Radiosynthesis of 6-([18F]fluoroacetamido)-1-hexanoic-anilide ([18F]FAHA) for PET imaging of histone deacetylase (HDAC)

Article abstract of DOI:10.1002/jlcr.1122

Radiosynthesis of a novel substrate for histone deacetylase (HDAC), 6-([¹⁸F]fluoroacetamido)-1-hexanoicanilide ([¹⁸F]FAHA, [¹⁸F]-3) is reported. For precursor synthesis, compound 1 (6-amino-1-hexanoicanilide) was prepared

Full text of DOI:10.1002/jlcr.1122

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 997–1006.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1122
Research Article
Radiosynthesis of 6-([18F]fluoroacetamido)-1-hexanoic-
anilide ([18F]FAHA) for PET imaging of histone
deacetylase (HDAC)
Uday Mukhopadhyay, William P. Tong, Juri G. Gelovani and
Mian M. Alauddin*
Department of Experimental Diagnostic Imaging, University of Texas MD Anderson
Cancer Center, Houston, TX, USA
Summary
Radiosynthesis of a novel substrate for histone deacetylase (HDAC), 6-([18F]fluor-
oacetamido)-1-hexanoicanilide ([18F]FAHA, [18F]-3) is reported. For precursor
synthesis, compound 1 (6-amino-1-hexanoicanilide) was prepared by the reaction of
6-amino hexanoic acid with thionyl chloride in dichloroethane followed by addition of
aniline. Compound 1 was reacted with bromoacetic anhydride in tetrahydrofuran
(THF) in the presence of triethylamine to produce the precursor compound
6-(bromoacetamido)-1-hexanoicanilide 2. Fluorination reactions were performed
using tetrabutylammonium fluoride in various solvents at 808C to prepare the
unlabeled reference compound 3. Radiofluorinations were performed using either n-
Bu4N18F or K18F/kryptofix, and the crude product was purified by high performance
liquid chromatography (HPLC). The radiochemical yields were 9–13% decay
corrected (d.c.) with an average of 11% using K18F/kryptofix, and specific activity
>2 GBq/mmol at the end of synthesis. The synthesis time was 67–75 min from the end
of bombardment (EOB). Copyright # 2006 John Wiley & Sons, Ltd.
Received 10 July 2006; Revised 1 August 2006; Accepted 2 August 2006
Key Words: fluorine-18; histone deacetylase; HDAC; PET
*Correspondence to: Mian M. Alauddin, 1515 Holcombe Blvd. T8.3895, Box 059 Houston, TX 77030,
USA. E-mail: alauddin@di.mdacc.tmc.edu
Contract/grant sponsor: The University of Texas MD Anderson Cancer Center
Contract/grant sponsor: DOD BCRP
Contract/grant sponsor: W81WXWH-04-1-0674
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U. MUKHOPADHYAY ET AL.
Introduction
The reversible acetylation of histones, mediated by histone acetyl transferases
(HATs) and histone deacetylase (HDACs), plays an important role in
remodeling chromatin architecture, and hence in regulation of gene expres-
sion.1,2 Acetylation of cationic lysine tails in nucleosome-associated histones
neutralizes charge and promotes relaxation of chromatin, leading to
transcriptional activation. Conversely, deacetylation of these lysine residues
promotes formation of condensed chromatin, and repression of transcription.
In some tumor cells excessive hypocetylation of histones results in the under-
expression of growth regulatory factors such as the cyclin-dependent kinase
inhibitor p21Wafl and thus contributes to the development of cancer.1–3
Histone hyperacetylation caused by HDAC inhibitors such as trichostatin
(TSA), MS-275 and suberoylanilide hydroxamic acid (SAHA) can cause
growth arrest in a wide range of transformed cells and can inhibit the growth
for human tumor xenografts.1–5 SAHA was in clinical trial and recently
achieved orphan drug status for multiple myeloma.6,7 Histone deacetylase is
under intense investigation in molecular biology possibly due to its function in
chromatin remodeling and effect on transcription regulation that leads to
many groups interested in drug development targeting histone deacetylases.8,9
Many HDAC inhibitors including SAHA have been developed, and shown to
cause growth arrest, differentiation and apoptosis.3 Some of these inhibitors
suffer from lack of specificity among the various forms of HDAC including
deacetylases that target non-histone proteins.3,10 Most recently several
structurally modified HDAC inhibitors have been reported with enhanced
activity and selectivity.3
Like many bio-modulating agents, SAHA has little host toxicity, and it is
difficult to evaluate its effectiveness as an anticancer agent, unless using
invasive techniques to biopsy the tumor.11 Therefore, interests remain in the
development of a non-invasive technique to evaluate HDAC expression and
activity in tumors in vivo before and during therapy. While much effort has
been directed towards the development of HDAC inhibitors, to our knowl-
edge, no substrate for HDAC, especially an imaging agent, has been reported
yet. In this paper we report on synthesis and radiolabeling a substrate for
HDAC, 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F)FAHA, [18F]-3),
which should allow for non-invasive whole body imaging of HDAC expression
and activity in tumors (including other organs and tissues) with positron
emission tomography (PET).
