Synthesis of [14C]ABT-770, matrix metalloproteinase inhibitor (MMPI), labelled in the phenoxy ring

Article abstract of DOI:10.1002/jlcr.727

The MMPI [¹⁴C]ABT-770 (1), N-[(1S)-1-[(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl)methyl]]-2-[[4′ -(trifluoromethoxy)[1,1′-biphenyl]-4-yl]oxy]ethyl]-N-hydroxyformamide was synthesized in 8 steps using 4-bromophenol-UL-¹⁴C (10) as a star

Full text of DOI:10.1002/jlcr.727

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 883–892.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.727
Research Article
Synthesis of [14C]ABT-770, matrix
metalloproteinase inhibitor (MMPI), labelled
in the phenoxy ring
Shirish N. Raja*
Drug Metabolism Department, R46 V, AP9, Abbott Laboratories,
100 Abbott Park Road, Abbott Park, IL 60064-6114, USA
Summary
The MMPI [14C]ABT-770 (1), N-[(1S)-1-[(4,4-Dimethyl-2,5-dioxo-1-imi-
dazolidinyl)methyl]]-2-[[40-(trifluoromethoxy)[1,10-biphenyl]-4-yl]oxy]ethyl]-N-
hydroxyformamide was synthesized in 8 steps using 4-bromophenol-UL-14C
(10) as a starting material. The Carbon-14 label was introduced in one of the
metabolically stable biphenyl rings. The key sequence of the synthesis was a
three-step one-pot reaction in which the hydantoin moiety was introduced, the
imine oxidized and further hydrolyzed to get the penultimate precursor to
[14C]ABT-770 (1) in 56% yield. Copyright # 2003 John Wiley & Sons, Ltd.
Key Words: matrix metalloproteinase inhibitors; 4-bromophenol-UL-14C;
ABT-770; trifluoromethoxy; retrohydroxamate
Introduction
The matrix metalloproteinases (MMPs) are a family of enzymes
containing zinc that degrade extra cellular matrix.1 It is now known
that the mammalian MMP family consists of at least 20 different
enzymes.2 An increase in MMP activity is associated with cancer and
inflammatory diseases such as arthritis and multiple sclerosis.1,2
*Correspondence to: S. N. Raja, Drug Metabolism Department, R46 V, AP9, Abbott
Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6114, USA. E-mail: shirishn.raja
@abbott.com.
Copyright # 2003 John Wiley & Sons, Ltd.
Received 31 January 2003
Revised 10 April 2003
Accepted 6 May 2003

884
S. N. RAJA
Therefore a variety of compounds have been synthesized as potential
therapeutic agents, acting by inhibition of matrix metalloproteinase
activity. They are known as matrix metalloproteinase inhibitors
(MMPIs). Our discovery group selected MMPI ABT-770 as a novel
and potent antitumor agent because of its potency, selectivity,
bioavailability and efficacy.3
It was shown that ABT-770 is highly selective for MMP-2 (gelatinase
A) and exhibits desirable pharmacokinetic properties such as long half-
life and high oral bioavailability in multiple species.3 For preclinical
development of this compound it was necessary to have a metabolically
stable 14C-labeled form of ABT-770 to be used in animal metabolism
studies. Selection of the carbon-14 label in the phenoxymethylene ring
was based upon earlier in vivo and in vitro metabolism studies with non-
radioactive ABT-770. These results showed that most of the metabolism
occurred in the hydroxamic acid portion of the molecule by formation
of formamide and amine.4 By taking advantage of the procedure used
by our process research group5 and by using readily available 4-
bromophenol- UL-14C (10), a radiosynthetic strategy for [14C]ABT-770
(1) was developed, as outlined in Scheme 1. The carbon-14 label was
introduced in one of the biphenyl rings using 4-bromophenol-UL-14C
(10). In the key sequence of this synthesis, a three-step, one-pot reaction
was carried out to obtain 3-[(2S)-3-(4-bromophenoxy)-2-(hydroxyami-
no)propyl]-5,5-dimethyl-1,3-diazolidine-2,4-dione[bromophenylUL-14C]
(8) which was further elaborated to complete the synthesis of [14C]ABT-
770 (1).
