Synthesis and Radiosynthesis of a Novel NMDA Ligand Labelled with Carbon-11

Full text of DOI:10.1002/jlcr.652

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 139–149.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.652
Research Article
3
14
Synthesis of H and C labeled (S)-
3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-
3-fluoro-6-(trifluoromethyl)-2H-indol-
2-one, MaxiPostTM. An agent for
post-stroke neuroprotection
Douglas D. Dischino1,*, Valentin K. Gribkoff2, Piyasena Hewawasam3,
George M. Luke4, J. Kent Rinehart4, Tony L. Spears5 and
John E. Starrett Jr3
1 Department of Chemical Synthesis, Bristol-Myers Squibb,
5 Research Parkway, Wallingford, CT 06492-7600, USA
2 Neuroscience Drug Discovery, Bristol-Myers Squibb, 5 Research Parkway,
Wallingford, CT 06492-7600, USA
3 Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway,
Wallingford, CT 06492-7600, USA
4 Department of Chemical Synthesis, Bristol-Myers Squibb, Rt. 206 &
Provinceline Road, Princeton, NJ 08540, USA
5 Analytical Research and Development, Bristol-Myers Squibb,
5 Research Parkway, Wallingford, CT 06492-7600, USA
Summary
The syntheses of tritium labeled (S)-3-(5-chloro-2-[OC3H3]methoxyphenyl-1,
3-dihydro-3-fluoro-6-(trifluoromethyl)-1H-indol-2-one, and carbon-14 (S)-3-
(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-
[2,3-14C2] indol-2-one are reported. The 3H-labeled compound was prepared in
a two-step synthesis from C3H3I. The final product was purified via chiral
HPLC to yield the desired enantiomer in a 4% radiochemical yield and a
specific activity of 60 Ci/mmol. The 14C-labeled compound was prepared in a
*Correspondence to: D. D. Dischino, Department of Chemical Synthesis, Bristol-Myers Squibb,
5 Research Parkway, Wallingford, CT 06492-7600, USA. E-mail: douglas.dischino@bms.com
Copyright # 2002 John Wiley & Sons, Ltd.
Received 19 June 2002
Revised 6 August 2002
Accepted 16 August 2002

140
D. D. DISCHINO ET AL.
four-step synthesis from diethyl [carboxylate-14C1,2] oxalate. The final product
was purified via chiral HPLC to yield the desired enantiomer in a 20%
radiochemical yield and a specific activity of 28.4 mCi/mg. Copyright # 2002
John Wiley & Sons, Ltd.
Key Words: neuroprotection; stroke; maxipostTM; tritium; carbon-14
Introduction
Stroke represents one of the largest disease states for which there
remains significant unmet medical need. In the United States alone,
there are more than 700,000 new cases each year.1 Stroke can be
classified as being either hemorrhagic in origin, resulting from vessel
rupture, or ischemic in origin resulting from vessel occlusion.
Approximately 85% of all strokes are ischemic in origin. In acute
ischemic stroke, a core area of severely damaged tissue located distal to
an occluded vessel, is surrounded by a penumbra of tissue at risk
because of proximity to the core and as a result of the low vascular
perfusion to the tissue.2 At the location of insult, the resulting hypoxia
results in release of an extraordinary level of excitatory neurotrans-
mitters resulting in pathologically high intracellular levels of calcium
(Ca2+). Our approach to neuroprotective therapy, has been to augment
the opening of a particular type of potassium channel, the large-
conductance maxi-K Ca2+-dependent potassium channel. These
channels constitute an intrinsic mechanism for controlling Ca2+ entry
into the cell, and as such, are an attractive target for reducing
potentially pathogenic levels of Ca2+ entry following stroke.3 The
ultimate goal of our approach is to rescue ischemically threatened but
potential viable tissue in the penumbra which surrounds the core of
infarcted tissue in acute stroke.
BMS-204352, 1a, MaxipostTM is a potent and selective opener of
maxi-K channels and is a clinical candidate for post-stroke neuropro-
3
tection (Figure 1).4,5 Herein, we report the synthesis of 14C and H-
labeled BMS-204352 as radioligands which have been used in studying
the pharmacokinetics and biodistribution of MaxipostTM
.
Results and discussion
Synthesis of 1b was accomplished in a two-step synthesis starting from
tritium labeled methyl iodide (Scheme 1). In the first reaction, the
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 139–149

