I in DMF containing a mixture of Pd2(dba)3, (o-Tol)3P,
CuCl and K2CO3, which corresponds to the optimized radiolabelling
conditions described by Bjorkman et al.,18 to afford intermediate [11C]-6
.
in an incorporation yield of 30–40%. After purification by solid-phase
extraction [11C]-6 was deprotected with NH4HCOO/Pd(0) in CH3OH
(>90% conversion yield) to give, after semipreparative high perfor-
mance liquid chromatography (HPLC) purification, radiochemically
Copyright # 2002 John Wiley & Sons, Ltd.
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PREPARATION OF 4-[11C]METHYLMETARAMINOL
OH
59
OH
BnO
NBn2
BnO
Sn
NBn2
[
11C]CH3I, Pd2(dba)3
(o-Tol)3P, CuCl,
H3*C
K2CO3, DMF, 110˚C
[
11C]-6
5
-
-
30-40%
* : [11C]
OH
Pd / C
HO
NH2
NH4HCOO
MeOH, 110˚C
H3*C
[
11C]-2
-
90%
Figure 3. Radiosynthesis of 4-[11C]methylmetaraminol ([11C]-2)
and chemically pure (>95%) [11C]-2. Compound [11C]-6 as well as
[11C]-2 coeluted with authentic samples of unlabelled 6 and 2,
respectively. The final decay-corrected radiochemical yield of [11C]-2
was 20–25% and the total synthesis time including HPLC purification
ranged from 60 to 80 min. The specific radioactivity at the end of the
synthesis was 18–37 GBq/mmol.
Experimental
General
Radiochemistry. [11C]CO2 was produced at the Karolinska Hospital/
Institute with a Scanditronix MC-16 cyclotron and at the Uppsala
University PET Centre with a Scanditronix MC-17 cyclotron using the
14N(p,a)11C reaction. [11C]CH3I was prepared from [11C]CO2 either (A)
via [11C]CH4 by catalytic gas-phase iodination in a GEMS MeI
PETtrace MicroLab (Karolinska)21 or (B) via [11C]CH3OH using
a semiautomated system for production of radiopharmaceuticals
(Uppsala).22,23
HPLC was performed using a Beckman 126 pump and a Beckman
166 UV detector in series with a b+-flow detector. Data collections were
performed using a Beckman System Gold Chromatography Software
Package for semipreparative HPLC and a Beckman System Nouveau
Chromatography Software Package for analytical HPLC. A C-18
Beckman Ultrasphere ODS 5 mm (250 Â 10 mm) column was used
for semipreparative HPLC and a Beckman Ultrasphere ODS 5 mm
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O. LANGER ET AL.
(250 Â 4.6 mm) column was used for analytical HPLC. Mobile phases
were 50 mM aqueous NaH2PO4 (A), methanol (B) and acetonitrile (C).
The HPLC was performed at room temperature and the wavelength for
UV-detection was 280 nm. The semipreparative HPLC purification of
the crude reaction mixture was performed at a flow rate of 4 ml/min
with the following gradient time program: 0–3 min, (A:B, v:v) 90:10
isocratic; 3–8 min, (A:B) 90:10–55:45; 8–14 min, (A:B) 55:45 isocratic;
14–16 min, (A:B) 55:45–5/95; 16–20 min, (A:B) 5:95 isocratic. Analytical
HPLC was performed at a flow rate of 1.5 ml/min employing the
following gradient time programs. Method A: 0–5 min, (A:C, v:v) 40:60
isocratic; 5–6 min, (A:C) 40:60–30:70; 6–10 min, (A:C) 30:70 isocratic.
Method B: 0–4 min, (A:C, v:v) 95:5 isocratic; 4–10 min, (A:C)
95:5–80:20; 10–12 min, (A:C) 80:20–5:95; 12–15 min, (A:C) 5:95
isocratic.
