The synthesis of a benzamidine-containing NR2B-selective NMDA receptor ligand labelled with tritium or fluorine-18

Article abstract of DOI:10.1002/jlcr.871

A novel tritium or flourine-18-labelled benzamidine-containing NR2B-selective NMDA receptor ligand has been synthesized. This compound was designed to contain the fluoromethoxy group to allow for the synthesis of a high specific activity, fluorine-18-labe

Full text of DOI:10.1002/jlcr.871

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 1–10.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.871
Research Article
The synthesis of a benzamidine-containing NR2B-
selective NMDA receptor ligand labelled with tritium
or fluorine-18
Terence G. Hamill1,*, John A. McCauley2 and H. Donald Burns1
1 Merck Research Laboratories, Imaging Research Department, WP44C-2, West Point,
PA 19486, USA
2 Merck Research Laboratories, Medicinal Chemistry Department, WP44C-2,
West Point, PA 19486, USA
Summary
A novel tritium or flourine-18-labelled benzamidine-containing NR2B-selective
NMDA receptor ligand has been synthesized. This compound was designed to
contain the fluoromethoxy group to allow for the synthesis of a high specific activity,
fluorine-18-labelled PET tracer for imaging studies of the NR2B receptor. In addition
to the fluorine-18-labelled compound, this compound was also tritium labelled. The
tritiated ligand (11 Ci/mmol) was synthesized by a gas tritiation reaction of an aryl
bromide precursor. The fluorine-18 ligand (2916 Ci/mmol), which was deuterated in
the fluoromethoxy group to aid in metabolic stability, was synthesized by alkylating a
phenolic precursor with [18F]fluoromethylbromide-d2. Copyright # 2004 John Wiley
& Sons, Ltd.
Key Words: fluorine-18; tritium; PET; NR2B; deuterium
Introduction
The NMDA receptor is highly expressed in the CNS and is comprised of a
minimum of two different subunits, NR1 and NR2. The NR1 subunit has at
least eight isoforms (NR1a–h) and the NR2 subunit has four distinct subtypes
(NR2A–D).1 It has been suggested that NR2B selective compounds may have
a reduced side-effect profile when compared to NMDA receptor antagonists,2
and have been shown to be efficacious in preclinical pain models.3,4 Among the
known NR2B-selective compounds are ifenprodil, CP-101,606, Ro-25-6981
and a novel series of benzamidines.5–8
*Correspondence to: T. G. Hamill, Merck Research Laboratories, Imaging Research Department, WP44C-
2, West Point, PA 19486, USA. E-mail: terence hamill@merck.com
Copyright # 2004 John Wiley & Sons, Ltd.
Received 23 January 2004
Revised 26 April 2004
Accepted 18 May 2004

2
T. G. HAMILL ET AL.
OH
N
OH
O11CH3
H
N
N
O
*
N
CH3
11C]Methoxy CP101,606
H
HO
[
11C]5-[3-(4-benzylpiperidin-1-yl)prop--1-ynyl]-1,3-
dihydrobenzo-imidazol-2-one (*=11C)
[
Figure 1.
NH
NH
NH
Cl
Cl
Cl
N
H
N
H
N
D
D
H
F3CO
F
O
18F
O
Cl
X
Cl
Cl
1
2c
2a, X=H
2b, X=T
Figure 2.
A suitable NR2B-selective PET tracer would be extremely useful, making
receptor imaging studies possible. At present no such ligand exists. The
synthesis of a carbon-11-labelled analog of CP-101, 606 (Figure 1) has been
reported,9 although in vivo studies showed no apparent specific binding in
mouse and monkey brains. More recently, [11C]5-[3-(4-benzylpiperidin-1-
yl)prop-1-ynyl]-1,3-dihydrobenzo-imidazol-2-one (Figure 1), which has high
affinity and selectivity for the NR2B subtype (IC50 5.3 nM) has also been
reported,10 but this tracer suffered from low and uniform brain uptake in rats
and did not exhibit specific binding.
