U.S. patent application number 15/172905 was filed with the patent office on 2016-12-08 for process for producing gallium-68 through the irradiation of a solution target.
This patent application is currently assigned to Ion Beam Applications. The applicant listed for this patent is Ion Beam Applications. Invention is credited to Antero ABRUNHOSA, Francisco ALVES, Vitor ALVES.
Application Number | 20160358683 15/172905 |
Document ID | / |
Family ID | 53298231 |
Filed Date | 2016-12-08 |
United States Patent
Application |
20160358683 |
Kind Code |
A1 |
ABRUNHOSA; Antero ; et
al. |
December 8, 2016 |
PROCESS FOR PRODUCING GALLIUM-68 THROUGH THE IRRADIATION OF A
SOLUTION TARGET
Abstract
The present invention relates to a process for purifying and
concentrating .sup.68Ga isotope produced by the irradiation with an
accelerated particle beam of a .sup.68Zn target in solution. The
process according to the invention allows for the production of
pure and concentrated .sup.68Ga isotope in hydrochloric acid
solution. The present invention also relates to a disposable
cassette suitable to perform the steps of purification and
concentration of the process.
Inventors: |
ABRUNHOSA; Antero; (Coimbra,
PT) ; ALVES; Vitor; (Coimbra, PT) ; ALVES;
Francisco; (Coimbra, PT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ion Beam Applications |
Louvain-la-Neuve |
|
BE |
|
|
Assignee: |
Ion Beam Applications
|
Family ID: |
53298231 |
Appl. No.: |
15/172905 |
Filed: |
June 3, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 59/008 20130101;
G21G 1/001 20130101; B01J 41/05 20170101; B01J 41/12 20130101; B01J
39/18 20130101; B01J 47/00 20130101; C07B 2200/05 20130101; A61K
51/088 20130101; C22B 58/00 20130101; G21G 1/10 20130101; B01J
39/05 20170101; G21G 2001/0021 20130101 |
International
Class: |
G21G 1/00 20060101
G21G001/00; B01J 39/18 20060101 B01J039/18; C07B 59/00 20060101
C07B059/00; B01J 41/12 20060101 B01J041/12; B01J 47/00 20060101
B01J047/00; A61K 51/08 20060101 A61K051/08; B01J 39/04 20060101
B01J039/04; B01J 41/04 20060101 B01J041/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 5, 2015 |
EP |
15170854.2 |
Claims
1. A process for producing and purifying .sup.68Gallium
radioisotope, the process comprising the following steps:
irradiating a target containing a target solution including zinc
using an accelerated particle beam; diluting the irradiated target
solution with water; feeding the diluted target solution into a
strong cation exchanger; washing the strong cation exchanger;
eluting zinc isotopes from the strong cation exchanger with a zinc
elution solution including acetone; washing the strong cation
exchanger; eluting .sup.68Gallium isotope from the strong cation
exchanger with hydrochloric acid solution to obtain an eluted
solution; feeding the eluted solution into a strong anion
exchanger, washing the strong anion exchanger; and eluting
.sup.68Gallium isotope from the strong anion exchanger with
hydrochloric acid solution to obtain a final solution.
2. The process according to claim 1, wherein the irradiated target
solution is diluted at least 5 volume times with water.
3. The process according to claim 1, further comprising the
following step: complementing the eluted solution with another
hydrochloric acid solution to obtain a complemented solution,
wherein the complementing step is performed before feeding the
eluted solution into the strong anion exchanger.
4. The process according to claim 3, the complemented solution
includes a molarity in hydrochloric acid between 7 M and 10 M.
5. The process according to claim 1, wherein the accelerated
particle beam is a proton beam produced by a cyclotron.
6. The process according to claim 1, wherein the strong cation
exchanger is preconditioned with water before feeding the diluted
target solution into the strong cation exchanger.
7. The process according to claim 1, wherein eluting zinc isotopes
from the strong cation exchanger is performed with a solution of
acetone 80%/HBr 0.5 M.
