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Cyclotron Radiopharmaceuticals Production
at the V.G.Khlopin Radium Institute
L.M.Solin, B.K.Kudelin, V.A.Jakovlev, T.S.Potapova, E.A.Gromova
V.G.Khlopin Radium Institute, 2nd Murinsky pr., 28, 194021 St.Petersburg, Russia
Abstract. For more than 10 years Radium Institute is producing radiopharmaceuticals for St. Petersburg (Russia)
hospitals. We have developed technologies for sodium iodide, sodium iodohippurate, MIBG and BMIPP, labeled by
iodine-123, and gallium-67 citrate. Radionuclidic purity of 99,98% is reached for radiopharmaceuticals labeled by
iodine-123. Radionuclidic purity is over 99.9% for gallium-67 citrate on the date of delivery. Radiochemical purity of
95% and more is reached through the application of appropriate technologies for each RPH. It takes no longer than 4
hours for all technologies. Over 150,000 patients were investigated.
isotopes for single-photon diagnostics are presented in
table 1.
INTRODUCTION
Now it is difficult to imagine modern medicine
without the application of radiopharmaceuticals
(RPH). Radiopharmaceutical are substances labeled by
radioisotopes and designed to reach a certain place in
human body. There are different kinds of RPH used
for diagnostics of practically any human organ. Now
rapid growth is seen in the field of RPH for therapy.
This report deals with RPH for diagnostics. Depending
on the mode of production, radioisotopes for RPH
synthesis can be divided into two groups: reactor and
cyclotron. Isotopes of the first group are produced by
neutron irradiation from nuclear reactor, and the
second group of isotopes is obtained by means of
charged particles irradiation from cyclotron. Cyclotron
medical isotopes with positron emission are used for
PET (Positron Emission Tomograph) investigations,
and gamma-emitting isotopes for single-photon
diagnostics. As a rule every PET has a special
cyclotron providing short-lived isotopes (with halflives from 2 min to 2 hours). Positron Emission
Topography is a very sensitive and precise method, but
it is also a rather expensive one. In many cases it is not
necessary to get such detailed information and a
single-photon analysis is quite sufficient; huge
amounts of investigations are performed with gammacameras, scanners and other detectors by means of
single-photon studies. The most important cyclotron
TABLE 1. The Most Important Cyclotron Isotopes
for Single-Photon Diagnostics.
RadioMedical Application
isotope
I-123
Tl-201
Ga-67
In-111
Thyroid, kidney, endocrine system,
myocardial imaging, brain, cerebral
blood flow, neurological disease
(Alzheimer's)
Clinical cardiology, heart imaging,
myocardial perfusion
Oncology for malignant neoplasm and
soft tissue inflammation
Detection of heart transplant rejection,
imaging of abdominal infections, soft
tissue infection
This article is devoted to the production of the most
claimed by St.Petersburg radiologists cyclotron
radiopharmaceuticals labeled by iodine-123 and by
gallium-67.
CP680, Application of Accelerators in Research and Industry: 17th Int'l. Conference, edited by J. L. Duggan and I. L. Morgan
© 2003 American Institute of Physics 0-7354-0149-7/03/$20.00
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applied in investigations of endocrine system, and as
an unique method for imaging of pheochromocytoma
and neuroblastoma in children. 123I-BMIPP (123I-betamethyliodophenyl-pentadecanoic acid) – is a powerful
tool for various heart disease studies; Gallium-67
citrate is used for tumor imaging and localization of
inflammatory infections.
RADIUM INSTITUTE MGC-20
CYCLOTRON
It was 1989 when the first proton beam was
extracted from the Radium Institute cyclotron MGC20. Cyclotron MGC-20 has been developed by the
Efremov
Scientific
Research
Institute
of
Electrophysical Apparatus (ESRIEA, St.Petersburg)
more than 30 years ago for fundamental and applied
research. 4 machines of such type were installed in
Russia and 4 abroad (Finland, Hungary, North Korea,
Egypt). Now most of them are used for medical
isotopes production. The last cyclotron MGC-20 was
put into operation last year in Cairo and it is supposed
to be used for both gamma-emitting and positronemitting isotopes.