We were interested in developing NR2B-selective PET tracers for receptor
occupancy studies of unlabelled NR2B-selective antagonists, and a fluorine-
18-labelled tracer was attractive to us. Because of the longer half-life of
flourine-18, as compared to carbon-11 (110 vs 20 min), longer imaging times
with a fluorine-18-labelled tracer would be possible if the in vivo kinetics
required longer times for a specific signal to develop. Based on the
benzamidine class of compounds,8 we have synthesized the fluorine-18-
labelled tracer 2c (Figure 2) for PET imaging studies and the tritium-labelled
tracer 2b for in vitro studies.
Results and discussion
The known trifluoromethoxy-containing compound 18 is a high affinity
(Ki 0.6 nM), NR2B-selective compound with a log P value of 2.9. Due to the
lack of methods for producing high specific activity [18F]trifluoromethoxy
groups, and with the possibility of synthesizing high specific activity
[18F]fluoromethoxy containing compounds,11,12 we thought compound 2a, if
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 1–10

THE SYNTHESIS OF A LABELLED NMDA RECEPTOR LIGAND
3
it maintained affinity and selectivity, could be labelled with fluorine-18 and
would make an attractive NR2B-selective PET tracer. The lipophilicity of 2a
would also be expected to be less than that of 1.
Compound 2a was synthesized as shown in Scheme 1. Commercially
available cyanophenol 3 was alkylated using chlorofluoromethane in DMF
with cesium carbonate as the base. The resulting nitrile 4 was converted to 2a
via the Pinner synthesis.13 Compound 2a was found to have an NR2B Ki value
of 1.5 nM14 and a log P value of 0.9. This compound also maintained its
selectivity for the NR2B subtype (NR2B Ca2+ influx IC50 (nM) 3.4. NR2A
Ca2+ influx IC50 (nM) >10; 000. See Reference7 for details.). Encouraged by
these properties, we proceeded to synthesize 2b and 2c for use in in vitro/in vivo
assays and imaging studies.
NH
CN
CN
Cl
N
H
a
b,c
HO
F
O
F
O
Cl
3
4
2a
Scheme 1. (a) FCH2Cl, DMF, Cs2CO3, RT, (b) EtOH, HCl (g), 08C–RT,
(c) 3,5-dichlorobenzylamine, Et3N, EtOH, RT
Scheme 2 shows the route followed for synthesizing 2b, the tritium-labelled
ligand. As in Scheme 1, commercially available 5 was alkylated using
chlorofluoromethane. Conversion of 6 to the imidate and coupling with 3,5-
dichlorobenzylamine gave 7, the bromo-containing benzamidine precursor for
the tritiated ligand. Model tritiation reactions using hydrogen gas in the
1
presence of triethylamine led to loss of the aryl chlorides as shown by H
NMR and mass spectral analysis. Eliminating triethylamine from the reaction
NH
CN
CN
Cl
N
H
a
b,c
HO
F
O
F
O
Br
Br
X
d
Cl
5
6
7, X=Br
2b, X=T
Scheme 2. (a) FCH2Cl, DMF, Cs2CO3, RT, (b) EtOH, HCl (g), 08C–RT,
(c) 3,5-dichlorobenzylamine, EtOH, RT, (d) T2, 10% Pd/C, DMF
Copyright # 2004 John Wiley & Sons, Ltd.
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T. G. HAMILL ET AL.
mixture eliminated this side reaction. The gas tritiation reaction was carried
out to give crude 2b, which had a radiochemical purity of ꢀ95%. Purification
of the tracer gave 2b with a specific activity of 11 Ci/mmol and > 98%
radiochemical purity.
The route used for the synthesis of the fluorine-18-labelled ligand 2c is
shown in Scheme 3. As in Scheme 1, nitrile 3 was converted to the imidate and
then coupled with 3,5-dichlorobenzylamine to give the phenolic precursor 8.