Results and discussion
Figure 1 represents the scheme for the synthesis of the HDAC substrate,
6-(fluoroacetamido)-1-hexanoicanilide (FAHA, 3). Compound 1 was prepared
from 6-amino hexanoic acid by treatment with thionyl chloride in
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 997–1006
DOI: 10.1002/jlcr

[
18F]FAHA FOR PET
i. CH2Cl-CH2Cl, SOCl2
NH2
999
O
H
N
NH2
4
HO
NH2
ii.
4
O
1
i. THF, Et3N
ii. BrAA
H
N
H
N
H
N
H
N
4
4
F
Br
MeCN
F-
O
O
O
O
2
3
Figure 1. Synthetic scheme of 6-(fluoroacetamido)-1-hexanoicanilide (FAHA)
dichloroethane followed by addition of aniline. In this step the reaction was
straight forward, which provided 80% yield of the desired product. The
1
product was characterized by H NMR spectroscopy and mass spectrometry.
Compound 1 was then reacted with bromoacetic anhydride in tetrahydrofuran
(THF) in the presence of triethylamine to produce the precursor compound 2
1
in 62% yield. Compound 2 was characterized by H NMR spectroscopy and
high-resolution mass spectrometry. When the NMR spectrum was run in
CDCl3 the amido protons were not observed due to fast exchange with the
solvent, however, in DMSO-D6 all amido protons were observed and could be
accounted in the spectrum.
Fluorination reactions were performed using tetrabutylammonium fluoride
(Bu4NF) in various solvents at 808C. The precursor compound 2 was sparingly
soluble in MeCN, relatively more soluble in THF and much more soluble in
N,N-dimethylsulfoxide (DMSO). Fluorination in THF produced the desired
product in 50–54% yield. Most of the starting material disappeared in
15–20 min as observed by high performance liquid chromatography (HPLC).
Reactions in MeCN and DMSO produced identical results (HPLC).
Purification of the crude product on normal phase silica gel column produced
50–54% yield of the cold compound 3. The unlabeled reference compound 3
was fully characterized by 1H and 19F NMR spectroscopy and high-resolution
1
mass spectrometry. H NMR spectrum showed a doublet of the fluoromethyl
protons at 4.80 ppm with a coupling constant 47.4 Hz, characteristic coupling
between fluorine and the geminal protons. Interestingly, 19F NMR spectrum
showed a peak at À224.7 ppm as a doublet of triplate with coupling constants
47.4 and 3.0 Hz, which are due to the geminal coupling between fluorine and
Copyright # 2006 John Wiley & Sons, Ltd.
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U. MUKHOPADHYAY ET AL.
proton, and long range coupling between fluorine and the C6-amido proton,
respectively.
Radiofluorination of compound 2 was performed using either Bu4N18F or
K18F/kryptofix. The 18F-fluoride was obtained from the cyclotron in the form
of either aqueous Bu4N18F or K18F/kryptofix, which was evaporated to
dryness by azeotropic removal of water with MeCN. The reactions were
performed at 808C for 20 min with Bu4N18F, and 1158C for 25 min with K18F/
kryptofix. Un-reacted fluoride was removed from the reaction mixture by
passing the crude reaction mixture through a silica Sep-Pak cartridge, which
was then eluted with 30% MeOH in CH2Cl2. The eluate was then injected into
the semi-preparative HPLC system. The crude product was purified by HPLC
on a semi-prep column. Figure 2 shows a representative semi-preparative
HPLC chromatogram of the crude reaction mixture. The desired product
fraction containing [18F]-3 was collected at a retention time of about 12 min.
