Synthesis of an18F-fluorobenzoate idarubicin derivative as new potential PET radiotracer to predict chemotherapy resistance

Article abstract of DOI:10.1002/jlcr.990

Anthracyclines are among the most widely used antineoplastic agents in current clinical practice. Nevertheless, chemoresistance, which results in failure to eradicate the tumor, is often observed after administration of anthracyclines, and no assay system

Full text of DOI:10.1002/jlcr.990

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 819–827.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.990
Research Article
Synthesis of an 18F-fluorobenzoate idarubicin derivative
as new potential PET radiotracer to predict
chemotherapy resistance
Yann Seimbille*, Johannes Czernin, Michael E. Phelps and
Daniel H. S. Silverman
Ahmanson Biological Imaging Division, Department of Molecular & Medical
Pharmacology, UCLA School of Medicine, Los Angeles, CA, USA
Summary
Anthracyclines are among the most widely used antineoplastic agents in current
clinical practice. Nevertheless, chemoresistance, which results in failure to eradicate
the tumor, is often observed after administration of anthracyclines, and no assay
system has yet been found to accurately predict tumor resistance to those antitumor
agents. We sought to prepare an F-18 labeled derivative of idarubicin, a 4-demethoxy-
daunorubicin analogue, to use in helping to assess physiologic resistance to
anthracyclines in vivo. Two different synthetic pathways, which required the
preparation of the key intermediate [18F]fluorobenzoic acid ([18F]FBA), are advanced
to label idarubicin with F-18 on its primary amine. The first approach yielded the
desired [18F]fluorobenzoate idarubicin derivative in two steps from [18F]FBA, while
the second strategy consisted of a direct acylation of idarubicin by treatment with
[18F]FBA in presence of diethyl cyanophosphonate. Although the first method led
to fewer byproducts, it required more time to obtain the HPLC-purified radio-
pharmaceutical (100 min vs 90 min) and resulted in lower radiochemical yields (8–25%
vs 25–39% decay corrected from starting fluoride). Copyright # 2005 John Wiley
& Sons, Ltd.
Key Words: chemotherapy; anthracyclines; fluorine-18; positron emission tomography
*Correspondence to: Yann Seimbille, Ahmanson Biological Imaging Division, UCLA School of Medicine,
Department of Molecular & Medical Pharmacology, 10833 Le Conte Avenue, CHS AR-264, Los Angeles,
CA 90095-6942, USA. E-mail: yseimbille@mednet.ucla.edu
Contract/grant sponsor: California Breast Cancer Research Program; contract/grant number: 7KB0155
Copyright # 2005 John Wiley & Sons, Ltd.
Received 2 March 2005
Revised 28 March 2005
Accepted 19 May 2005

820
Y. SEIMBILLE ET AL.
Introduction
Several radiolabeled chemotherapeutics have been advanced in the past to
allow in vivo prediction of therapeutic efficacy prior to treatment.1–4 Positron
emitter labeled derivatives of antitumor agents commonly used in clinical
practice have been examined in this context.5ꢀ8 We have recently explored the
possibility of predicting breast cancer therapy in vivo with fluorine-18 labeled
analogs of paclitaxel and cyclophosphamide.9,10 Anthracycline glycosides are
among the most widely used antineoplastic agents in current clinical practice.
Doxorubicin and daunorubicin are natural glycosides whose antitumor
activity against a relatively broad spectrum of human cancers was demon-
strated in the 1960s, while epirubicin and idarubicin (4-demethoxy-daunor-
ubicin analogue, 1) are semisynthetic analogues endowed with different
pharmacological and toxicological profiles (Figure 1).11 Despite their extensive
clinical use, their specific mechanism of action has never been well established,
but anthracyclines are considered likely to interact with topoisomerase II by
stabilization of the ternary DNA–enzyme–drug complex, which hinders the
relegation of the DNA strands and ultimately induces irreversible DNA
breaks.12 This interaction between the drug and the enzyme leads to delay in
cell cycle progression and eventually apoptosis.
