Preparation and biodistribution of [125I]Melphalan: A potential radioligand for diagnostic and therapeutic applications

Article abstract of DOI:10.1002/jlcr.1698

This paper addresses the development of a new radiopharmaceutical for cancer imaging and therapy. The optimization of the labeling conditions of thymidine analogue, melphalan, with ¹²⁵I is described. High radiochemical yield 96.8% was obtained by reacting 0.2mg melphalan with ¹²⁵I in the presence of choloramin-T as oxidizing agent in 0.5M phosphate buffer, pH 7, at 70°C for 15 min. Preliminary in vivo study was done in non-tumor bearing mice. The results revealed that this new tracer, ¹²⁵I-melphalan, has a high affinity to be localized in the tumor site for a long period, which indicates the specificity of this tracer to the tumor cells. The labeled compound was cleared quickly from most of the body organs. These findings suggest that ¹²⁵I-melphalan allows imaging and treatment of cancer. ¹²⁵I-melphalan meets most of the requirements necessary to be used as a successful diagnostic and therapeutic agent: it is a low-molecular-weight molecule that diffuses readily in the tissues, and dose not induce an antibody response. Copyright

Full text of DOI:10.1002/jlcr.1698

Review Article
Received 27 May 2009,
Revised 14 October 2009,
Accepted 15 October 2009
Published online 25 November 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1698
Preparation and biodistribution
of [125I]Melphalan: a potential radioligand
for diagnostic and therapeutic applications
Ã
A. M. Amin,a S. E. Soliman,b and H. A. El-Azizc
This paper addresses the development of a new radiopharmaceutical for cancer imaging and therapy. The optimization of
the labeling conditions of thymidine analogue, melphalan, with125I is described. High radiochemical yield 96.8% was
obtained by reacting 0.2 mg melphalan with 125I in the presence of choloramin-T as oxidizing agent in 0.5 M phosphate
buffer, pH 7, at 701C for 15 min. Preliminary in vivo study was done in non-tumor bearing mice. The results revealed that
this new tracer,125I-melphalan, has a high affinity to be localized in the tumor site for a long period, which indicates the
specificity of this tracer to the tumor cells. The labeled compound was cleared quickly from most of the body organs. These
findings suggest that 125I-melphalan allows imaging and treatment of cancer. 125I-melphalan meets most of
the requirements necessary to be used as a successful diagnostic and therapeutic agent: it is a low-molecular-weight
molecule that diffuses readily in the tissues, and dose not induce an antibody response.
Keywords: melphalan; iodine-125; biodistribution
shown to improve progression-free and overall survival in some
but not all studies.9–11
Introduction
Nitrogen mustards are bifunctional alkylating agents, and one of
the main classes of clinically used anticancer drugs. These drugs
react extensively with cellular macromolecules (DNA, RNA, and
proteins), thus inducing multiple kinds of molecular lesions. The
critical cellular target of these agents is DNA, which is alkylated
primarily at the N-7 position of guanine with lesser reaction at
the N-3 position of adenine.1 Besides monofunctional binding of
the drug to a single site in the DNA molecule (monoadducts),
drug-induced cross-linking between bases in the complementary
strands of a DNA molecule (DNA interstrand cross-links), as well
as DNA-protein cross-links, also occur.2,3 Nucleotide excision
repair and base excision repair have a crucial role in the repair of
monoadducts.4,5 Furthermore, a number of multistep DNA repair
pathways including nucleotide excision repair, homologous
recombination, and postreplication/translation repair, all con-
tribute to the DNA interstrand cross-link repair.6
One of the chemotherapeutic agents,cytarabine, which was
successfully labeled with iodine-125, allows imaging and
treatment of cancer. 125I-cytarabine meets most of the require-
ments to be used as a successful diagnostic and therapeutic
agent.12
Iodomelphalan has been prepared by iodination. The position
of the iodine as ortho-position to the alanine moiety.13 The
present work deals with the labeling of melphalan by iodine-
125. The factors affecting the labeling yields were investigated
and the bio-distribution in mice was performed.
The structure of 125I-melphalan via the reaction of melphalan
with iodine-125 in the presence of chloramine-T at pH 7 is
shown in Equation (1).