SYNTHESIS OF 3H AND 14C LABELED
141
Figure 1. 1a, MaxipostTM
Scheme 1. Synthesis of (S)-3-(5-chloro-2-[OC3H3]methoxyphenyl)-1,3-dihydro-
3-fluoro-6-(trifluoromethyl)-2H-indol-2-one, 1b
phenolic hydroxyl of 2 was selectively methylated with tritium labeled
methyl iodide. In order to optimize the yield of 3, the methylation of 2
was carried out under a variety of conditions with non-radioactive
material. The major issue to be addressed with this approach was
the instability of 2 under the basic conditions necessary for the
methylation. In the presence of base, 2 undergoes dehydration to the
corresponding quinonemethide intermediate which subsequently de-
composed to a complex mixture of products. We evaluated several base/
solvent pairs for this methylation including NaH/DMF, K2CO3/
acetone, Ag2CO3/acetone–H2O, aqueous NaOH/phase-transfer cata-
lyst/CH2Cl2, Et4NF Á xH2O/DME, K2CO3/DMF, and CsCO3/DMF
with K2CO3/DMF, or CsCO3/DMF providing higher yields of 3, with
fewer side products. Yields of 3 were slightly better with CsCO3/DMF
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 139–149

142
D. D. DISCHINO ET AL.
(53%) as compared to K2CO3/DMF (48%). Fluorination of 3
with DAST yielded the racemic material which was then purified via
chiral HPLC.
Synthesis of the carbon-14 labeled MaxipostTM 1c, was achieved in a
four-step synthesis from diethyl [carboxylate-14C1,2] oxalate (Scheme 2).
In this reaction, 3-(trifluoromethyl)aniline was protected as the
t-Boc derivative and then reacted with diethyl [carboxylate-14C1,2]
oxalate. Rigorous anhydrous conditions were essential for obtaining
satisfactory yields of the intermediate keto-ester 12. Deprotection of
the keto-ester with 3 N HCl followed by reflux for 6 h yielded the 6-
(trifluoromethyl)[2,3-14C2]isatin 13. The sodium salt of 13 was then
allowed to react with the Grignard reagent 9 prepared from 2-bromo-4-
chloroanisole 8 to yield the penultimate product 14, 3-(5-chloro-2-
methoxyphenyl)-3-hydroxy-2,3-dihydro-6-(trifluoromethyl)-2H-[2,3-14C2]
indol-2-one. Fluorination of 14 with DAST afforded the racemic product
15 which was purified on a semi-preparative Chiralpak OD column to
yield the desired enantiomer 1c in a 20% radiochemical yield and with a
specific activity of 28.4 mCi/mg.
Scheme 2. Synthesis of carbon-14 labeled (S)-3-(5-chloro-2-methoxyphenyl)-1,
3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one[2,3-14C2], 1c
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 139–149