ADC1 A, ADC1 CHANNEL A (HDAC\HDAC0001.D)
mAU
100
[18F]-3
90
Radioactivity
80
70
60
50
0
2.5
5
7.5
10
12.5
15
17.5
mi
VWD1 A, Wavelength=254 nm (HDAC\HDAC0001.D)
mAU
2
3000
2500
2000
1500
1000
500
UV
0
0
2.5
5
7.5
10
12.5
15
17.5
m
Time (min)
Figure 2. HPLC purification of crude [18F]FAHA, prepared by radiofluorination
with Bu4N18F: Semi-prep C18 column; 35% MeCN and 65% sodium phosphate
(50 mM) in H2O; flow 4.0 ml/min
Copyright # 2006 John Wiley & Sons, Ltd.
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DOI: 10.1002/jlcr

[
18F]FAHA FOR PET
1001
The radiochemical purity of the purified [18F]-3, which co-eluted on analytical
HPLC with an authentic sample of unlabeled 3, was > 99% (Figure 3).
The cold fluorination with Bu4NF and normal phase purification using
organic solvents produced >50% yield of the desired product, however, the
radiochemical yields using the described approach was only 1.0–3.8% (d.c.)
with an average of 1.8%. Therefore, a carrier added synthesis was performed,
but did not provide any significant improvement in yields.
Radiofluorination reactions with Bu4N18F were also carried out in several
solvents such as THF, MeCN, DMSO and DMSO/MeCN mixture to optimize
the radiochemical yields. However, no significant improvement in yields was
obtained. When the reactions were carried out with K18F/kryptofix at 1158C
in MeCN, the radiochemical yields were significantly increased from 3 to 13%.
Although, we have been using Bu4N18F as a preferred fluorinating agent in
many syntheses,12–15 the approach using K18F/kryptofix appears to be
superior to that using Bu4N18F for radiofluorination of 2.
The crude yields in the Bu4N18F reactions were in the range of 4–14%,
however, purified yields were much less (Table 1). There are several reasons for
an overall low radiochemical yields. In addition to the low labeling efficiency,
Figure 3. Analytical HPLC chromatogram of purified [18F]FAHA, co-injected
with standard FAHA: analytical C18 column; 35% MeCN and 65% sodium
phosphate (50 mM) in H2O; flow 1.0 ml/min
Copyright # 2006 John Wiley & Sons, Ltd.
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U. MUKHOPADHYAY ET AL.
Table 1. Radiochemical yields of [18F]FAHA with two different [18F]-fluoride salts in
various solvent systems under different reaction conditions
No. of Fluoride
Expt.
Solvent
Temperature Time
(8C)
%Yield
(min.) crude (d.c.) pure (d.c.)
%Yield
1
2
3
4
5
6
7
8
Bu4N18F
Bu4N18F
Bu4N18F
Bu4N18F
Bu4N18F
Bu4N18F
Bu4N18F
Bu4N18F
Bu4N18F
MeCN
MeCN
THF
THF
THF
DMSO
DMSO/MeCN
DMSO/MeCN
DMSO/MeCN
80
80
80
80
80
80
80
80
20
20
20
20
20
20
20
20
20
25
25
25
12.83
14.83
6.5
3.8
4.0
1.0
1.8
1.92
2.7
1.8
7.1
3.03
3.87
1.76
2.03
12.5
9.1
11.44
2.75
3.69
30.9
22.5
27.3
9
80
10
11
12
K18F/Kryptofix MeCN
K18F/Kryptofix MeCN
K18F/Kryptofix MeCN
115
115
115
11.5
the major loss of the product was during the HPLC purification step; only
40–50% of the total radioactivity was eluted from the column, while 50–60%
radioactivity, including by-products, was retained on the column. The loss of
the product during HPLC purification is due to poor solubility of the product
in aqueous solvents. When the crude product was mixed with the HPLC
solvent (water/MeCN), the compound had partially precipitated out of the
solution, and therefore, could not be analyzed by HPLC. The use of an
aqueous buffer (50 mM Na2HPO4) instead of water in MeCN as a HPLC
solvent, had improved the HPLC peak shape and to some extent, the yield due
to enhanced solubility of the product in the buffer.