8. The process according to claim 1, wherein the final solution
includes .sup.68Gallium in a hydrochloric acid solution of molarity
between 0.08 M and 1.2 M.
9. The process according to claim 1, wherein the strong anion
exchanger is preconditioned with hydrochloric acid solution before
feeding the eluted solution into the strong anion exchanger.
10. The process according to claim 1, wherein the target solution
including zinc further includes a zinc salt diluted in nitric acid
or hydrochloric acid, wherein the zinc salt is selected from the
group consisting of zinc nitrate, zinc chloride, zinc chlorate,
zinc bromide, zinc iodide or zinc sulfate.
11. The process according to claim 1 further comprising the
following steps: reacting the final solution including
.sup.68Gallium isotope with a peptide dissolved in a buffer at a pH
between 3.5 and 3.9 to obtain a radiolabelled-peptide; cooling the
radiolabelled-peptide to a temperature below 40.degree. C.; and
purifying the radiolabelled-peptide on a C18 column.
12. A cassette for purifying and concentrating .sup.68Gallium
isotope from an outlet of a target containing a target solution
including zinc, comprising: a first conduit having a first end
connected to an inlet of a strong cationic exchanger and a second
end connected to a dilution vial, wherein the first conduit
includes a first 3-way valve; a first bottle, a second bottle, and
a third bottle containing chemical reagents and connected to the
first 3-way valve; an outlet of the strong cationic exchanger
connected by a second conduit to an elution vial, wherein the
second conduit includes a second 3-way valve connected to a first
waste vial; a third conduit connecting the elution vial to an inlet
of a strong anionic exchanger, wherein the third conduit includes a
third 3-way valve; a fourth bottle and a fifth bottle containing
chemical reagents and connected to the third 3-way valve; an outlet
of the strong anionic exchanger connected by a fourth conduit to a
final solution vial, wherein the fourth conduit includes a fourth
3-way valve connected to a second waste vial; a sixth bottle
containing water and connected to the dilution vial by a fifth
conduit; and a sixth conduit connecting the dilution vial to the
outlet of the target.
13. The cassette of claim 12, wherein the elution vial is connected
to a seventh bottle containing hydrochloric acid.
14. The cassette of claim 12, wherein the first conduit further
includes a fifth 3-way valve, the first and second bottles are
connected to the first 3-way valve, and the third bottle is
connected to the fifth 3-way valve.
15. (canceled)
16. The process according to claim 1, wherein the irradiated target
solution is diluted at least 10 volume times with water.
17. The process according to claim 3, wherein the strong anion
exchanger is preconditioned with hydrochloric acid solution before
feeding the complemented solution into the strong anion
exchanger.
18. A cassette for a device that synthesizes radiopharmaceuticals
products from chemical reagents, comprising: a first conduit having
a first end connected to an inlet of a strong cationic exchanger
and a second end connected to a dilution vial, wherein the first
conduit includes a first 3-way valve; a first bottle, a second
bottle, and a third bottle containing chemical reagents and
connected to the first 3-way valve; an outlet of the strong
cationic exchanger connected by a second conduit to an elution
vial, wherein the second conduit includes a second 3-way valve
connected to a first waste vial; a third conduit connecting the
elution vial to an inlet of a strong anionic exchanger, wherein the
third conduit includes a third 3-way valve; a fourth bottle and a
fifth bottle containing chemical reagents and connected to the
third 3-way valve; an outlet of the strong anionic exchanger
connected by a fourth conduit to a final solution vial, wherein the
fourth conduit includes a fourth 3-way valve connected to a second
waste vial; a sixth bottle containing water and connected to the
dilution vial by a fifth conduit; and a sixth conduit connecting
the dilution vial to an outlet of a target containing a target
solution including zinc.
19. The cassette of claim 18, wherein the elution vial is connected
to a seventh bottle containing hydrochloric acid.