Idarubicin has been reported to be a useful alternative to other
anthracyclines due to its therapeutic efficacy against a wide range of human
tumors and its reduced cardiotoxicity.11 Nevertheless, chemoresistance, which
results in failure to eradicate the tumor, is often observed after administration
of idarubicin. However, no assay system has yet been found to accurately
predict tumor resistance to anthracyclines. Therefore, the opportunity to
radiolabel idarubicin with a positron emitter would provide an experimental
tool to assess drug concentration in the tumor tissue and to monitor
anthracycline based therapy. Previous studies reported an iodine-124 labeled
doxorubicin derivative and a carbon-11 analogue of daunorubicin. However,
so far those imaging agents have not been extensively evaluated for clinical
purposes.10,13–17
We sought to prepare an F-18 labeled derivative of idarubicin to use in
helping to assess physiologic resistance to anthracyclines in vivo, and thus to
O
OH
O
O
O
OH
O
O
O
OH
O
O
C
OH
B
O
OH
OH
9
OH
OH
D
A
7
OH
OH
4
O
OH
O
OH
O
O
OH
O
O
O
CH O
O
OH
O
CH O
O
CH O
3
3
3
3'
4'
HO
NH
NH
NH
NH
2
2
2
2
HO
HO
HO
Doxorubicin
Daunorubicin
Epirubicin
Idarubicin (1)
Figure 1. Molecular structures of the clinically active anthracyclines
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F-18 LABELED IDARUBICIN
821
prevent those patients who would not respond to idarubicin from suffering
toxicities of that chemotherapy regimen without clinical benefit, and possibly
delay the initiation of a more effective regimen. We herein report the synthesis
of (8S,10S)-9-acetyl-7-[[3-[(4-fluorobenzoyl)amino]-2,3,6-trideoxy-a-l-lyxo-hexo-
pyranosyl]oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphthacenedione (2),
as well as the radiolabeling of idarubicin on its primary amine from
[18F]fluorobenzoic acid.
Results and discussion
Chemistry
We synthesized the fluorobenzoate idarubicin derivative 2 by treatment of
idarubicin hydrochloride 1 with 4-[19F]fluorobenzoyl chloride in presence of
triethylamine in CH3CN. The reaction afforded the desired amide 2 in 96%
yield (Scheme 1). The regioselectivity of the coupling was assigned from the
signals in the 1H NMR. The amide proton gives a characteristic broad singlet
at 5.26 ppm, and two additional groups of two aromatic protons correspond-
ing to the fluorobenzoate substituent were observed. Identity of the product
was also confirmed by mass spectrometry.
O
OH
O
O
OH
O
O
Cl
OH
OH
F
O
OH
O
O
O
OH
O
O
Et3N, CH2Cl2
1
2
HN
NH2
HO
F
HO
O
Scheme 1. Synthesis of the cold reference 2, (8S,10S)-9-acetyl-7-[[3-[(4-
fluorobenzoyl)amino]-2,3,6-trideoxy-a-l-lyxo-hexopyranosyl]oxy]-7,8,9,10-tetra-
hydro-6,9,11-trihydroxy-5,12-naphthacenedione
Radiochemistry
Two different synthetic pathways, which required the preparation of the key
intermediate [18F]fluorobenzoic acid ([18F]FBA; 5) are advanced to label
idarubicin with the positron emitter F-18 on its primary amine (Scheme 2).
Preparation of [18F]FBA was achieved in two steps from the pentamethyl-
benzyl 4-trimethylammoniumbenzoate precursor: (1) incorporation of
[18F]fluoride into the activated trimethylammonium triflate salt, followed by
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 819–827

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Y. SEIMBILLE ET AL.
O
O
O
18
-
O
F , K CO /K
222
O
-
TFA, Anisole
OH
2
3
OTf
+
N
18
F
18
F
5
3
4
O
OH
O
O
O
O
O
P
1, Et N
OH
OH
CN
3
18
F
O
OH
O
O
5
18
F-2
O
Cl CHOCH
2
3
Et N
3
HN
Cl
18
HO
F
O
18
F
6
Scheme 2. Synthesis of [18F]fluorobenzoate idarubicin derivative ([18F]-2)
Table 1. Preparation of [18F]fluorobenzoic acid ([18F]FBA; 5)
Solvent
Temperature
Time (min)
RCY (%) (decay corrected)
Step 1
Step 2
CH3CN
DMSO
DMSO
1108C
140–1508C
140–1508C
10
10
15
13–27 (n ¼ 6)
54–59 (n ¼ 4)
30–42 (n ¼ 3)
TFA
RT
2
50–77 (n ¼ 10)
(2) cleavage of the ester. A pentamethylbenzyl 4-trimethylammoniumbenzoate
triflate salt (3) was chosen to prepare [18F]FBA, since it was extensively used in
our laboratory to synthesize an F-18 analog of paclitaxel, as described earlier
by Kiesewetter et al.18
The first radiochemical step consisted of the introduction of the fluorine-18
using a no-carrier-added nucleophilic substitution with K[18F]F-K222 (K222
:
Kryptofix [2.2.2]; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane)
and was initially performed in acetonitrile (non-stirred sealed V-vial placed in
a heating block at 1108C for 10 min), leading to relatively low radiochemical
yields (Table 1). However, the multi-step radiosynthesis approaches proposed
here to radiolabel idarubicin require optimized reaction conditions, high yields
for each step and short-time reactions compatible with the short half-life of the
radioisotope concerned (t1/2=109.8 min). Therefore, we investigated whether
we could improve the nucleophilic F-18 exchange reaction with the trimethyl
ammonium triflate precursor, by changing the reaction conditions (solvent,
temperature, and time). Incorporation of fluorine-18 into the trimethylammo-
niumbenzoate precursor was significantly increased by using DMSO instead of
CH3CN, since the reaction could be performed at higher temperature (Table 1).