Experimental
Materials
Melphalan is a member of the nitrogen mustard class of
chemotherapeutic agents and elicits its mechanism of action by
the alkylation of DNA. The nitrogen mustard melphalan does not
require metabolic activation to become an alkylating agent and
forms ꢀ38% N-7-guanine monoadducts, 20% N-3-adenine mono-
adducts, 20% N-7-guanine-N-7-guanine diadducts, and 13% N-3-
adenine-N-7-guanine diadducts.7 The role of melphalan today is
essentially reserved for the management of multiple myeloma
(MM). MM is a malignant plasma cell disorder accounting for about
10% of hematologic malignancies. This malignancy, although
treatable, is considered incurable and accounts for 1% of all cancer
deaths.8 For several decades, melphalan and corticosteroids were
the main drugs for the treatment of MM. Subsequently, high-dose
melphalan supported by autologous stem cell transplantation was
All chemicals and laboratory reagents used in this work were
of the highest purity grade. In all cases, double distilled water
aLabeled Compounds Department, Hot Lab. Center, Atomic Energy Authority,
P.O. Box 13759, Cairo, Egypt
bHot Lab. Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt
cRadioisotope Production Project, Atomic Energy Authority, P.O. Box 13759,
Cairo, Egypt
*Correspondence to: A. M. Amin, Labeled Compounds Department, Hot Lab.
Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt.
E-mail: ab_amin@hotmail.com
J. Label Compd. Radiopharm 2010, 53 1–5
Copyright r 2009 John Wiley & Sons, Ltd.

A. M. Amin et al.
was used. Melphalan and Chloramine-T (N-chloro-p-toluene
1H NMR spectrum of iodo-melphalan in (DMSO-d6) revealed
sulfonamide sodium salt) (CAT) were purchased from Sigma- signals at: d (ppm) = 12.57(s, H,OH-carboxylic), 8.81(d, 2 H, NH2-
Aldrich, Germany. Iodine-125 was purchased from (H-1121 amine), 7.59(s, 1 H, CH(a)), 7.10(d, 1 H, CH(b)), 6.48(d, 1 H, CH(c)),
`
`
Budapest, Konkoly-Thege Miklos ut 29-33) as no-carrier added 4.18(t, 1 H, CH-NH2), 3.63(t, 4 H, methylene-N(CH2)2), 3.61(t, 4 H,
methylene (CH2)2 Cl2), 3.43(d, 2 H, CH2-benzen), Figure 1.
solution, radionuclidic purity 4 99%.
Animals: Albino type mice, weighing 25–30 g, were used in
groups containing three mice.
Biodistribution studies
This experiment was done by diluting the neutral solution of the
purified labeled melphalan with 1 mL saline for injection, and
filtration of the solution through 0.22 mm Millipore filter into a
sterile sealed vial. 100 mL (3.7 MBq) was injected in the tail vein of
the healthy and tumor-bearing Albino mice, weighing approxi-
mately 30 g each (three groups each of three mice). The mice
were maintained on normal diet in a metabolic cage, then
sacrificed at 0.5 h, 2 h post injection, and in addition to 4 h and
24 h in the case of tumor-bearing mice. Samples of fresh blood,
bone, and muscle were collected in pre-weighed vials and
counted. The different organs were removed, counted, and
compared to the standard solution of the labeled melphalan.
The average percent values of the administrated dose/organ
were calculated. Blood, bone, and muscles were assumed to be
7, 10, and 40% of the total body weight, respectively.15
Method
Radioiodination
Ethanolic solution of melphalan (200 mg) was added to 150 mL of
CAT (150 mg) and 150 mL phosphate buffer pH 7, in a screw
caped reaction vial. Then 10 mL Na125I (3–5 MBq) was added and
the reaction mixture was heated to 701C for 15 min. The reaction
was terminated by the addition of 50 mL of Na2S2O3 (20 mg/mL,
0.12 M).
Radiochemical analysis
The radiochemical yield of the labeled melphalan was deter-
mined using aluminum-backed silica gel-60 (TLC). The strips
were previously impregnated with Na2S2O3 (20 mg/mL, 0.12 M)
to inhibit the oxidation of the radioiodide to a volatile form.
Volume of 5 mL of the reaction mixture was spotted on the start
line, then the strip was developed using n-butanol:acetic
acid:water (4:1:2, v/v/v) as a developing system. The strips were
removed, dried, cut to 1 cm segments, and assayed for the
radioactivity using a well-type Na/T1 crystal connected to the g
Tumor implementation
For non-hypoxic tumor, 2.5 ꢁ 106 cells (200 mL) of Erlich culture
was injected intraprotenial and the mice were kept for 10 days
on normal diet in a metabolic cage until the tumor growth
appeared.
counter. The free iodide remains near the origin with Rf
=
Results and discussion
0.1–0.2, while the labeled melphalan migrates with the solvent
front with Rf = 0.8–1.0. An HPLC analysis and purification was
performed with a reverse phase C18 column and the elution was
done using the methanol:water:acetic acid (49.5:49.5:1) system
with a flow rate of 1 mL/min.14
Effect of melphalan concentration
The radiochemical yield of 125I-melphalan as a function of
melphalan concentration was studied as shown in Table 1. The
results indicate that the radiochemical yield of 125I-melphalan
increased from 81.2 to 96.8% by increasing the amount of
melphalan from 50 to 200 mg. The radiochemical yield is not
affected by the amount of melphalan higher than 200 mg. This
may be attributed to the fact that the yield reaches the
saturation value (96.8%) because the entire generated iodonium
ions in the reaction are captured at that concentration.