Because the fluoromethyl group can be metabolically labile (for benzyl fluoride
see Reference15; for S-fluoromethyl see Reference16; for stable O-fluoromethyl
see Reference17)15–17 we routinely synthesize [18F]fluoromethoxy-containing
tracers12 with deuterium incorporated into the methylene group to slow
defluorination.18,19 By substituting commercially available dibromomethane-
d2 for dibromomethane, [18F]FCD2Br was synthesized and used in the
alkylation reaction. In this manner, high specific activity 2c was synthesized by
alkylating 8 with [18F]FCD2Br at 1008C in DMF for 5 min with cesium
carbonate as the base. After HPLC purification, 2c was isolated with a
radiochemical purity of >98% and a specific activity of 2916 Ci/mmol as
measured by HPLC. The uncorrected radiochemical yield from starting
fluoride was ꢀ5% (24 syntheses). When carrying out this reaction,
rather than distilling the [18F]FCD2Br until the amount of radioactivity in
the precursor vessel peaked, and thus optimizing the radiochemical yield, the
distillation was generally carried out until there was sufficient
[18F]FCD2Br trapped to synthesize the amount of 2c needed for the
planned study. The overall radiochemical yields, starting from [18F]Fꢁ,
ranged from ꢀ2 to 10%, with the lower yields resulting from a partial
distillation. In cases where the amount of trapped [18F]FCD2Br was counted
(n ¼ 22), the radiochemical yield of 2c based on [18F]FCD2Br trapped was
27% (range 7–48%).
NH
NH
CN
Cl
Cl
a,b
N
N
e
D D
18FCD2Br
c,d
+
H
H
HO
18F
O
HO
Cl
Cl
3
8
2c
18F-
Scheme 3. (a) EtOH, HCl (g), 08C–RT, (b) 3,5-dichlorobenzylamine, EtOH,
RT, (c) K2CO3, Kryptofix222, MeCN, (d) CD2Br2, MeCN, 958C, (e) Cs2CO3,
DMF, 1008C, 5 min
Conclusion
We have synthesized the NR2B-selective NMDA ligands 2b and 2c for use in
in vitro/in vivo studies of the NR2B receptor system. The tritiated ligand was
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 1–10

THE SYNTHESIS OF A LABELLED NMDA RECEPTOR LIGAND
5
synthesized from the corresponding aryl bromide by catalytic gas tritiation to
give 2b with a specific activity of 11 Ci/mmol. The deuterium containing
fluorine-18-labelled compound was synthesized by alkylating the correspond-
ing phenol with [18F]FCD2Br to give 2c with a specific activity of 2916 Ci/
mmol. The in vitro and in vivo characterization of these ligands will be reported
elsewhere.
Experimental
Materials and methods
1H NMR spectra were recorded using a Varian Unity Inova 400 spectrometer
or a Varian Infinity-300 spectrometer. Samples provided for accurate mass
measurement were taken up in acetonitrile:water:glacial acetic acid
(50:50:0.1%v/v). The solutions were analyzed by use of electrospray ionization
(ESI) or atmospheric pressure chemical ionization (APCI) on either a Bruker
Daltonics 3T or 7T Fourier transform ion cyclotron resonance (FTICR)
mass spectrometer. External calibration was accomplished with polypropy-
lene glycol (425 or 750). Melting points were taken using a Thomas
Hoover capillary melting point apparatus or a Fisher Scientific hot stage
melting point apparatus and are uncorrected. Analytical and preparative
HPLC was carried out using a Waters 600E Powerline Multi Solvent Delivery
System with 100 ml heads, a Rheodyne 7125 injector, a Waters 990 Photodiode
Array Detector and a Gilson FC203 Microfraction collector. The aceto
nitrile used for the HPLC purification and analyses was Fisher Optima
grade. The [18F]Fꢁ was purchased from PETNet Pharmaceuticals Inc.,
North Wales, PA and was delivered on an anion-exchange resin. The
HPLC radiodetector used was either a Beckman 171 Radioisotope detector
with a Beckman 110B solvent delivery system and Beckman Ready Flow III
scintillation cocktail (tritium) or a photodiode radiodetector (Pharmacia-
Biotech, fluorine-18). For HPLC purification of the tritiated ligand, a Vydac
C18 Protein and Peptide column (4.6 ꢂ 250 mm, 5 mm, The Nest Group) was
used, and for HPLC purification of the fluorine-18 ligand, a C18 mBondapak
column, (7.8 ꢂ 300 mm, 10 mm, Waters) was used. Solutions of tritium
radioactivity were concentrated using a Jouan vacuum centrifuge. Calibration
curves and chemical concentrations used to determine the specific activity
of the tritium-labelled compound was determined using a Hewlett
Packard Model 8452A UV/Vis Diode Array Spectrophotometer.