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F-18 LABELED IDARUBICIN
823
Radiochemical yields were, with respect to initial [18F]fluoride: 54–59%
decay corrected when the reaction mixture was heated in DMSO for 10 min at
140–1508C vs 13–27% in CH3CN at 1108C. However, a longer reaction time
led to a decreased yield, probably due to a rapid degradation of the fluorinated
compound 4 in hot DMSO.
Treatment of 4 in trifluoroacetic acid (TFA) resulted in the cleavage of the
ester to yield [18F]FBA. Although the hydrolysis was quantitative and
occurred cleanly in 2 min at room temperature, we observed loss of activity
during the subsequent evaporation of the TFA. Therefore, the decay corrected
radiochemical yields reported for this step were only 50–77% (Table 1).
Typically, starting from a 1.6–1.8 GBq (42–49 mCi) aliquot of a cyclotron
[18F]Fꢀ batch, 0.5 GBq (13–14 mCi) of [18F]FBA (5) could be obtained in 50–
55 min.
Two different strategies were elaborated to radiolabel idarubicin from
[18F]fluorobenzoic acid. The first approach allowed us to obtain the final F-18
labeled compound in two steps from [18F]FBA and was developed to mimic
the synthesis of the unlabeled compound 2. [18F]FBA was converted into its
corresponding acyl chloride 6 by treatment with a,a-dichloromethyl methyl
ether. Subsequent coupling of 4-[18F]fluorobenzoyl chloride (6) with idarubicin
in presence of triethylamine afforded, after HPLC purification, [18F]-2 in
8–25% (decay corrected and based on starting aliquot of cyclotron-produce
[18F]fluoride, n ¼ 5). The average total synthesis time was about 100 min and
identity of the new radiopharmaceutical was confirmed by comparing its
HPLC mobility upon co-injection with authentic non-radioactive analogue.
The second strategy provided the desired [18F]fluorobenzoate idarubicin
derivative by direct acylation, in only one step from [18F]FBA. Idarubicin
was treated with [18F]fluorobenzoic acid ([18F]FBA; 5) in presence of
triethylamine and diethyl cyanophosphonate at 1108C for 10 min. According
to this procedure, pure [18F]-2 was obtained in about 90 min and the
radiochemical yields, based on starting [18F]fluoride, were 25–39% (decay
corrected, n ¼ 5).
Although the first method had the general advantage of leading to fewer
radioactive byproducts, as seen by HPLC, it required more time and resulted
in significantly lower radiochemical yields. The labeling intermediate used in
the first approach, 4-[18F]fluorobenzoyl chloride, is known to be volatile and
therefore loss of activity occurred by co-evaporation of 6 during the removal
of the excess of chlorinating reagent. Furthermore, the high sensitivity of 4-
[18F]fluorobenzoyl chloride (6) to hydrolysis could impair the efficiency of the
coupling reaction, resulting in relatively low radiochemical yields obtained
with the two-step procedure. Also, we observed that the additional radio-
chemical step included in the first method significantly increased our radiation
exposure.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 819–827

824
Y. SEIMBILLE ET AL.
Experimental
General
All reagents, including anhydrous solvents, were purchased from Aldrich,
Sigma and Acros, and were used without further purifications. The
pentamethylbenzyl 4-trimethylammoniumbenzoate triflate precursor (3) was
synthesized as previously described by Lang et al.19 Analytical thin layer
chromatography (TLC) was performed on Sigma–Aldrich silica gel pre-coated
plastic sheets with fluorescent indicator (UV 254). Visualization was achieved
with short-wave ultraviolet light. Column chromatography was performed
using silica gel (60–200 mesh). High performance liquid chromatography
(HPLC) was carried out on an Agilent 1100 Series system. HPLC eluates were
monitored for their UV absorbance at 254 nm, and their radioactivity content
by connecting the outlet of the UV-photometer to a NaI detector. The
recorded data were processed by an Agilent ChemStation software system.