SYNTHESIS OF 3H AND 14C LABELED
143
Materials and methods
All experimental conditions were optimized using non-labeled materials.
All reagents were obtained from Aldrich and were either ACS grade or
the highest quality material commercially available. The radiosynthesis
of 3 was carried out at Vitrax. Carbon-14 labeled diethyl oxalate
[carboxylate-14C1,2] was purchased from Vitrax. The identity of
intermediates and final product was established by co-elution of the
radiolabeled material with authentic unlabeled compound on HPLC.4,6
Radioactive TLC analysis was obtained using a Bioscan QC Scan
system. HPLC purification and analysis was performed on a
Rainin Dynamax HPLC system consisting of two SD-200 pumps, a
Rainin UV-1 detector and an INUS b-RAM radioactive flow through
detector. Radiochemical purity was determined by HPLC. The specific
activity of the tritiated samples were determined via HPLC. In this
procedure, a radioactive sample was applied to the column, and the
mass was determined by comparison of the UV absorbance to a
standard curve and the total radioactivity was measured via liquid
scintillation counting. Specific activity of the carbon-14 samples were
determined gravimetrically with liquid scintillation counting.
High performance liquid chromatography
Method A: Samples were loaded on a Zorbax C18 column
(4.6 Â 250 mm2) equilibrated with 50% CH3CN/50% H2O containing
0.1% TFA. The flow rate through the column was 1 ml/min and the
sample was monitored by both UV (230 nm) and radioactivity.
Method B: Samples were loaded on a Chiralcel OD column
(4.6 Â 250 mm2) equilibrated with 90% hexane/10% isopropanol. The
flow rate through the column was 1 ml/min and the sample was
monitored by both UV (220 nm) and radioactivity.
Method C: Samples were loaded on a YMC-Pack PVA-SIL NP
column (4.6 Â 250 mm2) equilibrated with 99% CH2Cl2/1% CH3OH.
The flow rate through the column was 1 ml/min and the sample was
monitored by both UV (245 nm) and radioactivity.
Method D: Samples were loaded on a Chiralcel OD column
(20 Â 250 mm2, 10 mm) equilibrated with 90% hexane/10% isopropanol.
The flow rate through the column was 6 ml/min and the sample was
monitored by both UV (220 nm) and radioactivity.
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 139–149

144
D. D. DISCHINO ET AL.
Method E: Samples were loaded on a YMC-Pack ODS-A column,
(150 Â 6 mm2) equilibrated with 70% CH3CN/30% H2O containing
0.1% TFA. The flow rate through the column was 1 ml/min and the
sample was monitored by both UV (220 nm) and radioactivity.
Experimental
3-(5-chloro-2-[OC3H3]methoxyphenyl-3-hydroxy-1,3-dihydro-6-
(trifluoromethyl)-2H-indol-2-one, 3
%
3-(5-Chloro-2-hydroxyphenyl)-3-hydroxy-1,3-dihydro-6-(trifluoro-
methyl)-2H-indol-2-one4, 2, (3.5 mg, 0.01 mmol) and cesium carbonate
(5.0 mg, 0.015 mmol) were combined in a 10 ml recovery flask. To this
was added anhydrous DMF (100 ml) and the reaction vessel attached to
a vacuum line bridge. A break seal ampoule containing H-3 labeled
methyl iodide, (300 mCi, 0.004 mmol) was attached to the opposite side
of the bridge. C3H3I was then vacuum transferred into the reaction flask
at À1978C. The flask pressure was adjusted to 0.5 atm with N2, isolated
and allowed to stir at room temperature for 3 h. The volatiles were
removed under full vacuum, trapped and quenched for disposal. The
reaction residue was opened to the atmosphere and quenched with 0.5 N
HCl (1.0 ml). The product was extracted Et2O (5 ml, 3X), dried
(Na2SO4), and filtered to yield crude 3 (155 mCi). The radiochemical
purity of crude 3 was approximately 52% (method A). In this system, 2
has a retention time of approximately 5.6 min, while 3 has a retention
time of approximately 9.3 min. The solvent was removed in vacuo and
the residue was purified by HPLC (method A). The combined purified
fractions were pooled, concentrated to dryness, extracted with
absolute ethanol and filtered (0.22 mm) to yield 3 (80 mCi, 27%). The
identity of the product was established by co-elution of the radiolabeled
material with authentic unlabeled compounds4,6 on HPLC. The
radiochemical purity of 3 was >98% and the specific activity was
found to be 68 Ci/mmol (method A). Analysis of 3 via chiral HPLC
(method B) showed the two enantiomers with retention times of
approximately 17.4 and 18.6 min).
(S-)-3-(5-Chloro-2-[OC3H3]methoxyphenyl-1,3-dihydro-3-fluoro-6-
(trifluoromethyl)-2H-indol-2-one, 1b
3 (8 mCi) was added to a 5 ml thick wall screw cap V-Vial and the
sample was concentrated to dryness in a Savant speedvac. The residue
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 139–149