Chemistry. (-)-Metaraminol (1) bitartrate was purchased from Sigma-
Aldrich, Sweden AB. Other chemicals were obtained from standard
commercial sources and were of analytical grade. Analytical TLC was
run on pre-coated plates of silica gel 60 F254 (Merck). The compounds
were localized using an UV-lamp at 254 nm and/or by dipping the TLC
plates into an aqueous KMnO4 solution (1%) and heating on a hot
plate. Flash chromatography was conducted on silicagel of 63–200 mm
(Merck). 1H NMR spectra were recorded on Bruker DRX500 or
DRX600 spectrometers using the hydrogenated residue of the
deuteriated solvents (CDCl3, d=7.24 ppm; DMSO-d6, d=2.49 ppm)
and/or TMS as internal standards. The chemical shifts (d) are reported
in ppm, downfield from TMS (s, d, dd, bd, t, m, bm for singlet, doublet,
doublet of doublet, broad doublet, triplet, multiplet and broad
multiplet, respectively). Electro spray time of flight mass spectra
(TOF MS ES+) were recorded on an AutoSpec-OATOFFPD
(Micromass, Manchester, UK) double focusing high resolution tandem
mass spectrometer.
Chemistry
(1R,2S)-2-amino-1-(3-hydroxy-4-iodophenyl)-1-propanol (4-iodometar-
aminol, 3). To a solution of metaraminol (1) bitartrate (2 g, 6.3 mmol)
in NH4OH (10 M, 200 ml), iodine (1.6 g, 6.5 mmol) dissolved in absolute
ethanol (120 ml) was added dropwise over a period of 45 min. The
reaction mixture was stirred in the dark at room temperature for 12 h.
Copyright # 2002 John Wiley & Sons, Ltd.
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PREPARATION OF 4-[11C]METHYLMETARAMINOL
61
The ethanol was then removed under vacuum and the aqueous residue
extracted with ethyl acetate. After washing of the combined organic
layers with brine and drying (Na2SO4) concentration to dryness
afforded the title compound (1.6 g, 85% yield) in the form of a
yellowish solid. Compound 3 was used in the following step without
further purification: Rf 0.15–0.20 (CHCl3/CH3OH/28% NH4OH,
80/20/1); 1H NMR (DMSO-d6) d 0.93 (d, J 7.6 Hz, 3 H), 2.93 (m, 1 H),
4.31 (d, J 6.1 Hz, 1 H), 6.62 (d, J 7.1 Hz, 1 H), 6.98 (s, 1 H), 7.65 (d, J
7.1 Hz, 1 H); TOF MS ES+ (C9H12INO2):294.0 [M+H+].
(1R,2S)-2-N,N-dibenzylamino-1-(3-benzyloxy-4-iodophenyl)-1-propanol
(4). To a solution of compound 3 (1.6 g, 5.5 mmol) in DMF (20 ml)
K2CO3 (1.3 g, 10 mmol) and benzyl chloride (3.5 g, 27.5 mmol) were
added and the reaction mixture was heated at 1008C for 2 h. The
reaction mixture was cooled and diluted with H2O (100 ml). Extraction
with CH2Cl2, washing of the combined organic layers with brine, drying
(Na2SO4) and concentration to dryness yielded a dark oil. Silica gel
flash chromatography purification (heptane/ethyl acetate, 95/5–90/10)
afforded the title compound (0.57 g, 18% yield) in the form of fluffy
1
white crystals: Rf 0.40–0.45 (heptane/ethyl acetate, 80/20); H NMR
(CDCl3) d 1.11 (d, J 6.9 Hz, 3 H), 3.06 (m, J 6.5 Hz), 3.47 (d, J 14.1 Hz,
2 H), 3.71 (d, J 14.1 Hz, 2 H), 4.66 (d, J 6.5 Hz, 1 H), 4.77 (d, J 11.7 Hz,
1 H), 4.89 (d, J 11.7 Hz, 1 H), 6.58 (dd, J 8.1 Hz & 1.6 Hz, 1 H), 6.67 (d, J
1.6 Hz, 1 H), 7.15–7.50 (m, 15 H), 7.68 (d, J 8.1 Hz, 1 H); TOF MS ES+
(C30H30INO2) : 564.0 [M + H+].