Sample radioactivities were determined in an LKB Wallac 1410 liquid
scintillation counter. The identity of labelled compounds was determined by
HPLC coelution with authentic compounds. The chlorofluoromethane was
purchased from Synquest and all other reagents were purchased from Aldrich
Chemical Co.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 1–10

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T. G. HAMILL ET AL.
Nonradioactive syntheses
4-(Fluoromethoxy)benzonitrile (4). To a solution of 4-cyanophenol 3 (4.0 g,
33.6 mmol) in DMF (50 ml) was added cesium carbonate (21.9 g, 67.2 mmol).
In a separate flask, chlorofluoromethane (6.9 g, 100 mmol) was condensed at
ꢁ788C. The condensed chlorofluoromethane was transferred via canula to the
4-cyanophenol solution. The reaction mixture was stirred at room temperature
for 22 h at which time HPLC analysis showed complete conversion. The
reaction mixture was partitioned between Et2O and water and the layers
separated. The organic layer was washed with brine, dried over MgSO4,
filtered and concentrated to give 4-fluoromethoxy-benzonitrile (4) as a clear oil
1
(4.6 g, 91% yield): H NMR (400 MHz, CDCl3) d 7.65 (d, J ¼ 9:0 Hz, 2 H),
7.15 (d, J ¼ 9:0 Hz, 2 H), 5.76 (d, J ¼ 53:6 Hz, 2 H) ppm; HRMS (APCI) m/z
152.0505 [(M+H)+; calcd. for C8H7FNO: 152.0506].
N-(3,5-Dichlorobenzyl)-4-(fluoromethoxy)benzenecarboximidamide (2a). A
solution of 4-fluoromethoxy-benzonitrile 4 (3.0 g, 19.9 mmol) in EtOH (40 ml)
under N2 was cooled to 08C. HCl (g) was bubbled through the solution for
10 min and the solution was warmed to room temperature and stirred for 1 h.
The reaction mixture was concentrated, diluted with Et2O, sonicated for 5 min
and filtered to give the corresponding imidate salt as a white solid.
To a solution of the imidate salt in EtOH (20 ml) at ambient temperature
was added 3,5-dichlorobenzyl amine (3.49 g, 19.9 mmol) and triethylamine
(3 ml). After 4 h, the reaction mixture was concentrated and purified by
reverse-phase HPLC. The TFA salt of 2a was partitioned between EtOAc/
NaHCO3, dried and evaporated to give the free base. A solution of HCl/Et2O
(7.0 ml, 7.0 mmol) was then added to a CH2Cl2 (10 ml) solution of the free base
(2.3 g, 7.0 mmol). The mixture was sonicated and filtered to give the HCl salt
1
of 2a as a white solid (2.2 g, 30% yield, 2 steps): mp ¼ 21222138C; H
NMR (400 MHz, MeOH-d4) d 7.81 (d, J ¼ 8:8 Hz, 2 H), 7.50 (s, 1 H), 7.43
(s, 2 H), 7.33 (d, J ¼ 8:8 Hz, 2 H), 5.88 (d, J ¼ 53:4 Hz, 2 H), 4.68 (s, 2 H) ppm;
HRMS (APCI) m/z 327.0439 [(M+H)+; calcd. for C15H14Cl2FN2O:
327.0462].
3-Bromo-4-(fluoromethoxy)benzonitrile (6). To a solution of 2-bromo-4-
cyanophenol 5 (4.0 g, 20.2 mmol) in DMF (50 ml) was added cesium carbonate
(13.1 g, 40.4 mmol). In a separate flask, chlorofluoromethane (6.9 g, 100 mmol)
was condensed at ꢁ788C. The condensed chlorofluoromethane was transferred
via canula to the 2-bromo-4-cyanophenol solution. The reaction mixture was
stirred at room temperature for 48 h and was partitioned between Et2O and
water and the layers separated. The organic layer was washed with 1 M
aqueous NaOH, water, brine, dried over MgSO4, filtered and concentrated to
give 3-bromo-4-(fluoromethoxy)benzonitrile (6) as a white solid (3.0 g, 64%
Copyright # 2004 John Wiley & Sons, Ltd.