O
OHC
OH
OH
N
N
O
NH
*
O
*
Br
F3CO
[14C]ABT-770 (1)
10
Results and discussion
[14C]ABT-770 (1) was synthesized using 4-bromophenol-UL-14C (10) as
radioactive starting material. Thus the alkylation of (l)-serine
oxazolidinone tosylate (made by the Abbott process chemistry research
group by following the procedure in Sibi et al.),6 2 with 1 molar
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 883–892

SYNTHESIS OF [14C]ABT-770
885
equivalent of 4-bromophenol-UL-14C (10) and potassium carbonate
gave only 50% conversion of 2 to 3. To complete the reaction another
1 molar equivalent of potassium carbonate and 2 in MeCN were added
to give the displacement product (l)-serine oxazolidinone p-bromo-
phenyl ether [bromophenyl-UL-14C] (3) in a 78% yield. This was
followed by the hydrolysis of the oxazolidone ring by using potassium
hydroxide in methanol to yield (L)-2-amino-3-hydroxypropyl
(p-bromophenyl) ether [bromophenyl-UL-14C] (4) in 90% yield. Initially
3 was not soluble in methanolic KOH but as the reaction progressed it
formed a homogeneous mixture. Condensation of 4 with p-anisaldehyde
in toluene at elevated temperature occurred readily to give 73% yield of
iminoalcohol 5 as a key intermediate. Because of degradation observed
during silica gel TLC analysis, imino alcohol 5 was characterized only
1
by H NMR spectroscopy and was used in the next step without
purification. The iminoalcohol [bromophenyl-UL-14C] 5 thus obtained
was subjected to the key transformation which involved a three steps,
one-pot reaction sequence to yield N-hydroxyl amine [bromophenyl-
UL-14C] 8. The sequence involved coupling 5,5-dimethyl hydantoin with
iminoalcohol [bromophenyl-UL-14C] 5 by using triphenyl phosphine in
the presence of diisopropyl azodicarboxylate (DIAD) under Mitsunobu
conditions to yield imine [bromophenyl-UL-14C] 6. This product was
further subjected to m-chloroperbenzoic acid (m-CPBA) oxidation to
yield oxaziridine [bromophenyl-UL-14C] 7. The formation of diaster-
eomers was indicated by observation of three radiochemical peaks in the
HPLC trace. Hydrolysis of oxaziridine [bromophenyl-UL-14C] 7 was
accomplished with excess aqueous N-hydroxylamine hydrochloride to
form the N-hydroxide [bromophenyl-UL-14C] 8. The overall radio-
chemical yield for these three steps was 56%, starting from 5. During
the transformation of 5 to 8 a number of byproducts were formed, as
observed in the HPLC trace. These byproducts were not analyzed for
their identity. Instead, HPLC analysis was utilized to monitor
consumption of starting material. Suzuki coupling of N-hydroxide
[bromophenyl-UL-14C] 8 with 4-(trifluoromethoxy)phenyl boronic acid
(made by process research group by using bromo-4-(trifluorometh-
oxy)benzene, n-BuLi, and triisopropyl borate) in the presence of
PdCl2(dppf) and K3PO4 gave trifluoromethoxybiphenyl ether [phe-
noxy-UL-14C] (9). The yield for this reaction was 22%. After silica gel
column purification the product obtained was only 40% pure. It was
speculated that this low yield was due to instability on silica gel, so 9
was subjected immediately to formylation. In the final step, formylation
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 883–892

886
S. N. RAJA
O
O
K2CO3 / CH3CN
KOH / MeOH
90%
NH2
HN
O
O
HN
O
O
OH
TsO
Br
OH
, 78%
*
10
*
*
Br
Br
4
2
3
OCH3
OHC
OCH3
Ph3P, DIAD
H
N
O
N
Toluene, 73%
O
OH
O
HN
*
Br
5
OCH
3
OCH
3
m-CPBA
NH OH.HCl
2
O
H
H O
2
THF
N
N
56% from 5
O
O
N
O
N
*
O
O
*
O
Br
Br
HN
HN
(7)
(6)
O
N
O
N
HO
NH
HO
NH
PdCl2(dppf)
O
NH
O
NH
F3CO
B(OH)2
O
O
*
*
Br
22%
F3CO
8
9
EtOCHO
55%
[14C]ABT-770
1
Scheme 1.
of 9 was carried out in presence of excess of ethyl formate to yield
[14C]ABT-770 (1). The overall yield for 8 steps was 3.5%.