(1R,2S)-2-N,N-dibenzylamino-1-(3-benzyloxy-4-trimethylstannylphenyl)
-1-propanol (5). To a solution of 4 (0.45 g, 0.8 mmol) in dioxane (20 ml)
tetrakis(triphenylphosphine)palladium (49 mg, 0.043 mmol) and hexam-
ethyldistannane (0.34 g, 1.0 mmol) were added. The reaction mixture
was refluxed under nitrogen overnight, cooled and filtered. The filtrate
was diluted with ethyl acetate (100 ml), washed with H2O and brine,
dried (Na2SO4) and concentrated to dryness to afford a yellow oil that
was purified by silica gel flash chromatography (heptane/EtOAc, 100/0–
90/10) to give the title compound (293 mg, 61% yield) in the form of
1
white crystals: Rf 0.50–0.55 (heptane/ethyl acetate, 80/20); H NMR
(CDCl3) d 0.21 (s, with tin satellites: 2J[119Sn–H] 56.2 Hz & 2J [117Sn–H]
53.5 Hz, 9 H), 1.15 (d, J 6.7 Hz, 3 H), 3.08 (m, J 6.8 Hz, 1 H), 3.51 (d, J
14.0 Hz, 2 H), 3.75 (d, J 14.0 Hz, 2 H), 4.70 (d, J 11.0 Hz, 1 H), 4.75 (d, J
6.0 Hz, 1 H), 4.79 (d, J 11.0 Hz, 1 H), 6.69 (s, with tin satellites: 2J[Sn–H]
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O. LANGER ET AL.
18.2 Hz, 1 H), 6.85 (dd, J 7.8 and 1.3 Hz, 1 H), 7.10–7.75 (m, 16 H); TOF
MS ES+ (C33H39NO2Sn) : 606.1, 604.1, 602.1, 601.1, 600.1, 599.1,
598.1 [M+H+] for Sn isotopes of 124, 122, 120, 119, 118, 117 and 116,
respectively.
(1R,2S)-)-2-N,N-dibenzylamino-1-(3-benzyloxy-4-methylphenyl)-1-pro-
panol (6). Approach A: Tris(dibenzylideneacetone)dipalladium(0)
(3.0 mg, 3.4 mmol), tri(o-tolyl)phosphine (4.0 mg, 13.4 mmol), copper(I)
chloride (1.4 mg, 14.1 mmol) and potassium carbonate (1.8 mg,
13.0 mmol) were dissolved in DMF (0.3 ml) and the solution was stirred
and purged with N2 for 30 min at room temperature. Then compound 5
(32 mg, 53.3 mmol) dissolved in DMF (0.2 ml) and methyl iodide
(142 mg, 1.0 mmol) were added and the mixture heated at 808C for
24 h. The reaction mixture was then cooled, diluted with H2O (10 ml)
and extracted with CH2Cl2. After washing of the combined organic
layers with brine, drying (Na2SO4) and concentration to dryness,
a brownish solid was obtained. The crude product was purified
by semipreparative HPLC [column: Waters mBondapak C18
(300 Â 7.8 mm, 10 mm); eluent: 0.01 M aqueous phosphoric acid/
acetonitrile 50/50; flow rate: 6 ml/min; UV detection at l:280 nm]. The
product was collected at Rt 6.0–6.5 min. The combined HPLC fractions
were made alkaline with aqueous ammonia, the acetonitrile removed
in vacuo and the aqueous residue extracted with CH2Cl2. Washing with
brine, drying (Na2SO4) and concentration to dryness yielded pure title
compound (5 mg, 21% yield) in the form of a white solid: Rf 0.45–0.50
1
(heptane/ethyl acetate, 80/20); H NMR (CDCl3) d 1.13 (d, J 6.7 Hz,
3 H), 2.27 (s, 3 H), 3.08 (m, J 6.4 Hz, 1 H), 3.47 (d, J 13.8 Hz, 2 H), 3.72
(d, J 13.8 Hz, 2 H), 4.70 (d, J 6.4 Hz, 1 H), 4.72 (d, J 11.3 Hz, 1 H), 4.83
(d, J 11.3 Hz, 1 H), 6.70 (d, J 0.7 Hz, 1 H), 6.73 (dd, J 7.8 and 0.7 Hz,
1 H), 7.08 (d, J 7.8 Hz, 1 H), 7.15–7.45 (m, 15 H); TOF MS
ES+(C31H33NO2): 452.2 [M+H+].
Approach B: Tris(dibenzylideneacetone)dipalladium(0) (7 mg,
7.9 mmol) and tetramethyltin (78 mg, 436 mmol) were dissolved in
DMF (0.3 ml). The solution was stirred and purged with N2 for
30 min at room temperature. Then, compound 4 (41 mg, 72.8 mmol)
dissolved in DMF (0.2 ml) was added and the mixture heated at 1008C
for 2 days. Work up of the reaction and semipreparative HPLC
purification were performed as described under approach A to yield
pure compound 6 (4 mg, 12% yield).