20. The cassette of claim 18 wherein: the first conduit further
includes a fifth 3-way valve; the first and second bottles are
connected to the first 3-way valve; and the third bottle is
connected to the fifth 3-way valve.
Description
TECHNICAL FIELD
[0001] The present invention relates generally to the field of
radiopharmaceutical production. More particularly, the present
invention relates to a process for the production of .sup.68Gallium
radioisotope from a suitable solution target irradiated by an
accelerated particle beam.
[0002] The invention also relates to a disposable cartridge for
purifying and concentrating the Gallium-68 produced by the
irradiation of a isotopically enriched Zinc solution target by an
accelerated particle beam.
DESCRIPTION OF RELATED ART
[0003] Gallium-68 (.sup.68Ga) is of special interest for the
production of Ga-radiolabelled compounds used as tracer molecules
in positron emission tomography (PET) imaging technique. .sup.68Ga
forms stable complexes with chelating agents, like DOTA
(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA
(1,4,7-triazacyclononane-1,4,7-triacetic acid) and HBED-CC
(N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic-
acid) for example. .sup.68Gallium tracers may be used for brain,
heart, bone, lung or tumor imaging.
[0004] To obtain .sup.68Ga, the most common technique is the use of
a .sup.68Ge/.sup.68Ga generator. Unfortunately, .sup.68Ge/.sup.68Ga
generators can only produce small quantities of .sup.68Ga per
elution, suffer from limited lifetime and present the risk of
contaminating the final preparation with the long-lived parent
nuclide .sup.68Ge.
[0005] Traditionally, .sup.68Ga is also produced in a cyclotron via
the .sup.68Zn(p,n).sup.68Ga reaction in a metal (solid) target. In
short, the parent compound .sup.68Zn is deposited as solid phase on
a metallic substrate that is irradiated with a proton beam. After
irradiation, the target is dissolved in a strong acid solution to
obtain a solution that is then purified to obtain .sup.68Ga. The
process involves many time consuming steps, requires expensive
hardware including solid targets and special systems to transport
the irradiated target from cyclotron to the processing area and
poses radioprotection issues of handling the materials after
irradiation as well as liquid waste handling. This process is prone
to contamination by metallic ions that can compromise the
purification of the .sup.68Ga and subsequent labeling reaction.
[0006] Alternative methods have been proposed to simplify and
improve the process of .sup.68Ga production by a cyclotron. For
example, Pandey et al., (Am J Nucl Med Mol Imaging 2014;
4(4):303-310) discloses the cyclotron production of .sup.68Ga via a
.sup.68Zn(p,n).sup.68Ga reaction in aqueous solution. After
irradiation of the .sup.68Zn(NO.sub.3).sub.2 target in solution,
.sup.68Ga is purified by passing the irradiated solution through a
cation-exchange column, wherein .sup.68Zn and .sup.68Ga
radioisotopes are trapped. The cation-exchange column is afterwards
washed, and a step of elution of .sup.68Zn is performed in order to
recover the .sup.68Zn that can be purified afterwards and used in a
next irradiation. A final elution of .sup.68Ga is thereafter
performed with 3N HCl to a product vial.
[0007] Although the process presents some advantages over the
traditional irradiation of solid targets, there is a need for an
improved process, especially regarding the quantity of .sup.68Ga
produced, the overall time needed to perform the process and the
purity of the final gallium in order to provide an economically
viable alternative to .sup.68Ge/.sup.68Ga generators. For suitable
chelating of the .sup.68Ga it is especially important to avoid any
metal ions in the final solution.
SUMMARY OF THE INVENTION
[0008] The invention is defined by the independent claims. The
dependent claims define advantageous embodiments.
[0009] The present invention aims at providing a process that
overcomes the above-discussed drawbacks of the prior art.
[0010] In particular, it is an object of the present invention to
provide an efficient and reliable process for producing and
purifying .sup.68Ga isotope from a solution comprising zinc
irradiated by an accelerated particle beam, like a proton beam. It
is a further object of the invention to achieve a high yield in the
production of .sup.68Gallium. It is a further object of the
invention to provide a process with low contaminants concentration,
especially metal ions.