Also, we have explored the feasibility of product purification using organic
solvent systems. In one preparation, we purified the crude product on a small
silica gel column using 30% acetone in hexane as eluent with manual fraction
collection. The radiochemical yield was increased from 13 to 15% in this
normal phase purification approach suggesting that the compound was not
retained on the column. However, the product had a small amount of chemical
impurities. The later suggests that use of HPLC with a normal phase column
may be suitable for purification of [18F]FAHA to improve recovery, however,
this HPLC method has to be further optimized.
In the current work, the method of choice for radiosynthesis and
purification of [18F]FAHA involved K18F/kryptofix as the fluorinating agent,
and aqueous buffer on a reverse phase HPLC column. The radiochemical
purity in this synthesis was >99% with specific activity >74 GBq/mmol. The
specific activity in this no carrier added synthesis was very high and
comparable with that of [18F]FDG. The synthesis time was 67–75 min from
the end of bombardment (EOB). In a representative synthesis, 2.5 mCi
(92.5 MBq) of labeled product 3 could be obtained starting from 25 mCi
(925 MBq) of [18F]fluoride.
Copyright # 2006 John Wiley & Sons, Ltd.
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[
18F]FAHA FOR PET
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Experimental
Reagents and instrumentation
All reagents and solvents were purchased from Aldrich Chemical Co.
(Milwaukee, WI), and used without further purification. Solid phase
extraction cartridges (silica gel, 900 mg) were purchased from Alltech
Associates (Deerfield, IL).
Thin layer chromatography (TLC) was performed on pre-coated Kieselgel
60 F254 (Merck) glass plates. Proton and 19F NMR spectra were recorded at
the University of Texas MD Anderson Cancer Center on a Brucker 300 MHz
spectrometer using tetramethylsilane as an internal reference and hexafluor-
obenzene as an external reference, respectively. Low-resolution mass spectral
analysis was performed in house on HPLC-mass spectrometer (Applied
Biosystem Q-Trap LC/MS/MS). High-resolution mass spectra were obtained
on a Waters Micromass Q-TOF Ultima mass spectrometer at the University of
Texas MD Anderson Cancer Center using electrospray ionization (ESI)
technique.
HPLC was performed on a 1100 series pump (Agilent, Germany), with built
in UV detector operated at 254 nm, and a radioactivity detector with single-
channel analyzer (Bioscan, Washington DC) using a semi-preparative C18
reverse phase column (Alltech, Econosil, 10 Â 250 mm, Deerfield, IL) and an
analytical C18 column (Rainin, Microsorb-MV, 4.6 Â 250 mm, Emeryville,
CA). A mixture of acetonitrile and sodium phosphate solution (35% MeCN
and 65% 50 mM Na2HPO4 in H2O) solvent system was used for purification
of the radiolabeled compound, and for quality control analysis on analytical
HPLC.
Preparation of 6-amino-1-hexanoicanilide: 1
To a solution of 6-amino hexanoic acid (2.5 g, 19 mmol) in dichloroethane
(25 ml) thionyl chloride (2.5 g, 21 mmol in 25 ml dichloroethane) was added
and the reaction mixture stirred for 2 h at room temperature (r.t.). Aniline
(1.3 g, 14.3 mmol) was added to the reaction mixture, which was first stirred at
r.t. for 0.5 h and then refluxed for 1.5 h. The reaction mixture was then cooled
to 08C, which resulted in the formation of a precipitate. The residue was
filtered washed with dichloromethane and dried under vacuum. The product
was obtained in 80% yield and used for the next step without further
1
purification. H NMR (DMSO-D6) d: 9.96 (s, 1H, NH), 7.86 (bs, 2H, NH2),
7.62 (d, 2H, J=7.5 Hz, aromatic), 7.30 (t, 2H, J=7.8 Hz, aromatic),
6.98 (t, 1H, J=7.5 Hz, aromatic), 2.80–2.74 (m, 2H, C6H), 2.32 (t, 2H,
J=7.2 Hz, C2H), 1.64–1.48 (m, 4H, C3,5H), 1.39–1.29 (m, 2H, C4H). MS:
M+1, 207.5
Copyright # 2006 John Wiley & Sons, Ltd.
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U. MUKHOPADHYAY ET AL.