Activity of labeled product
Radiochemical yield; % ¼
ꢁ 100
Total activity
Preparation and structure confirmation of unlabeled iodo-
melphalan
Effect of chloramine-T concentration
The unlabeled iodo-melphalan is prepared by the same method
on a larger scale (to provide enough iodo-melphalan) to allow
isolation and characterization. Unlabelled iodo-melphalan is
characterized by proton NMR.
Radioiodination of organic molecules has been performed by
using a mild oxidizing agent such as chloramine-T, which
decomposes to hypochlorite anion that acts as an oxidizing
Figure 1. 1H NMR spectrum of iodo-melphalan.
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Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 1–5

A. M. Amin et al.
Table 1. Effect of the amount of melphalan on the
radiochemical yield of 125I-melphalan
Table 3. Effect of the temperature of the reaction mixture
on the radiochemical yield of 125I-melphalan
Melphalan amount (mg)
125I-melphalan (%)
125I (%)
Reaction temperature (1C) 125I-melphalan (%)
125I (%)
50
81.272.2
84.971.9
93.171.5
96.871.8
94.571.2
95.370.9
18.871.5
15.170.9
6.970.3
3.270.4
5.570.2
4.770.2
25
50
70
100
85.571.5
92.871.3
96.870.9
95.870.8
14.571.2
7.270.3
3.270.2
4.270.4
100
150
200
250
300
Mean7SD ( mean of three experiments). Reaction condition:
200 mg melphalan, 150 mg chloramine-T, 150 mL phosphate
buffer at pH 7 and 10 mL Na125I. The reaction mixture was
kept in a water bath (X1C) for 15 min.
Mean7SD (mean of three experiments). Reaction condition:
X mg melphalan, 150 mg chloramine-T, 150 mL phosphate
buffer at pH 7 and 10 mL Na125I. The reaction mixture was
kept in a water bath (701C) for 15 min.
Table 4. Effect of reaction time on the radiochemical yield
of 125I-melphalan
Table 2. Effect of the amount of chloramine-T on the
radiochemical yield of 125I-melphalan
Reaction time (min)
125I-melphalan (%)
125I (%)
Chloramine-T amount (mg) 125I-melphalan (%)
125I (%)
5
84.271.5
96.871.3
93.170.9
94.270.8
95.370.9
15.871.2
3.270.3
6.970.2
5.870.4
4.770.2
15
30
60
120
50
82.471.8
93.872.2
96.872.4
90.171.2
88.071.4
17.671.1
6.270.8
3.270.3
9.970.6
12.070.9
100
150
200
250
Mean7SD (mean of three experiments ). Reaction condition:
200 mg melphalan, 150 mg chloramine-T, 150 mL phosphate
buffer at pH 7 and 10 mL Na125I. The reaction mixture was
kept in a water bath (701C) for X min.
Mean7SD ( mean of three experiments). Reaction condition:
200 mg melphalan, X mg chloramine-T, 150 mL phosphate
buffer at pH 7 and 10 mL Na125I. The reaction mixture was
kept in a water bath (701C) for 15 min.
agent transforming iodine from Iꢂ to oxidative state I1. The
influence of chloramine-T concentration on the radiochemical
yield of 125I-melphalan was studied. The experiment was carried
out by the addition of 200 mg melphalan to different amounts of
CAT (50, 100, 150, 200, and 250 mg), and 5 mL Na125I. The reaction
mixture was heated to 701C for 15 min. The results of this
experiment are presented in Table 2. As it is clear from this data,
the radiochemical yield of 125I-melphalan was low when the
concentration of chloramine-T was not sufficient to oxidize all
the free iodide present in the solution. Increasing the amount of
chloramine-T to 150 mg caused an increase in the radiochemical
yield of 125I-melphalan to more than 96%. Increasing the
amount of oxidizing agent above 150 mg leads to a decrease
in the radiochemical yield of 125I-melphalan due to the
formation of undesirable oxidative side reactions like chlorina-
tion,16 polymerization, and denaturation of substrate.