[0011] To this end, the process according to the invention
comprises the following steps: [0012] a) irradiating a target
containing a target solution comprising Zinc using an accelerated
particle beam, [0013] b) feeding the irradiated target solution
into a strong cation exchanger, [0014] c) washing the strong cation
exchanger, [0015] d) eluting Zinc isotopes from the strong cation
exchanger with a Zinc elution solution comprising acetone, [0016]
e) washing the strong cation exchanger, [0017] f) eluting
.sup.68Gallium isotope from the strong cation exchanger with
hydrochloric acid solution to obtain an eluted solution, [0018] g)
feeding said eluted solution into a strong anion exchanger [0019]
h) washing the strong anion exchanger, [0020] i) eluting
.sup.68Gallium isotope from the strong anion exchanger with
hydrochloric acid solution to obtain a final solution.
[0021] The process is characterized in that a step of diluting the
irradiated target solution comprising zinc with water is performed
after irradiation of the target solution comprising zinc and before
feeding the irradiated target solution into the strong cation
exchanger, the irradiated target solution being diluted at least 5
times its volume with water.
[0022] Indeed, the authors have surprisingly found that the overall
quantity of .sup.68Ga radionucleide recovered after separation and
purification is greatly enhanced when the irradiated target
solution is diluted at least 5 times its volume with water. The
inventors have surprisingly found that, when the irradiated target
is diluted 5 volume times, the retention of .sup.68Gallium on the
strong cation exchanger is greatly improved and the majority of
.sup.68Gallium is adsorbed on the exchanger, while the Zinc tends
towards being eluted more easily. Accordingly, the overall yield of
the process is greatly improved. The overall quantity of .sup.68Ga
purified and recovered by the method according to the invention
allows an economically viable process to produce .sup.68Ga for the
facilities that have a particle accelerator like a cyclotron
on-site.
[0023] In a preferred embodiment, the eluted solution comprising
.sup.68Ga is complemented with hydrochloric acid solution to obtain
a complemented solution, this complementation being performed
before feeding said eluted solution into the strong anion
exchanger.
[0024] The authors have also found that the overall quantity of
.sup.68Ga isotope present in the final solution is more important
when the eluted solution is, after elution from the strong cation
exchanger, complemented with hydrochloric acid solution. This step
allows adjusting the pH of the eluted solution, leading to a more
efficient process.
[0025] It is also an object of the present invention to provide a
disposable cassette for performing the steps of purification and
concentration of .sup.68Ga isotope after the irradiation of the
solution target by an accelerated particle beam. There is a need
for a disposable cassette that enables correct implementation of
the method for purifying and concentrating Gallium-68. The
disposable cassette should be used easily, and should be easy to
maintain and service. The disposable cassette according to the
invention may be used in connection with a device for synthesis of
radiopharmaceuticals products.
[0026] To this end, a disposable cassette according to the
invention comprises: [0027] a first conduit of which a first end is
connected to an inlet of a strong cationic exchanger, said first
conduit furthermore comprising one or more first 3-way valve,
[0028] at least three first bottles containing chemical reagents
being connected to the one or more first 3-way valve, [0029] an
outlet of the strong cationic exchanger being connected by a second
conduit to an elution vial, said second conduit comprising a second
3-way valve that is connected to a first waste vial, [0030] the
elution vial being connected by a third conduit to an inlet of a
strong anionic exchanger, [0031] the third conduit comprising a
third 3-way valve that is connected to at least two second bottles
containing chemical reagents, [0032] an outlet of the strong
anionic exchanger being connected by a fourth conduit to a final
solution vial, said fourth conduit comprising a fourth 3-way valve
that is connected to a second waste vial.