The main requirements for RPH technologies
introduced at the Radium institute were: simplicity and
economy of radioisotopes production; high quality of a
final product; short time for the total cycle from the
EOB to the dispatch to customers (especially for
iodine-123 labeled RPH)
IODINE-123 AND GALLIUM-67
RADIOISOTOPES PRODUCTION
The wide application of a cyclotron of such type is
obliged to the possibilities of particle acceleration with
a broad range of variable energies (Table 2) and a
relatively low cost of facilities
Many authors consider iodine-123 as an ideal
radionuclide for Nuclear medicine. I-123 is a gamma
emitter with electron capture mode of decay. The main
gamma ray energy is 159 keV that is convenient for
registration. Relatively short half-life (an 13.2 hours
half-life), soft gamma rays and the absence of beta
emission provide a low dose for patients. I-123 may be
applied to pregnant and the newborn. Iodine is
excellent for the synthesizes of a number of
compounds. Therefore many investigations were
performed to find an effective and cheap method of
iodine-123 production. About 20 nuclear reactions
were tried to produce iodine-123. At the Radium
Institute it is produced via nuclear reaction
123
Te(p,n)123I. Enriched tellurium-123 dioxide is used
as a target. To prevent its overheating under irradiation
water and helium cooling is used. Iodine-123 formed
in the target under proton bombardment is extracted by
a rather simple dry distillation method in a form
suitable for labeling a number of compounds. At high
temperatures (about tellurium dioxide melting point)
iodine is released from the target. Then by air flow
iodine is carried to vessel with sodium hydroxide
where iodine is associated.
TABLE 2. The Main Characteristics of Accelerated
Particles.
Internal Beam
External Beam
Accelerated
Energy Current Energy Current
Particles
MeV
µA
MeV
µA e
Protons
2-20
200
5-18
50
Deuterons
1-11
300
3-10
50
Helium-3
4-27
50
8-24
20
Helium-4
2-22
50
8-20
20
Iodine-123 as well as gallium-67 may successfully
be produced by means of MGC-20 cyclotron in p,n
nuclear reaction.
RADIOPHARMACEUTICALS
PRODUCED AT THE RADIUM
INSTITUTE
Table 3 shows a list of RPH produced in the
Radium Institute which are labeled by iodine-123 and
gallium-67.
Gallium-67 is a gamma emitter with electron
capture decay mode, 78.1 hours half-life. The main
gamma ray energies are 93.3, 184.6, and 300.2 keV.
Nuclear reaction is 67Zn(p,n)67Ga. Enriched zinc-67
oxide is used as a target. Water and helium are used
for cooling. Irradiated zinc is solved in the
hydrochloric acid and then gallium-67 is extracted by
means of ion exchange column with high efficiency.
TABLE 3. Radiopharmaceuticals Produced by
V.G.Khlopin Radium Institute.
Labeled by I-123
Labeled by Ga-67
Sodium Iodide
Gallium Citrate
Sodium-Iodohippurate
MIBG
BMIPP
Sodium iodide is used for thyroid glands
investigations; Sodium iodohippurate – manly for
kidney studies; MIBG (metaiodobenzylguanidine) – is
Extracted radioisotopes (iodine-123 and gallium67) are used to prepare radiopharmaceuticals.
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(approximation 1). Table 4 shows the influence of
target composition on RNP for targets used at different
time at the Radium institute.
RADIOPHARMACEUTICALS QUALITY
The quality assurance is provided by means of
GMP (Good Manufacturing Practice) for every
pharmaceutical production. Radioactivity presence has
two specific characteristics: radionuclidic purity RNP
and radiochemical purity RCP.
TABLE 4. Isotope Composition of Tellurium Targets
and 124I Content in a Final Product .