SYNTHESIS OF 3H AND 14C LABELED
145
was dissolved in hexane (2 ml) concentrated to dryness in a Savant
speedvac and then resuspended in hexane (2 ml) and ether (1 ml). The
solution of 3 was passed through a MgSO4 column (0.5 Â 2 cm2)
and collected in a conical vessel (15 ml). The solvent removed (N2)
and the residue resuspended in ether (1 ml). The solution was placed in
an ice-bath for 10 min, DAST, (diethylamino)sulfur trifluoride, (60 ml,
0.45 mmol) was added and the reaction allowed to stir at 08C for 30 min
after which time ether (10 ml) was added to the reaction vessel and
the mixture washed with saturated NaHCO3 (5 ml), H2O (5 ml),
saturated NaCl (5 ml), dried (MgSO4), and filtered. The solvent was
then removed in a Savant speedvac. The residue, 4, was then dissolved
in 90% hexane/10% isopropanol for purification by chiral HPLC
(method B). In this system, 1b had a retention time of approximately
8.7 min while the undesired enantiomer 5 had a retention time of
approximately 12.0 min. The combined purifications were pooled,
concentrated to dryness and redissolved in absolute ethanol to yield
1b (1.2 mCi, 15%). The identity of the product was established by co-
elution of the radiolabeled material with authentic unlabeled com-
pound4,6 on HPLC. The radiochemical purity of 1b was >99.5% and
the specific activity was found to be 68 Ci/mmol (method B).
2-Bromo-4-chloroanisole, 8
%
2-Bromo-4-chlorophenol (64.24 g, 0.30 mol) was added in portions to an
ice-cold solution of 5 N NaOH (64 ml, 0.32 mol) under N2 and stirred
until dissolution was complete (ꢀ75 min). Dimethyl sulfate (43.7 g,
0.35 mol,) was slowly added to the stirred solution at 0–58C. The
mixture was allowed to warm to room temperature and then stirred for
16 h. The two-phase mixture was extracted with ether (2 Â 100 ml) and
the combined extracts were washed with 1 N NaOH (40 ml), water
(40 ml), brine (40 ml), dried (Na2SO4) and filtered. The filtrate was
concentrated in vacuo and the crude product 8 was distilled under
vacuum to give 64.5 g (97%) of 2-bromo-4-chloroanisole, 8, as a
1
colorless oil, bp 78–818C/ 4 torr. H NMR (300 MHz, CDCl3) d 3.88
(s, 3 H), 6.81 (d, 1 H), 7.24 (dd, 1 H), 7.53 (s, 1 H); MS m/e 220 (M+).
(5-Chloro-2-methoxyphenyl)magnesium bromide, 9
%
Magnesium turnings (0.335 g, 0.0138 mol) were suspended in anhydrous
THF (10 ml) in a 50 ml two-neck round-bottom flask equipped with a
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 139–149