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PREPARATION OF 4-[11C]METHYLMETARAMINOL
63
(1R,2S)-2-amino-1-(3-hydroxy-4-methylphenyl)-1-propanol (4-methyl-
metaraminol, 2). To a solution of compound 6 (15 mg, 33.3 mmol) in
CH3OH (5 ml), ammonium formate (40 mg, 0.63 mmol) and palladium
on carbon (5% Pd, 10–20 mg) were added. The reaction mixture was
refluxed for 2 h, and then cooled, filtered and concentrated to dryness to
afford the title compound (4 mg, 67% yield) as an oily residue: 1H NMR
(CDCl3) d 0.97 (d, J 6.5 Hz, 3 H), 2.25 (s, 3 H), 3.20 (bm, w1/2 11 Hz,
1 H), 4.48 (bd, w1/2 12 Hz, 1 H), 6.76 (d, J 7.6 Hz, 1 H), 6.80 (s, 1 H), 7.08
(d, J 7.6 Hz, 1 H); TOF MS ES+ (C10H15NO2): 182.2 [M+H+].
Radiochemistry
(1R,2S)-2-N,N-dibenzylamino-1-(3-benzyloxy-4-[11C]methylphenyl)-1-
propanol ([11C]-6). A solution of tris(dibenzylideneacetone)dipalla-
dium(0) (1.2 mg, 1.3 mmol) and tri(o-tolyl)phosphine (1.5 mg, 4.9 mmol)
in DMF (200 ml) was prepared in a dry 0.8 ml septum-equipped vial and
purged with N2 gas for 5 min. [11C]CH3I was passed through a Sicapent
drying tower and trapped in the solution at room temperature. After
trapping, the solution was transferred to a septum-equipped vial
containing compound 5 (1.6 mg, 2.7 mmol), copper(I) chloride (1.2 mg,
12.1 mmol) and potassium carbonate (1.4 mg, 10.1 mmol) dissolved in
DMF (100 ml). The latter mixture had been dissolved in DMF and
purged with N2 just prior to the transfer of the trapped [11C]CH3I. The
reaction vial was then shaken vigorously and heated at 1108C for
10 min. The conversion of [11C]CH3I into [11C]-6 was determined by
analysing an aliquot of the reaction mixture on analytical HPLC
[method A: Rt ([11C]-6) 7.5–8 min, Rt ([11C]CH3I) 2–3 min (void
volume)].
(1R,2S)-2-amino-1-(3-hydroxy-4-[11C]methylphenyl)-1-propanol (4-
[11C]methylmetaraminol, [11C]-2). The reaction mixture from the
Stille coupling was diluted with H2O (3.5 ml) and passed through a
Supelco LC-18 cartridge that had been washed with methanol (10 ml)
and H2O (20 ml) prior to use. The cartridge was washed with H2O
(1.5 ml) and eluted with methanol (2 ml) into a vial containing
ammonium formate (40 mg, 0.63 mmol) and palladium on carbon (5%
Pd, 10–20 mg). The vial was sealed and heated for 10 min at 1108C. The
conversion of [11C]-6 into [11C]-2 was determined on analytical HPLC
[method A: Rt ([11C]-6) 7.5–8.0 min, Rt ([11C]-2) 2–3 min (void volume);
method B: Rt ([11C]-2) 9.5–10.0 min]. The reaction mixture was filtered
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O. LANGER ET AL.
over a Supelco LC-18 cartridge that was then washed with methanol
(3 ml). The filtrate was concentrated to dryness under vacuum, dissolved
in 50 mM aqueous NaH2PO4/methanol (90/10, 4 ml) and injected on the
semipreparative HPLC system. Derivative [11C]-2 was collected at Rt
10–12 min. The methanol from the HPLC fraction was removed
in vacuo and the aqueous residue passed through a Millipore filter
(0.22 mm). The radiochemical purity and specific radioactivity of
[11C]-2 were determined by HPLC (method B: Rt ([11C]-2) 9.5–10.0 min).
Conclusion
With the aim to develop a metabolically stable PET tracer to assess
myocardial sympathetic innervation 4-[11C]methylmetaraminol ([11C]-2)
was prepared by a 2-step radiochemical pathway.
Acknowledgements
This work was performed within the COST B12 working group 2
‘Radioligands for Heart Receptors’.
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