Mass
1990
1994
1997
Number
Year
Year
Year
120
<0.1
<0.1
<0.01
122
1.6
0.5
0.6
123
95.6
98.5
99.3
124
2.7
0.9
0.06
125
<0.1
<0.1
<0.01
126
<0.1
<0.1
<0.01
128
<0.1
<0.1
<0.01
130
<0.1
<0.1
<0.01
124
I Impurities in % of Activity for 1
Hour Irradiation
0.37
0.16
0.024
RNP
99.63%
99.84 %
99.976 %
Radionuclidic purity (RNP) is determined
by the contribution of the main isotope activity (in%)
in the total radiopharmaceutical activity. Impurities
radiation may deteriorate the image contrast in
diagnostics and increase the exposure dose to the
patient. RNP depends on: the nuclear reaction, the
target material chemical purity and the target material
isotope enrichment.
In recent years there has been a trend to increase
RNP for a longer preparation application time and a
better quality of images.
It is easy to see that the impurity content (iodine-124)
was reduced by factor 12 (table 6) at the expense of
the increased enrichment. However, we can expect
reduction in 45 times in accordance with the tellurium124 content change. It may be possible there is another
reaction for iodine-124 production [1]
123
Te(p,γ)124I
and we have approximation 2
The highest RNP for iodine-123 labeled RPH can
be achieved through a nuclear reaction
124
123
123
123
Xe(p,2n) Cs(β+) Xe(e,β+) I
It employs a cyclotron with the energy of about 30
MeV, Xenon-124 with high enrichment and
complicated targetry. In the case of nuclear reaction
123
Te(p,n)123I RNP depends on the isotopic enrichment
on 123Te.
A 124
A 123
It is obvious that we have to apply enriched
tellurium-123. When tellurium-123 enrichment
reaches 95%, only iodine-124 remains as an impurity.
Let us consider simple relations taken that A124 impurity iodine-124 activity, A123 – iodine-123
activity, then
Imp ≈ A124/A123 ×100%
(1)
RNP ≈ (1-A124/A123)×100%
=
C124
C123
pγ
× 0.136 × F + A 124
( 5)
To fit the experimental data it should be = 0.017%
and it will determine a limit for impurity of iodine-124
at the tellurium-124 content reduction. And,
consequently, the limit for RNP should be 99.983% (at
the EOB of 1hour irradiation).
(2)
H.B. Hupf et. al. [2] had the same tellurium-123
(99.3% enrichment) as in our last investigation; and
they received RNP of 99.9+% at EOB and thirty hours
after EOB, the average RNP - 99.8+%. It is consistent
with approximation 2 – 99.96% and 99.87%
correspondingly, but not with approximation 1 –
99.99% and 99.96% correspondingly. Thus we have
indirect confirmation of the RNP limitation reached
by enrichment of tellurium-123.
(1 − exp( − λ 124 × t))
× F(E p )
(3)
A 123
C123 (1 − exp( − λ 123 × t))
C124, C123 - isotopes concentrations in the target
λ124, λ123 – are the constants of decay for 124I and 123I,
F(Ep) – is a function of proton energy
For t=1 hour and for Ep constant F(Ep) = F
It is seen that the reduction of tellurium-124
A 124
×
C124
123
124
pγ
A 124 is an artificial addition from the Te(p,γ) I
nuclear reaction
It is easy to show that in the case of target irradiation
during “t” hours at the proton energy of Ep we have
A 124
=
As we have the limitation on RNP at the expense of
tellurium-124 content, we can use target material with
a slightly smaller enrichment on tellurium-123 keeping
the content of tellurium-124 at the same level. It means
that we will use cheaper material. We have added to
C124
=
× 0.136 × F
(4)
A 123
C123
content leads to a proportional increase of RNP
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the highly enriched tellurium-123 of about 10% of
highly enriched tellurium-122. RNP measurements
showed that we have about the same value.
Technological yield is over 99%. RCP is over 98%.
Sodium iodide, 123I, is a raw material for other
radiopharmaceuticals.
For all the targets under consideration the impurity
of I in the final product does not affect the image
quality, and the 124I radiation exposure on the
production date was considerably less than that of 123I.
Sodium o-iodohippurate, 123I. Sodium iodide, 123I,
and O-iodohippuric acid are used as start materials.