Experimental
All chemicals and solvents were reagent grade or better and purchased
from commercial suppliers. They were used without further purification.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 883–892

SYNTHESIS OF [14C]ABT-770
887
4-bromophenol-UL-14C was purchased from American Radiolabelled
Chemicals, St. Louis, MO. (l)-serine oxazolidinone tosylate (2)6 was
obtained from the Abbott process chemistry group. The identity of
intermediates was confirmed by comparison with authentic samples
supplied by the Abbott process chemistry group. Liquid scintillation
counting was performed on a LKB-Wallac 1214 Rack Beta ‘Excel’
counter. TLC plates were coated with Kieselgel 60 (0.25 mm, Merck)
and were scanned for radioactivity with a Radiomatic RS chromato-
1
graph. The H-NMR spectrum of 5 was recorded at 500 MHz and
chemical shifts are reported in ppm (d). [14C]ABT-770 was analyzed
using a Hitachi L-7000 Series analytical HPLC system consisting of an
auto-sampler, a pump, a variable wavelength UV detector, and a Flow-
One/Beta Model A-500 liquid scintillation radioactivity flow detector
(Packard Instruments, 0.5 ml flow cell, 3:1 ratio of Packard Ultima-Flo
M scintillant to effluent). A Perkin Elmer 250 analytical HPLC system
and an Applied Biosystems UV detector were used to analyze 6, 7, 8 and
9 along with the same liquid scintillation radioactivity flow detector as
above. Preparative HPLC was performed using a Shimadzu system
consisting of a Shimadzu SIL-10A autosampler and two Shimadzu LC-
8A pumps. Peak detection and chromatograms were obtained with a
Shimadzu SPD-10A VP variable wavelength UV detector set at 260 nm
and Shimadzu Ezchrom software. Fractions of the [14C]ABT-770 (1)
peak were collected using a Shimadzu FRC-10A fraction collector. An
Eppindorf CH-30 column heater was used to maintain columns at 30oC
and 35oC.
ð4RÞ-4-[(4-Bromophenoxy)methyl]-1,3-oxazolidin-2-one[bromophenyl-
UL-14C] ð3Þ
To a solution of (l)-serine oxazolidinone tosylate (2, 0.600 g, 2.4 mmol)
in dry CH3CN (4 ml) was added anhydrous K2CO3 (0.33 g, 2.4 mmol)
and 4-bromophenol-UL-14C (100 mCi, 2.0 mmol) under N2. The
reaction mixture was stirred at 80oC for 15 h. TLC analysis (silica gel,
5% MeOH and 1% NH4OH in CH2Cl2) showed 50% product
formation. Additional K2CO3 (0.330 g, 2.4 mmol), CH3CN (2 ml) and
compound 2 (0.600 g, 2.4 mmol) were added and heating was continued
at 808C for 4 h. The reaction mixture was then cooled to room
temperature and diluted with water (10 ml). The aqueous layer was
extracted with CH2Cl2 (3 ꢀ 10 ml) and the combined organic layers were
successively washed with 1N NaOH (3 ml) and a brine solution (25 ml).
Copyright # 2003 John Wiley & Sons, Ltd.
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S. N. RAJA
The organic layers were concentrated on a rotary evaporator to yield
(4R)-4-[(4-bromophenoxy)methyl]-1,3-oxazolidin-2-one [bromophenyl-
UL-14C] (3) (78 mCi). TLC analysis (silica gel, 5% MeOH and 1%
NH4OH in CH2Cl2) indicated the compound (Rf ꢁ 0.3) was 97% pure.