Preparation of 6-(bromoacetamido)-1-hexanoicanilide: 2
Crude compound 1 (1.0 g, 4.8 mmol) was dissolved in THF (20 ml) under
argon and triethylamine (0.77 g, 7.6 mmol) was added. The reaction mixture
was cooled to À108C, and bromoacetic anhydride (2.0 g, 7.7 mmol) in 20 ml
THF was added in 2 min. The reaction mixture was stirred for 20 min in the
cold and subsequently at r.t. until TLC analysis (40% acetone in hexane)
showed that no starting material (s.m.) remained (Rf; s.m.=0.00, pro-
duct=0.38). The reaction mixture was quenched with cold water (10 ml) and
extracted with 50% EtOAc/hexane (3 Â 50 ml). The organic extract was dried
(MgSO4) and evaporated to dryness. The crude product was recrystallized
from dichloroethane and hexane mixture. Pure compound (1.0 g) was obtained
1
in 62% yield. H NMR (CDCl3) d: 7.54 (d, 2H, J=9.0 Hz, aromatic), 7.34
(t, 2H, J=9.0 Hz, aromatic), 7.12 (t, 1H, J=6.0 Hz, aromatic), 3.90 (s, 2H,
CH2-Br), 3.36 (q, 2H, J=6.00 Hz, C6H), 2.40 (t, 2H, J=6.0 Hz, C2H), 1.79 (q,
2H, J=6.9 Hz, C5H), 1.61 (q, 2H, J=7.0 Hz, C3H), 1.45 (q, 2H, J=6.6 Hz,
1
C4H). H NMR (DMSO-D6) d: 9.85 (s, 1H, NH), 8.26 (s, 1H, NH), 7.58 (d,
2H, J=7.5 Hz, aromatic), 7.28 (t, 2H, J=6.6 Hz, aromatic), 7.01 (t, 1H,
J=7.5 Hz, aromatic), 3.8 (s, 2H, CH2-Br), 3.07 (q, 2H, J=6.9 Hz, C6H), 2.29
(t, 2H, J=7.5 Hz, C2H), 1.59 (q, 2H, J=7.5 Hz, C5H), 1.42 (q, 2H, J=7.0 Hz,
C3H), 1.30 (q, 2H, J=4.5 Hz, C4H). High resolution MS: M+Na, Calculated
349.0528; found 349.0249.
Preparation of 6-(fluoroacetamido)-1-hexanoicanilide (FAHA): 3
To a solution of 6-(bromoacetamido)-1-hexanoicanilide 2 (50mg, 0.15mmol) in
dry THF (2.5 ml) was added tetrabutylammonium fluoride solution in THF
(1M Bu4NF, 0.30ml). The resulting mixture was heated at 808C for 20min
when TLC analysis (40% acetone in hexane) showed that no starting material
remained (Rf; s.m.=0.38, product=0.29). The solvent was evaporated and the
crude product was purified by flash chromatography on a silica gel column
using 30% acetone/hexane solvent system. The appropriate fractions were
combined and evaporated to dryness. Pure compound 3 (22 mg) was obtained in
54% yield. 1H NMR (CDCl3) d: 7.54 (d, 2H, J=7.8 Hz, aromatic), 7.34 (t, 2H,
J=7.5 Hz, aromatic), 7.12 (t, 1H, J=7.5 Hz, aromatic), 4.80 (d, 2H, J=47.4 Hz,
CH2-F), 3.36 (q, 2H, J=6.6 Hz, C6H), 2.40 (t, 2H, J=7.5 Hz, C2H), 1.80 (q,
2H, J=7.2 Hz, C5H), 1.60 (q, 2H, J=7.2Hz, C3H), 1.46 (q, 2H, J=7.1 Hz,
C4H). 19F NMR: (CDCl3) d: À224.9 (dt, Jgem=47.4 Hz and Jlong range=3.0 Hz).
High resolution MS: M+Na, Calculated 289.1328; found 289.1324.
Preparation of 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]AHA):
The aqueous [18F]fluoride produced from the cyclotron by the reaction
18O(p, n)18F was trapped on anion exchange cartridge (ABX, Germany) and
Copyright # 2006 John Wiley & Sons, Ltd.