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THE SYNTHESIS OF A LABELLED NMDA RECEPTOR LIGAND
1
7
yield): mp ¼ 104–1058C; H NMR (400 MHz, CDCl3) d 7.89 (d, J ¼ 2:0 Hz,
1 H). 7.63 (dd, J ¼ 8:6, 2.0 Hz, 1 H), 7.24 (d, J ¼ 8:6 Hz, 1 H), 5.81 (d,
J ¼ 53:0 Hz, 2 H) ppm.
3-Bromo-N-(3,5-dichlorobenzyl)-4-(fluoromethoxy)benzenecarboximidamide
(7). A solution of 3-bromo-4-(fluoromethoxy)benzonitrile
6 (600 mg,
2.61 mmol) in EtOH (10 ml) under N2 was cooled to 08C. HCl (g) was
bubbled through the solution for 10 min and the solution was warmed to room
temperature and stirred for 15 h. The reaction mixture was concentrated,
diluted with Et2O, sonicated for 5 min and filtered to give the corresponding
imidate salt as a white solid.
To a solution of the imidate salt in EtOH (5 ml) at room temperature was
added 3,5-dichlorobenzyl amine (460 mg, 2.61 mmol) and triethylamine
(0.5 ml). After 3 h, the reaction mixture was concentrated and purified by
reverse-phase HPLC. The TFA salt of 7 was partitioned between EtOAc/
NaHCO3, dried and evaporated to give the free base. A solution of HCl/Et2O
(1.06 ml, 1.06 mmol) was then added to a CH2Cl2 (2 ml) solution of the free
base (430 mg, 1.06 mmol). The mixture was sonicated and filtered to give the
HCl salt of 7 as a white solid (400 mg, 35% yield, 2 steps): mp ¼ 206–2078C;
1H NMR (400 MHz, MeOH-d4) d 8.11 (d, J ¼ 2:4 Hz, 1 H), 7.82 (dd, J ¼ 8:7,
2.4 Hz, 1 H), 7.49–7.44 (m, 4 H), 5.94 (d, J ¼ 52:8 Hz, 2 H), 4.67 (s, 2 H);
HRMS (APCI) m/z 404.9529 [(M+H)+; calcd. for C15H13BrCl2FN2O:
404.9567].
N-(3,5-Dichlorobenzyl)-4-hydroxybenzenecarboximidamide (8). A solution of
4-cyanophenol 3 (500 mg, 4.2 mmol) in ethanol (10 ml) was cooled to 08C and
HCl (g) was bubbled through the reaction mixture. The solution was stirred at
08C for 1 h and at room temperature for 1 h, giving a white opaque mixture.
The mixture was filtered, rinsed with diethyl ether and dried to give the
corresponding imidate salt (470 mg, 56% yield) as a white solid.
A portion of this material (100 mg, 0.50 mmol) was added to ethanol
(2 ml), giving a slurry, and treated with 3,5-dichlorobenzylamine (88 mg,
0.50 mmol) and triethylamine (0.25 ml). After 3 h, the reaction mixture
was concentrated and purified by reverse-phase HPLC. The TFA salt
of 8 was partitioned between EtOAc/NaHCO3, dried and evaporated to
give the free base. A solution of HCl/Et2O (0.31 ml, 0.31 mmol) was then
added to a CH2Cl2 (1 ml) solution of the free base (93 mg, 0.31 mmol).
The mixture was sonicated and filtered to give the HCl salt of 8 as a white
solid (90 mg, 54% yield): mp ¼ 108–1118C; 1H NMR (400 MHz, MeOH-d4) d
7.67 (d, J ¼ 8:7 Hz, 2 H), 7.47 (s, 1 H), 7.40 (s, 2 H), 6.97 (d, J ¼ 8:7 Hz, 2 H),
4.66 (s, 2 H) ppm; HRMS (APCI) m/z 295.0405 [(M+H)+; calcd. for
C14H13Cl2N2O: 295.0399].