146
D. D. DISCHINO ET AL.
reflux condenser, stir bar, 10 ml addition funnel and nitrogen inlet.
Dibromoethane (85 mg, 0.45 mmol) was added and the mixture stirred
for 10 min, after which time a solution of 8 (2.03 g, 0.00917 mol) in
anhydrous THF (7 ml) was added over 4 min. The mixture was heated at
reflux for 6 h and stirred at ambient temperature for 16 h yielding a clear
dark solution of 9 (and a small amount of unreacted magnesium), which
was used directly in the next reaction.
N-(tert-Butoxycarbonyl)-3-(trifluoromethyl)aniline, 11
A neat mixture of 3-(trifluoromethyl)aniline, 10 (33.00 g, 0.20 mol) and
di-tert-butyl dicarbonate (49.20 g, 0.22 mol) was stirred at 808C for 3 h
and then allowed to cool to room temperature. The resulting t-BuOH
formed in the reaction was removed on a rotary evaporator leaving the
crude product as an amber oil which solidified on standing. The crude
product was crystallized from hot hexane (ꢀ35 ml) to yield 45.61 g
1
(85.3%) of 11 as white needles. H NMR (300 MHz, CDCl3) d 1.53
(s, 9 H), 6.56 (s br, 1 H) 7.28 (d, 1 H) 7.39 (t, 1 H), 7.49 (d, 1 H), 7.71
(s, 1 H); MS m/e 260 (M-H)À.
6-(Trifluoromethyl) [2,3-14C2] isatin, 13
Rigorous anhydrous conditions were followed in this procedure. All
glassware, syringes, needles, pipettes and stir bar were oven dried at
1208C for 16 h prior to use. N-(tert-butoxycarbonyl)-3-(trifluoromethyl)
aniline, 11, (2.61 g, 0.010 mol) was dissolved in anhydrous THF
(11 ml, added via syringe through the septum) in a 100 ml two-neck
round-bottom flask, equipped with a stir bar, nitrogen inlet and
rubber septum. The colorless solution was stirred and cooled with a
dry ice/acetone bath to À788C (bath temperature). After 10 min,
sec-butyllithium (16.90 ml, 0.022 mol, 1.3 M solution in cyclohexane)
was added dropwise over 9 min from a syringe inserted through the
septum. The cooling bath was changed to a dry ice/methanol system and
the yellow solution was allowed to stir at À45 to À358C (bath
temperature) for 2 h. The resulting yellow-brown mixture was cooled
to À788C and a solution of diethyl oxalate[carboxylate-14C1,2] (272 mg,
1.863 mmol, 51 mCi/mmol, 95 mCi) and non-labeled diethyl oxalate
(1.266 g, 0.00866 mol) in anhydrous THF (1.5 ml) was added rapidly
from a syringe. The resulting orange-brown solution was allowed to stir
at À758C for 1 h. The reaction mixture was diluted with ether (12 ml)
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 139–149

SYNTHESIS OF 3H AND 14C LABELED
147
and quenched with 3 N HCl. The cooling bath removed and the mixture
was allowed to reach ambient temperature. (This mixture turns deep
blue before turning yellow as it warms to room temperature.) The organic
layer was separated, and washed with water (10 ml), brine (10 ml) and
dried (Na2SO4). The solvent was removed on a rotary evaporator to
yield a dark yellow oil that was chromatographed on 65 g of silica gel.
Elution with CH2Cl2 yielded the desired carbon-14 labeled keto-ester,
12, as a bright yellow oil.
A solution of 12 in anhydrous THF (40 ml) and 3 N HCl (10 ml) was
stirred under reflux for 6 h. The clear orange-red solution was cooled to
308C, the solvent removed on a rotary evaporator and the resulting
suspension cooled to 08C. After 30 min, the resulting solid was filtered,
rinsed with water and dried under vacuum for 64 h. Additional drying
under vacuum for 12 h at 788C yielded 13 (1.209 g, 57.7 mCi, 56.2%) as
an orange–red solid. RadioTLC analysis of 13 showed Rf 0.32 (Analtech
Silica Gel GHLF Uniplates, 250 mm, 10 Â 20 cm2 scored, 95% CH2Cl2,
5% CH3OH).
3-(5-Chloro-2-methoxyphenyl)-3-hydroxy-2,3-dihydro-6-
(trifluoromethyl)-2H-[2,3-14C2] indol-2-one, 14
A 100 ml round bottom flask, equipped with a stir bar and nitrogen
inlet was charged with a suspension of oil-free sodium hydride
(268 mg, 6.69 mmol) in anhydrous THF (11 ml). The isatin 13 (1.20 g,
0.0056 mol) was added in portions and the resulting purple solution
was stirred for 30 min after which the slurry was cooled to 58C
and a solution of 9 was added via syringe inserted through a rubber
septum. The resulting mud-brown solution was stirred at room
temperature for 2 h. The mixture was diluted with ether (35 ml),
cooled in an ice bath and acidified (pH paper) with 1 N HCl (ꢀ20 ml).
The organic layer was separated, washed with 0.5 N NaOH (10 ml),
1 N HCl (10 ml), water (10 ml), brine (10 ml), and dried (Na2SO4).
The solvent was removed on a rotary evaporator to yield a brown
greasy solid, which was purified by flash chromatography (65 g silica
gel, 50/50 ethyl acetate/hexane) to yield 14 (1.86 g, 53.0 mCi, 93.5%) as
a yellow brown solid. RadioTLC analysis of 14 showed Rf 0.14
(Analtech Silica Gel GHLF Uniplates, 250 mm, 10 Â 20 cm scored, 95%
CH2Cl2, 5% CH3OH). The radiochemical purity of 14 was >95%
(HPLC method C). In this system, 14 has a retention time of
approximately 11.0 min.
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 139–149