The isotope exchange reaction is a method for
production. Isotope exchange time is 40 min. Total
time of RPH preparation is 2 hours. Technological
yield is over 99%. This technology provides RCP of
98% and higher.
124
For using 123I produced by proton irradiation of
tellurium target with 124Te content of <0.9%, the
radiopharmaceuticals in 30 hours after EOB, has about
the same quality as for using iodine obtained from
124
Xe(p,2n) reaction.
123
I-MIBG. Solid phase isotope exchange in the
presence of sulfate-ions is a production method.
Sodium iodide, 123I, with high specific activity (10-12
GBk/ml) and M-iodobenzylguanidine sulfate are used
as start materials. Isotope exchange time is 50 min.
Total time RPH preparation is 2 hours. Technological
yield is over 97%. RCP is over 98%
For gallium-67 the product radionuclidic purity
depends on the isotope composition of target zinc. The
isotope composition of the starting material used at the
Radium Institute is presented in Table 5.
TABLE 5. The Isotope Composition of the Target Zn.
Zn-64 Zn-66 Zn-67 Zn-68 Zn-70
Contents (in %) 1.59
3.13 90.06 5.16
0.06
123
I-BMIPP. Catalytic isotope exchange is applied
to 123I-BMIPP production. Sodium iodide, 123I, and 15(p-iodophenyl)-3-methylpentadecanoic acid are used
as start materials. Isotope exchange occurs in the
presence of a copper catalyst. Isotope exchange time is
20 min. There is only one-stage chromatographic
extraction and purification of a final product on a
disposable cartridge. Total time for RPH preparation is
3 hours. Technological yield is 90-92%. RCP is over
96%.
Radioisotopes produced by proton irradiation except
67
Zn are short-lived enough to decay in a few hours
after the end of bombardment. The only product which
could compete with 67Ga is 66Ga with the 9.4 hours
half-life and 511, 1039 and 2752 keV gamma ray
energies. It is a product of both 66Zn(p,n) and
67
Zn(p,2n) reactions. At the end of bombardment its
activity achieves a value of about 20% of total product
activity. However, after cooling for 2 days its
contribution became negligible. The product
radionuclidic purity in two days is over 99.2 %. No
other gamma and beta emitters are present.
Gallium-67 citrate. Chemical complex formation
reaction is used to produce RPH. Gallium-67 chloride
solution in HCl and sodium citrate are used as start
materials. Total time RPH preparation is 1 hour.
Technological yield is 95%. RCP is over 95%.
Radiopharmaceuticals technologies introduced at
the Radium Institute take no longer than 4 hours to
prepare a drag form ready for application.
Radiochemical purity (RCP) is defined by the
amount (in %) of isotope activity in the appropriate
chemical form. Concentration of RPH in the target part
of body is determined by RCP. It is depends on: the
isotope production technology which determine a raw
material chemical form, the reagent chemical purity
and the labeling method. Isotopes production
technologies were discussed earlier. Reagents
chemical purity is dependent on the supplier. Labeling
methods are vary between all of produced
radiopharmaceuticals.
REFERENCES
1. Solin L. M,.Jakovlev V. A, Kaliteevsky A. K., Godisov
O. N.,.Mjazin L. P,.Shepelev P. K Cyclotron and their
Applications 1998, Proceedings of the 15th International
Conference, Caen, France, 70-73 (1998).
2. Hupf H. B., Beaver J. E., Armbruster J. M. and Pendola
J. P., 16th International Conference on the Application of
Accelerators in Research and Industry 2000
Sodium iodide, 123I. It is produced through
interaction between iodine-123 vapor and the sodium
hydroxide. In this case, different iodine chemical
forms may be produced. As a rule, following our
technology, 95% of iodine is produced in the form of
iodide. To get a higher RCP, it is necessary to use
autoclaving. Total time of RPH preparation is 2 hours.
3. Johansson L., Mattsson S., Nosslin B., Leide-Svegborn S
Eur. J. Nucl. Med., 19, 933 (1992).
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