(2S)-2-Amino-3-(4-bromophenoxy)propan-1-ol[bromophenyl-UL-14C] ð4Þ
Compound 3 (78 mCi, 1.56 mmol) was mixed with 2.5 M 90% methanolic
KOH solution (2.5 ml) and heated at 658C for 4h and 758C overnight. The
solvent was removed using a rotary evaporator, and the residue was
transferred into a separatory funnel using H2O (20 ml). The aqueous
solution was extracted with CH2Cl2 (3 ꢀ 20 ml), the combined organic
layers were washed with brine solution (25 ml), dried over anhydrous
Na2SO4, and filtered. The solvent was removed using a rotary evaporator
to yield (2S)-2-amino-3-(4-bromophenoxy)propan-1-ol[bromophenyl-
UL-14C] (4) (70 mCi). TLC analysis (silica gel, 5% MeOH and 1%
NH4OH in CH2Cl2) indicated the compound (Rf ꢁ 0.2) was 98% pure.
(3E)(2S)-3-Aza-2-[(4-bromophenoxy)methyl]-4-(4-methoxyphenyl)-
but-3-en-1-ol [bromophenyl-UL-14C] ð5Þ
(2S)-2-Amino-3-(4-bromophenoxy)-1-propanol
[bromophenol-UL-14C]
(4, 70 mCi, 1.4 mmol) and p-anisaldehyde (0.23 g, 1.7 mmol) were
dissolved in toluene (7 ml). The reaction flask was attached to a
(
Dean-Stark trap containing a few beads of 4 A molecular sieves. The
reaction mixture was heated at 1258C for 4 h, cooled to room
temperature and dried in vacuo to give a sticky solid, which upon
trituration with pentane (2 ml) provided 5 (51 mCi). 1H NMR
(500 MHz, DMSO-d6) ppm (d) 3.51 (dd, J=9.85, 6.96 Hz, 1 H) 3.62
(m, 1 H) 3.69 (m, 1 H) 3.80 (s, 3 H) 4.05 (dd, J=9.85, 7.54 Hz, 1 H) 4.22
(dd, J=9.85, 4.06 Hz, 1 H) 4.77 (s, 1 H) 6.90 (d, J=8.69 Hz, 2 H) 6.99 (d,
J=8.69 Hz, 2 H) 7.41 (d, J=8.69 Hz, 2 H) 7.69 (d, J=8.69 Hz, 2 H) 8.29
(s, 1 H). As judged by 1H NMR analysis, the pentane wash also
contained more of the desired product 5 (19 mCi).
3-{(3E)(2S)-3-Aza-2-[(4-bromophenoxy)methyl]-4-(4-methoxyphenyl)
but-3-enyl}-5,5-dimethyl-1,3-diazolidine-2,4-one[bromophenyl-UL-14C]
ð6Þ
A THF (4 ml) solution of 5 (50 mCi, 1 mmol), triphenylphosphine
(0.41 g, 1.57 mmol), and 5,5-dimethylhydantoin (0.22 g, 1.7 mmol) was
Copyright # 2003 John Wiley & Sons, Ltd.
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SYNTHESIS OF [14C]ABT-770
889
cooled to 08C under a nitrogen atmosphere. A solution of 95%
diisopropyl azodicarboxylate (0.318 g, 1.5 mmol) was slowly added over
10 min. The reaction was stirred at room temperature for 3.5 h. HPLC
analysis (Zorbax SB C8 column, 4.6 ꢀ 250 mm, 5 mm, UV at 230 nm,
flow rate=1 ml/min, at 308C, 20% CH3CN/0.1% H3PO4 to 60%
CH3CN/0.1% H3PO4 over 15 min, hold at this concentration for
10 min, RT=8.3 min) at this time showed complete consumption of 5.
The product was used directly in the next step.
3-{2-[(3R)-3-(4-Methoxyphenyl)(1,2-oxaziridin-2-yl)(2 S)-3-(4-bromophe-
noxy) propyl-5,5-dimethyl-1,3-diazolidine-2,4-dione [bromophenyl-UL-14C]
ð7Þ
The reaction mixture containing 6 from the previous step was cooled to
–78oC and to this was added a solution of mCPBA (0.703 g, 4.0 mmol)
in THF (1.5 ml). The reaction mixture was warmed to 08C and stirred at
that temperature for 1.5 h. The reaction progress was monitored by
HPLC (Zorbax SB C8 column, 4.6 ꢀ 250 mm, 5 mm, UV at 230 nm, flow
rate=1 ml/min, at 308C, 20% CH3CN/0.1% H3PO4 to 60% CH3CN/
0.1% H3PO4 over 50 min, hold at this concentration for 10 min
RT=20.8, 21.9, 22.7 min). Reactant 6 was completely consumed, and
three new peaks appeared, suggesting formation of a mixture of
diastereomers of the desired product. The crude product was used
directly in the next step.