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[
18F]FAHA FOR PET
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eluted with an aqueous solution of n-Bu4NHCO3 (400 ml, 1% by wt) or
K2CO3/kryptofix 2.2.2 solution (1.2 ml) into a V-vial. The K2CO3/kryptofix
2.2.2 solution was prepared by mixing a solution of kryptofix 2.2.2 (12 mg/ml
in MeCN) and K2CO3 (2.75 mg/ml in water) in the ratio of 80:20, respectively.
The solution was evaporated azeotropically with acetonitrile (1.0 ml) to
dryness at 79–808C (Bu4N18F) or 1158C (K18F/kryptofix) under a stream of
argon. To the dried n-Bu4N18F, a solution of 2 (3–4 mg, 9–12 mmol) in
anhydrous MeCN (0.4 ml) was added, and the mixture was heated at 79–808C
for 20 min. The reaction with K18F/kryptofix was performed at 1158C for
25 min. The reaction mixture was cooled, passed through a silica gel cartridge
(Alltech), and eluted with 30% methanol in dichloromethane (2.5 ml). After
evaporation of the solvent with a stream of argon at 808C, the residue was
diluted with HPLC solvent (0.5 ml) and purified by HPLC. The desired
product was isolated and radioactivity was measured in a dose calibrator
(Capintec, Ramsey, NJ). The solvent was evaporated on a high vacuum pump,
the product was re-dissolved in saline and filtered through a Millipore filter.
The product was co-injected with an authentic unlabeled sample onto an
analytical column to confirm its identity.
Conclusion
Cold synthesis and radiolabeling of a novel substrate for HDAC,
6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) has been accom-
plished. This new compound may be useful in measuring the level of HDAC
expression and activity in cancer patients using PET imaging.
Acknowledgements
This work was supported by start up funds from The University of Texas MD
Anderson Cancer Center, and DOD BCRP W81WXWH-04-1-0674.
References
1. Johnstone RW. Nat Rev Drug Discovery 2002; 1: 287–299.
2. Marks PA, Rifkind RA, Richon WM. Nat Rev Cancer 2001; 1: 194–202.
3. Varghese S, Gupta D, Baran T, Jiemjit A, Gore SD, Casero RA, Woster PM.
J Med Chem 2005; 48: 6350–6365.
4. Grozinger CM, Schrieber SL. Chem Biol 2002; 9: 3–16.
5. Weinmann H, Ottow E. Ann Rep Med Chem 2004; 39: 185–196.
6. Kelly WK, O’Connor OA, Krug LM, Chiao JH, Heaney M, Curley T,
MacGraygor CB, Tong W, Secrist JP, Schwartz L, Richardson S, Chu E,
Olgac S, Marks PA, Scher H, Richon VM. J Clin Oncol 2005; 23: 3923–3931.
7. Morgan GJ, Krishnan B, Jenner M, Davies FE. Lancet Oncol 2006; 7: 316–325.
8. Rodriquez M, Aquino M, Bruno I, De Martino G, Taddei M, Gomez-Paloma L.
Curr Med Chem 2006; 13(10): 1119–1139.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 997–1006
DOI: 10.1002/jlcr

1006
U. MUKHOPADHYAY ET AL.
9. Liu T, Kuljaca S, Tee A, Marshall GM. Histone deacetylase inhibitors: Cancer
Treat Rev 2006; 32(3):157–165.
10. Vanhaecke T, Papeleu P, Elaut G, Rogiers V. Curr Med Chem 2004; 11:
1629–1643.
11. Kelly WK, Richon VM, O’Connor O, Curley T, MacGregor- Curtelli B, Tong W,
Klang M, Schwartz L, Richardson S, Rosa E, Drobnjak M, Cordon-Cordo C,
Chiao JH, Rifkind R, Marks PA, Scher H. Clin Cancer Res 2003; 9(10 Pt 1):
3578–3588.
12. Alauddin MM, Fissekis JD, Conti PS. J Label Compd Radiopharm 2002; 45:
583–590.
13. Alauddin MM, Shahinian A, Park R, Tohmi M, Fissekis JD, Conti PS. J Nucl
Med 2004; 45: 2063–2069.
14. Alauddin MM, Fissekis JD, Conti PS. J Label Compd Radiopharm 2003; 46:
805–814.
15. Alauddin MM, Balatoni J, Gelovani JG. J Label Compd Radiopharm 2005; 48:
941–950.
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J Label Compd Radiopharm 2006; 49: 997–1006
DOI: 10.1002/jlcr