18F-activity was also measured with an ion chamber Capintec CRC11. The
HPLC column used for the characterization of the product against standards
and for the purification of radioactive compounds was a Phenomenex Luna-
C18 (5 mm, 250 mm ꢁ 10 mm) column, operated at a flow rate of 2 ml/min
(linear gradient over 20 min of 50–95% CH3CN in water containing 0.5%
1
AcOH followed by 10 min isocratic elution with 95% CH3CN). H NMR
spectrum was taken in chloroform-d on a Bruker AM360/Wb spectrometer (at
360 MHz) using Me4Si as an internal standard, and selected proton resonances
are reported. Chemical shifts are expressed in ppm (d) relative to the standard
and coupling constants (J) in Hz. Mass spectrum was obtained on MALDI-
TOF instrument (ABI DE STR).
Chemistry
Synthesis of (8S,10S)-9-acetyl-7-[[3-[(4-fluorobenzoyl)amino]-2,3,6-trideoxy-
a-l-lyxo-hexopyranosyl]oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphtha-
cenedione (2). Idarubicin hydrochloride (1) (10 mg, 19 mmol) in CH3CN (3 ml)
was treated with 4-fluorobenzoyl chloride (2.5 ml, 21 mmol) and triethylamine
(3 ml, 22 mmol) at room temperature for 30 min. The reaction mixture was
concentrated, poured onto a column of silica and was eluted with CH2Cl2/
MeOH (19/1). Evaporation of the fractions containing the expected product
1
led to 2 (11.5 mg, 96%) as a red solid. H NMR (360 MHz, CDCl3): d 13.60
(s, 1 H), 13.33 (s, 1 H), 8.34 (m, 2 H), 7.83 (m, 2 H), 7.72 (m, 2 H), 7.06
(t, J=8.4 Hz, 2 H), 6.49 (d, J=8.3 Hz, 1 H), 5.52 (d, J=3.6 Hz, 1 H), 5.26 (brs,
1 H), 4.45–4.25 (m, 2 H), 3.74 (brs, 1 H), 3.29 (d, J=18.7 Hz, 1 H), 2.98
(d, J=18.7 Hz, 1 H), 2.44 (s, 3 H), 2.36 (m, 1 H), 2.14 (dd, J=4.1 and 15.1 Hz,
1 H), 2.04 (dd, J=5 and 14 Hz, 1 H), 1.87 (dt, J=4.3 and 13 Hz, 1 H), 1.32
(d, J=6.5 Hz, 3 H). MS (MALDI-TOF) m/z 642.17 [M + Na]+. HRMS
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F-18 LABELED IDARUBICIN
825
(MALDI-TOF) m/z: [M+Na]+ calculated for C33H30NO10FNa+, 642.1746;
found, 642.1772.
Radiochemistry
Preparation of K[18F]F-K222 complex. A 5 ml V-vial was loaded with 0.5 ml of
a CH3CN/H2O solution of potassium carbonate (0.5 mg; 3 mmol) and
Kryptofix [2.2.2] (K222; 2.25 mg; 6 mmol). Fluorine-18 in water was added
and the V-vial was gently heated at 1108C. Water was removed under a stream
of argon by azeotropic distillation with acetonitrile (3 ꢁ 0.5 ml) to give the no-
carrier-added K[18F]F-K222 complex as a white semi-solid residue.
General procedure for preparation of fluorine-18-labeled 4-fluorobenzoic acid. A
solution of pentamethylbenzyl 4-trimethylammoniumbenzoate triflate (3,
3 mg; 6 mmol) in anhydrous acetonitrile or dimethyl sulfoxide (0.3 ml) was
added into the vial containing dry cryptate (K[18F]F-K222) and heated for
10 min, respectively at 1108C and 140–1508C (Scheme 2, Table 1). After
cooling the acetonitrile solution was diluted with ether (0.2 ml) and transferred
onto a silica Sep-Pak. The V-vial was subsequently washed twice with ether
(0.3 ml), used to elute 4 from the short silica gel column. If DMSO was used
instead of CH3CN, the reaction mixture was poured into water (8 ml), and the
aqueous solution was passed through a C18 Sep-Pak. Compound 4 was then
eluted through the column with ether (2.5 ml). The ethereal fraction containing
4 was subsequently evaporated under a stream of argon. Anisole (5 ml) was
added and the intermediate 4 was treated with trifluoroacetic acid (100 ml) for
2 min at room temperature. Finally, the volatiles were evaporated under an
argon stream to yield [18F]fluorobenzoic acid ([18F]FBA; 5). Typically, 0.5
GBq (13–14 mCi) of [18F]FBA (5) could be obtained in 50–55 min starting
from 1.6–1.8 GBq (42–49 mCi) aliquot of a cyclotron-produced [18F]F- batch
(overall radiochemical yields, based on starting [18F]fluoride: 39–45% decay
corrected).