3-[(2S)-3-(4-Bromophenoxy)-2-(hydroxyamino)propyl]-5,5-dimethyl-
1,3-diazolidine-2,4-dione [bromophenyl-UL-14C] ð8Þ
The mixture containing 7 from the previous step was cooled to 0oC and
aqueous solution (1.5 ml) of hydroxylamine hydrochloride (0.73 g,
10.6 mmol) was added. The reaction mixture was warmed to room
temperature and was stirred at that temperature for 15 h. HPLC
analysis (Zorbax SB C8 column, 4.6 ꢀ 250 mm, 5 mm, UV at 230 nm,
flow rate=1 ml/min, at 308C, 20% CH3CN/0.1% H3PO4 to 60%
CH3CN/0.1% H3PO4 over 50 min, hold at this concentration for
10 min, RT=10.5 min) of the organic layer showed complete disap-
pearance of the three peaks of 7. After cooling the reaction mixture to
08C, a saturated solution of K2CO3 was added until pH 8.0 (5 ml), and
the solution was extracted with EtOAc (2 ꢀ 40 ml). The combined
organic layers were washed with saturated NaHCO3 (10 ml) and a brine
solution (25 ml). The solvent was evaporated using a rotary evaporator,
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S. N. RAJA
and the crude product obtained was purified by silica gel column
chromatography using 5% MeOH in CH2Cl2 as an eluent followed by
preparative silica gel TLC using 5% MeOH in CH2Cl2 as eluent to yield
greater than 95% pure 8 (28 mCi). TLC analysis (silica gel, 5% MeOH :
CH2Cl2) Rf ꢁ 0.2.
3-(2S)-2-(Hydroxyamino)-3-{4-[4-(trifluoromethoxy)phenyl]phenoxy}
propyl)-5,5-dimethyl-1,3-diazolidine-2,4-dione[phenoxymethylene-UL-14C]
ð9Þ
To a slurry of compound 8 (25 mCi, 0.5 mmol) in 1:1 toluene : water
(2.5 ml each) was added 4-(trifluoromethoxy)phenylboronic acid
(0.199 g, 0.96 mmol) and K3PO4 (0.573 g, 2.7 mmol). Nitrogen was
sparged through the mixture for 20 min. [1,10-bis(Diphenylphosphino)-
ferrocene]-dichloropalladium (II) complex with dichloromethane
[PdCl2(dppf)] (0.0082 g, 0.01 mmol) was added and the reaction mixture
was heated at 69oC for 15 h. The reaction mixture was diluted with H2O
and extracted with EtOAc (3 ꢀ 25 ml). The combined organic layers
were washed with brine solution, and the solvent evaporated to give an
oily residue, which was triturated with 5% CH2Cl2/pentane (2 ml) to
provide a solid. Attempts to purify the crude product on a silica gel
column using 5% MeOH and CH2Cl2 gave 18 mCi containing >40% of
9 as indicated by HPLC analysis. (Zorbax SB C8 column, 4.6 ꢀ 250 mm,
5 mm, UV at 210 nm, flow rate=1.5 ml/min, at 358C, 20% CH3CN/
0.1% H3PO4 to 60% CH3CN/0.1% H3PO4 over 15 min, hold at this
concentration for 10 min, RT=10.9 min).