Effect of reaction time
As the reaction temperature was effective in the build up of the
energy required to breakdown the C–H bond and form the C–I
bond, also the reaction time has the same role. As it is clear from
Table 4, the minimum time required to get a maximum yield of
125I-melphalan was 15 min, and no valuable benefits can be
gained from increasing the reaction time.
Effect of pH
This experiment was carried out using different buffer systems
to obtain the required pH values; citrate buffer for pH 2 and 4,
phosphate buffer for pH 7 and 9, and bicarbonate buffer for
pH 11. The optimum amount of melphalan was added to the
buffer system and then 150 mL CAT (150 mg) followed by 5 mL
Na125I. The reaction mixture was heated to 701C for 15 min. The
results indicate to the effectiveness of pH of the reaction
mixture on the labeling yield. The radiochemical yield of
125I-melphalan was relatively poor at pH 2 and 4, as a result of
the predominance of ICl species, which have low oxidation
potential than HOCl species.17 At pH 7, the radiochemical yield
of 125I-melphalan reaches a maximum value of 96.8%. When the
pH increased towards the alkaline side (9 and 11) the
radiochemical yield decreased, this may be attributed to the
Effect of temperature
The reaction temperature has an important role in the
electrophilic substitution reactions. The leaving hydronium ion
requires some energy to break the C–H bond and to initiate the
introduction of the radioactive iodonium ion into the phenyl
ring. During this reaction, it was found that the kinetic energy
required to breakdown C–H bond and introduce I1 into the
phenyl ring of melphalan was build up when the reaction
mixture was heated to 701C for 15 min. The labeled melphalan
did not decompose on increasing the reaction temperature to
1001C, as it is clear from Table 3. This indicates that the labeled
melphalan was stable against rise in temperature.
Ã
decrease in HOI , which is responsible for the electrophilic
substitution reaction.18 The data is summarized in Figure 2. The
high radiochemical yield of 125I-melphalan at pH 7 maybe due to
many factors; the good solubility of melphalan in neutral pH,
and the efficiency of CAT at this pH value.19
J. Label Compd. Radiopharm 2010, 53 1–5
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

A. M. Amin et al.
125I - Melphalan
Free iodine
Radioactive
U.V
100
90
80
70
60
50
40
30
20
10
0
10000
8000
6000
4000
2000
0
125I-Melphalan
Melphalan
Free iodide
0
5
10
15
20
2
4
6
8
10
12
Retention Time,min
pH value
Figure 3. HPLC radiochromatogram of 125I-melphalan
Figure 2. Effect of pH of the reaction medium on the percent labeling yield of 125I-
melphalan. Reaction condition: 200 mg melphalan, 150 mg chloramine-T, 150 mL
phosphate buffer at pH X and 10 mL Na125I. The reaction mixture was kept in a
water bath (701C) for 15 min.
Table 6. Biodistribution pattern of 125I-melphalan in
normal mice
Table 5. The in vitro stability of 125I-melphalan
Time post labeling (hour)
125I-melphalan (%)
125I (%)
Organs
% Injected dose/organ
1
2
4
8
12
24
94.871.7
93.071.2
94.171.3
94.371.3
92.971.6
90.671.3
5.270.3
7.070.3
5.970.2
5.770.1
7.170.2
9.470.5
0.5 h post injection
2 h post injection
Blood
Bone
15.572.1
2.770.8
2.970.7
0.670.1
10.671.4
4.571.1
0.970.4
1.770.8
12.171.7
8.870.9
5.571.1
0.270.1
9.271.3
2.070.4
1.970.3
0.470.1
13.771.6
2.670.8
0.670.2
0.870.2
8.971.2
15.672.2
9.071.6
0.870.4
Muscle
Spleen
Stomach
Kidney
Heart
Lung
Liver
Intestine
Urine
Thyroid
Mean7SD (mean of three experiments ). Reaction condition:
200 mg melphalan, 150 mg chloramine-T, 150 mL phosphate
buffer at pH 7 and 10 mL Na125I. The reaction mixture was
kept at room temperature (251C).
Stability test
The stability of 125I-melphalan was studied in order to determine
the suitable time for injection to avoid the formation of the
undesired products. These undesired radioactive products may
be accumulated in non-target organs. Table 5 shows the
stability of 125I-melphalan up to 12 h.
iodine-125, in cancer site were examined in mice. The mice were
intravenously injected with 0.1 mL of the tracer. The bio-
distribution of 125I-melphalan in normal mice is presented in
Table 6. The data shows that the clearance of the tracer from the
blood was high as the percentage reached ꢀ9.271.3% at 2 h
post injection. Because the excretion route of this compound
occurs via liver, the intestine content increased by time from
8.870.9% to 15.672.2% at 0.5 and 2 h post injection,
respectively. In addition, part of this compound was excreted
through the kidneys, as the activity detected in the urine was
ꢀ9.071.6%. The uptakes of other organs (bone, muscle, lung,
heart, and spleen) were within the normal values. The in vivo
stability of the tracer can be seen, as the thyroid uptake did not
increase by time.