Preparation of the fluorine-18-labeled fluorobenzoate idarubicin derivative
([18F]-2) – Two steps approach. [18F]fluorobenzoic acid was treated with
a,a-dichloromethyl methyl ether (50 ml, 0.55 mmol) at 1108C for 5 min. The vial
was then cooled in an ice bath (2–3 min) and the excess of chlorinating reagent
was evaporated under an argon stream while the reaction vessel was
maintained in the ice bath. A solution of idarubicin (1 mg, 2 mmol) in CH3CN
(0.4 ml) and iPr2NEt (5 ml) were added to the residue and the solution was
stirred at room temperature for 10 min.The solution was diluted with water
containing 0.5% AcOH (0.4 ml) and the reaction mixture was injected onto a
reverse phase HPLC column (Phenomenex Luna C-18, 10 ꢁ 250 mm, 5 mm).
Retention time of the fluorine-18-labeled fluorobenzoate idarubicin derivative
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Y. SEIMBILLE ET AL.
[18F]-2 was 21 min vs 5 min for the starting material 1 under the same elution
conditions. Typically, 0.07–0.2 GBq (2–6 mCi) of pure [18F]-2 could be
obtained in 45–50 min starting from 0.5 GBq (13–14 mCi) of [18F]fluoroben-
zoic acid (overall radiochemical yields, based on starting [18F]fluorobenzoic
acid: 21–57% decay corrected). Specific activity, determined by using on-line
measurements of radioactivity and UV absorption, was >37 GBq/mmol
(>1000 Ci/mmol).
Preparation of the fluorine-18-labeled fluorobenzoate idarubicin derivative
([18F]-2) – One step approach. Idarubicin (1 mg, 2 mmol) in CH3CN
(0.4 ml), diethyl cyanophosphonate (1 mg, 6 mmol) in CH3CN (50 ml), and
iPr2NEt (10 ml) were added to the dried [18F]fluorobenzoic acid. The mixture
was heated at 1108C for 10 min and then cooled in a water bath for 1–2 min.
The solution was diluted with 450 ml water containing 0.5% AcOH, and
loaded onto a Phenomenex Luna C-18 column (10 ꢁ 250 mm, 5 mm).
Typically, 0.3–0.4 GBq (7–10 mCi) of pure [18F]-2 could be obtained in 35–
40 min starting from 0.5 GBq (13–14 mCi) of [18F]fluorobenzoic acid (overall
radiochemical yields, based on starting [18F]fluorobenzoic acid: 63–87% decay
corrected). Specific activity was estimated >37 GBq/mmol (>1000 Ci/mmol).
Formulation of the [18F]fluorobenzoate idarubicin derivative ([18F]-2) and
quality control. HPLC fractions (4–5 ml) containing the 18F labeled product
were collected and solvents were evaporated under reduced pressure. [18F]-2
was dissolved in ethanol and the solution was then diluted to the proper
dosage with sterile physiological saline, so that the injection dose contained no
more than 10% of alcohol.
As demonstrated by HPLC analysis (Phenomenex Luna C-18 column,
10 ꢁ 250 mm, 5 mm), radiolabeled idarubicin [18F]-2 obtained by both approaches
co-eluted with authentic synthesized unlabeled reference 2. The radiopharma-
ceutical was found to be >95% chemically and radiochemically pure.
Conclusion
In conclusion, this report describes two synthetic strategies for the production
of a new F-18 labeled anthracycline for in vivo prediction of physiologic
chemoresistance to therapy. Conditions for radiosynthesis are suitable for
preparation of the compound in quantities and times practical for use as a
PET radiopharmaceutical. However, considering the radiochemical yields,
time and radiation exposure, the direct acylation of idarubicin with
[18F]fluorobenzoic acid ([18F]FBA) appears preferable as a more robust
procedure for routine clinical production of the radiolabeled fluorobenzoate
idarubicin derivative. Future studies will be aimed at determining how useful
this imaging agent may be in assessing the biodistribution of idarubicin,
measuring drug concentration in tumor tissue, and monitoring therapy in vivo.
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Acknowledgements
This work was supported by California Breast Cancer Research Program
Grant 7KB-0155. We thank the cyclotron staff at UCLA and the UCLA
Pasarow Mass Spectrometry Laboratory for their collaboration to this work.
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