½14Cꢂ ABT-770 ð1Þ
A solution containing 40% of 9 (18 mCi) and EtOCHO (4 ml) was
heated at 658C for 15 h. Excess EtOCHO was removed on a rotary
evaporator to give an oil, which was transformed into a solid residue
after trituration with 5% CH2Cl2/pentane (2 ml). The crude [14C]ABT-
770 was dissolved in a solution of 0.1% TFA/CH3CN (1:1) and purified
by HPLC using a YMC Basic (250 mm ꢀ 20 mm i.d.) column. The
analyte was eluted at a flow rate of 20 ml/min with a mobile phase
consisting of 50% H2O and CH3CN containing 0.1% trifluoroacetic
acid. Peaks were detected with the UV detector set at 260 nm.Fractions
containing [14C]ABT-770 were pooled together and partially evaporated
on a rotary evaporator. The aqueous portion was made basic with
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 883–892

SYNTHESIS OF [14C]ABT-770
891
Na2CO3 and 1 was extracted with CH2Cl2 (25 ml). The solvent was
evaporated on a rotary evaporator and the residue obtained was
dissolved in ethanol to give 3.95 mCi of [14C]ABT-770 (1) with 96%
radiochemical purity (22% yield).
Determination of purity
High performance liquid chromatography (HPLC)
[14C]ABT-770 (1) was analyzed by reverse phase HPLC and compared
to authentic ABT–770. Each sample was injected onto a YMC-Pack
basic 5 m (250 ꢀ 4.6 mm i.d.) column and eluted at 1 ml/min with mobile
phase consisting of 50% 0.1% trifluoroacetic acid and 50% acetonitrile.
Peaks were detected with a UV detector at 260 nm and a liquid
scintillation radioactivity flow detector. Greater than 95% of radio-
activity corresponded to the UV peak of ABT-770 at 9.20 min. An assay
of effluent showed that greater than 98% of the activity was recovered
from the column. The specific activity was determined to be 48.1 mCi/
mmol (99.9 mCi/mg) by measuring mass and radioactivity concentra-
tions of the material in a given solution. The concentration of the
radioactivity was determined by liquid scintillation counting of an
accurately measured aliquot. The mass concentration was measured by
comparing the HPLC UV peak area of an accurately measured aliquot
to a standard curve fitting a straight line equation (correlation
coefficient of 0.998) generated by injecting a standard solution of
ABT-770 and measuring the resulting peak areas.
Conclusion
An efficient eight step synthetic sequence starting with 4-bromophenol-
UL-14C (10) was developed and executed for the preparation of
[14C]ABT-770 (1). A three-step, one-pot reaction sequence was the
unique feature of the synthetic scheme. This method gave the [14C]ABT-
770 (1) compound in a reasonable radiochemical yield with high specific
activity, which was suitable for use in in vivo and in vitro studies.
Acknowledgements
The author would like to gratefully acknowledge the process and
discovery chemistry groups for starting materials, intermediate samples
Copyright # 2003 John Wiley & Sons, Ltd.
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S. N. RAJA
and experimental details, Samuel B. Thomas for analytical support and
Tom Pagano for 1H-NMR analyses. It is a pleasure to acknowledge the
radiochemistry group and Stanley A. Roberts, Director, Drug
Metabolism and Preclinical Kinetics, for their helpful suggestions
during the preparation of this manuscript.
References
1. (a) White AD, Bocan TMA, Boxer PA, Peterson JT, Schrier D. Curr
Pharm Des 1997; 3: 45–58. (b) Michaelides MR, Curtin ML. Curr Pharm
Des 1999; 5: 787–819.
2. Whittaker M, Floyd CD, Brown P, Gearing AJH. Chem Rev 1999; 99:
2735–2776.
3. Curtin ML, Florjancic AS, Heyman HR, Michaelides MR, Garland RB,
Holms JH, Steinman DH, Dellaria JF, Gong J, Wada CK, Guo Y,
Elmore IB, Tapang P, Albert DH, Magoc TJ, Marcotte PA, Bouska JJ,
Goodfellow CL, Bauch JL, Marsh KC, Morgan DW, Davidsen SK.
Bioorg Med Chem Lett 2001; 11: 1557–1560.
4. Gum RJ, Hickman D, Fagerland JA, Heindel MA, Gagne GD,
Schmidt JM, Michaelides MR, Davidsen SK, Ulrich RG. Biochem
Pharmacol 2001; 62: 1661–1673.
5. Kurukulasuriya R, Wittenberger SJ, Hsiao CW, McDermott T, Hill DR,
Bailey A, McLaughlin MA. Poster presentation at the 220th ACS meeting
2000.
6. Sibi MP, Rutherford D, Sharma R. J Chem Soc, Perkin Trans 1994; 1:
1675–1678.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 883–892