HPLC analysis
A radiochromatogram for the iodination of Melphalan obtained
after HPLC separation on RP-18 column at the optimum
conditions is shown in Figure 3. Two peaks were obtained:
one at 4 min while the second at 7 min retention time. The first
peak corresponds to free iodide, whereas the second peak
corresponds to the 125I-melphalan. The eluted fractions contain-
ing the labeled compound are pooled together and evaporated
to dryness. The residue was dissolved in physiological saline and
sterilized by filtration through 0.22 mm Millipore filter, and the
125I-S6G is then suitable for use in biodistribution studies.
The biodistribution of 125I-melphalan in tumor-bearing mice is
presented in Table 7. The uptake of the tracer in bone, muscle,
lungs, heart, and spleen was similar to the uptake of the same
Biodistribution of melphalan
The biological distribution pattern and the ability of the organs in normal mice. In addition, the increased uptake of liver
melphalan compound to localize the therapeutic radionuclide, and kidneys may be due to the excretion pathway of the tracer.
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J. Label Compd. Radiopharm 2010, 53 1–5

A. M. Amin et al.
Table 7. Biodistribution pattern of 125I-melphalan in tumor bearing mice (Ascetics) at different times post injection
Organs
% Injected dose/ organ
0.5 h post injection
2 h post injection
4 h post injection
24 h post injection
Blood
Ascetic
Bone
Muscle
Spleen
Stomach
Kidney
Heart
Lung
Liver
Intestine
Urine
Thyroid
16.471.7
38.072.8
2.770.6
2.270.5
0.170.4
6.970.9
3.170.6
1.670.7
1.070.8
9.470.9
6.871.0
4.170.6
0.170.3
13.171.3
42.172.2
2.270.5
1.970.6
0.270.2
9.571.2
4.870.9
0.370.1
0.870.3
6.071.1
8.071.3
6.270.7
0.370.3
9.971.0
39.072.2
1.170.6
0.870.4
0.270.1
11.171.8
5.370.7
0.470.2
0.770.3
5.671.2
12.271.4
8.070.9
0.870.6
6.871.4
36.272.4
0.970.7
0.570.3
0.270.1
7.270.2
2.870.8
0.270.3
0.570.4
3.270.9
9.771.3
23.072.2
1.370.6
Total ascetic fluid has high activity reaching 42.172.8% at 2 h
post injection and decreased to 36.272.4% after 24 h post
injection. The localization of this tracer with this high
percentage in the tumor site for this long period indicates the
specificity of this tracer to the tumor cells.
Acknowledgement
The authors thank Prof. Dr Kamillia Farha for her assistance and
useful discussion. Authors also thank JLCR’s Editor and Reviewers.
All the obtained data demonstrate that the tracer was
distributed rapidly through out the body after intravenous
injection (2 h), and cleared rapidly through the hepatobiliary
system (4 h). The liver was the organ with the highest
radioactivity that was quickly excreted into the intestinal tract.
The presence of activity in the urinary bladder suggests the
excretion of the tracer through the kidneys to some extent.
The low activity located in the thyroid gland indicates that
125I-melphalane is stable in vivo against biological decomposi-
tion. Also, the biodistribution of the tracer in tumor bearing
mice pointed to the possibility of the use of this tracer as
imaging or therapeutic agent for cancer. However, many
biological studies are required to establish these findings as
the examination of the tracer in vitro preparation of hypoxic
tissue and the quantitative determination of the tissue uptake of
this tracer.
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The labeling of melphalan with radioactive iodine-125 was done.
The optimum conditions of the labeling of melphalan to give a
radiochemical yield of 96.8% were 200 mg melphalan, 150 mL of
CAT (150 mg), and 150 mL phosphate buffer pH 7 when the
reaction mixture was heated at 701C for 15 min. The ligand
studied provides efficient labeling and good in vitro stability. All
the obtained data demonstrate that the tracer was distributed
rapidly throughout the body after intravenous injection (2 h)
and cleared through the hepatobiliary system (24 h). In addition,
the biodistribution of the tracer in tumor-bearing mice
demonstrated the possibility of the use of this tracer as imaging
or therapeutic agent for cancer.
J. Label Compd. Radiopharm 2010, 53 1–5
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