Copyright # 2004 John Wiley & Sons, Ltd.
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T. G. HAMILL ET AL.
Radioactive syntheses
[3H]N-(3,5-Dichlorobenzyl)-4-(fluoromethoxy)benzenecarboximidamide (2b).
A room temperature solution of 7 (5.9 mg, 0.011 mmol) in DMF (1.6 ml)
was treated with 10% Pd/C (3.7 mg). The reaction vessel and its contents
were degassed by cooling with dry ice/acetone and evacuating quickly and
was then exposed to tritium gas (5 Ci). After 110 min at room temperature
and atmospheric pressure, the reaction was passed through a short column
of celite and rinsed with DMF (3 ꢂ 1 ml) and methanol (3 ꢂ 1 ml). The
solvents were removed in vacuo and labile tritium was washed out by
evaporation with methanol (3 ꢂ 2 ml). The residue was dissolved in ethanol
(20 ml) to give 208 mCi of activity. An aliquot (7 mCi) was concentrated in
vacuo, dissolved in ethanol (75 ml) for purification by HPLC (Vydac C18
Protein and Peptide column, 4.6 ꢂ 250 mm, 5 mm, 1 ml/min, 20 min linear
gradient of 10% MeCN:H2O(0.1% TFA) to 90% MeCN, 254 nm). Fractions
(0.2 ml) were collected and the product eluted at ꢀ17 min. Fractions
containing the most radioactivity were analyzed by HPLC and the center
cut was combined, concentrated in vacuo and diluted with ethanol (4 ml) to
give 3.2 mCi of 2b with a specific activity of 11 Ci/mmol and a radiochemical
purity > 98%.
N-(3,5-Dichlorobenzyl)-4[18F]-(fluoromethoxy)benzenecarboximidamide-d2 (2c).
The resin containing the [18F]Fꢁ was eluted with 1.5 ml of a solution of
80:20 MeCN:Oxalate solution [0.05 ml of (200 mg K2C2O4/3 mg K2CO3/5 ml
H2O)+0.25 ml H2O+1.2 ml MeCN] and transferred to the reaction
vessel giving 475 mCi of activity. A solution (0.2 ml) of Kryptofix222
(36 mg/ml MeCN) was added and the mixture was heated to 958C under
vacuum and argon flow to dryness. Additional aliquots of MeCN (3 ꢂ 0.7 ml)
were used to further dry the [18F]Fꢁ. A solution of CD2Br2 (0.05 ml) in MeCN
(1 ml) was added and the mixture was heated at 958C. Argon flow was used to
distill the [18F]FCD2Br into a 08C mixture of 8 (0.3 mg) in DMF (0.2 ml)
containing Cs2CO3 (ꢀ1–2 mg). When the amount of trapped activity was
sufficient, the mixture was heated at 1008C for 5 min. The reaction was diluted
with H2O (0.7 ml) and purified by HPLC (Waters C18 mBondapak,
7.8 ꢂ 300 mm, 10 mm, 3 ml/min, 254 nm, 30 min linear gradient, 10%
MeCN:95:5:0.1 H2O:MeCN:TFA to 80% MeCN, product elutes at
ꢀ20.5 min). The product fraction was collected in a heated round bottom
flask attached to a rotary evaporator, the solvent was removed and the
product was transferred to a vial using physiologic saline to give 42 mCi of 2c
in a synthesis time of 1 h. An aliquot (0.5 ml) was removed, counted and
allowed to decay. The mass contained in the aliquot was determined by HPLC
(254 nm) against a calibration curve of the standard to give a specific activity
of 2916 Ci/mmol.
Copyright # 2004 John Wiley & Sons, Ltd.
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THE SYNTHESIS OF A LABELLED NMDA RECEPTOR LIGAND
9
Acknowledgements
The authors thank Dr. Charles W. Ross, III and Ms. Joan S. Murphy for
determination of high resolution mass spectra, Mr. Matthew Zrada for
determining the log P value of 2a, and Chemsyn Science Laboratories for
carrying out the gas tritiation reactions.
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