148
D. D. DISCHINO ET AL.
3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-
2H-[2,3-14C2]indol-2-one, 15
Neat (diethylamino)sulfur trifluoride (DAST) (1.09 g, 0.0067 mol,)
was added dropwise via a 1.0 ml plastic syringe to a cold suspension
(À788C) of 14 (1.86 g, 53 mCi, 0.0052 mol) in dry CH2Cl2 (17 ml) under
nitrogen. The mixture was allowed to warm to 0–58C and was
maintained at that temperature for 45 min, after which time TLC
analysis (Analtech Silica Gel GHLF Uniplates, 250 mm, CH2Cl2)
showed that the reaction was complete. The solution was quenched
by the slow addition of water (9 ml) at 08C. The organic layer
was washed with water (15 ml), brine (15 ml) and dried (Na2SO4).
The solvent was concentrated on a rotary evaporator to yield an
amber foam which was purified by flash chromatography (34 g silica
gel) using a gradient elution of 0–0.5% CH3OH/CH2Cl2. The
desired fractions were combined and concentrated on a rotary
evaporator to yield racemic 15 (1.48 g, 42.03 mCi, 79%) as a cream
colored solid.
(S-)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-
(trifluoromethyl)-2H-[2,3-14C2]indol-2-one, 1c
Resolution of racemic 15 was obtained by chiral HPLC (HPLC
method D). In this procedure, 15 (1.42 g) was dissolved in mobile phase
(90% hexane/10% isopropanol, 84 ml) and the suspension was
sonicated until a clear solution was obtained. Aliquots (0.95 ml) were
injected onto the column and peaks corresponding to the (S)- and
(R)-enantiomers were collected. Fractions containing the desired
(S)-enantiomer were combined and concentrated on a rotary evapora-
tor. The residue was dried under vacuum for 4 h to yield 1c
(652 mg, 28.4 mCi/mg, 18.52 mCi) as a yellow-tinted solid. The identity
of the product was established by co-elution of the radiolabeled
material with authentic unlabeled compounds4,6 on HPLC. The
radiochemical purity of (1c) was >99.5% (HPLC method E). In
this system, 1c has a retention time of approximately 8.6 min. The
chiral purity of 1c was >99.5% (HPLC method B). In this system,
1c has a retention time of approximately 8.7 min, while the undesired
enantiomer, 16, has a retention time of approximately 12.0 min.
1H NMR (1c) (500 MHz, CDCl3) d 3.55 (s, 3 H), 6.78 (d, 1 H), 7.16
(s, 1 H), 7.20 (d, 1 H), 7.28 (d, 1 H), 7.34 (dd, 1 H), 7.80 (d, 1 H), 8.02
(s br, 1 H).
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 139–149

SYNTHESIS OF 3H AND 14C LABELED
149
References
1. Williams GR, Jiang JG, Matchar DB, Samsa GP. Stroke 1999; 30:
2523–2528.
2. Schlaug G, Benfield A, Baird AE, et al. Neurology 1999; 53: 1528–1537.
3. Gribkoff VK, Starrett Jr. JE, Dworetzky SI, et al. Nature Med 2001; 7:
471–477.
4. Hewawasam P, Meanwell NA, Gribkoff VK. US Patent # 5,565,483, 15
October 1996.
5. Hewawasam P, Gribkoff VK, Pendri Y, et al. Bioorg Med Chem Lett 2002;
12: 1023–1026.
6. Hewawasam P, Erway M, Moon SL, et al. J Med Chem 2002; 45:
1487–1499.
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 139–149