[0033] The cassette furthermore comprises a dilution vial connected
by a fifth conduit to a bottle containing water. The disposable
cassette is furthermore characterized in that the dilution vial is
connected by a sixth conduit to the outlet of a target containing a
target solution comprising zinc. The disposable cassette is
furthermore characterized in that the first conduit comprises a
second end connected to the dilution vial.
[0034] Such disposable cassette is particularly suitable for
performing the purification and concentration steps of a method
according to the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] These and further aspects of the invention will be explained
in greater detail by way of examples and with reference to the
accompanying drawings in which:
[0036] FIG. 1 shows a flow chart which represents a process
according to the invention.
[0037] FIG. 2 shows a schematic view of a disposable cassette
according to a first embodiment of the invention.
[0038] FIG. 3 shows a schematic view of a disposable cassette
according to a second embodiment of the invention.
[0039] The drawings of the figures are neither drawn to scale nor
proportioned. Generally, similar or identical components are
denoted by the same reference numerals in the figures.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0040] According to a first aspect of the invention, it is provided
a process for producing and purifying .sup.68Gallium from a target
solution comprising zinc irradiated by an accelerated particle
beam. Preferentially the target solution is a target solution
comprising .sup.68Zn, and more preferentially a target solution
comprising isotopically enriched .sup.68Z. Preferentially, the
target solution is irradiated by a proton beam. The present
invention is intended to be used preferably with a cyclotron
apparatus, which delivers high energy proton beams.
[0041] A flow chart of the process according to the invention is
illustrated on FIG. 1. First, a target containing a target solution
(10) comprising zinc, preferentially an isotopically enriched
zinc-68 solution, is irradiated by an accelerated particle beam
(step a). The target solution (10) may comprises a zinc salt
selected among zinc nitrate, zinc chloride, zinc chlorate, zinc
bromide, zinc iodide, zinc sulfate. The zinc salt may be diluted in
nitric acid or hydrochloric acid. As an example, the target
solution (10) is a Zinc-68 nitrate solution diluted in low
concentrated nitric acid solution, for avoiding precipitation of
zinc nitrate. For example, the target is an isotopically enriched
1.7 M solution of .sup.68zinc nitrate in 0.2 N nitric acid in a
closed target system. The target may for example be any Nirta.RTM.
Conical target sold by Ion Beam Applications, Louvain-La-Neuve,
Belgium. The target system may also be the target system as
described in international patent publication WO 2012/055970. The
target containing the target solution (20) is irradiated by an
accelerated particle beam. Preferentially, the accelerated particle
beam is a proton beam when the zinc target is isotopically enriched
.sup.68Zn. More preferentially, the proton beam is produced by a
cyclotron, for example a low or mid energy cyclotron producing a
proton beam in the range of 12 to 30 MeV. The irradiation step may
last around 30 min at a beam of current of 20 .mu.A. The overall
volume of the target solution comprising zinc or .sup.68Zinc may be
comprised between 0.5 mL and 10 mL.
[0042] After irradiation of the target (10), the irradiated target
solution is received in a collection vial. There, the irradiated
target is diluted (step .alpha.) in water to obtain a diluted
solution (20). The dilution of the irradiated target solution is at
least 5 volume times the volume of the solution comprising the
irradiated target. In a preferred embodiment, the irradiated
solution target (10) is diluted at least 10 times. For example,
when the overall volume of the irradiated target solution
comprising zinc is around 1 mL, the volume of the diluted solution
(20) is around 5 mL. In a preferred embodiment the dilution of the
irradiated target solution is comprised between 5 and 15 volume
times, more preferably between 10 and 15 volume times. The
inventors have surprisingly found that the process is less
efficient when lower dilution volumes than 5 volume times are used.
Moreover, higher volumes increase process time, and thus loss of
Gallium-68 isotope by radioactive decay.
[0043] This step of dilution allows achieving high .sup.68Gallium
adsorption yields into a strong cation exchanger (30). Indeed, over
90% of the total .sup.68Gallium comprised in the diluted solution
(20) is adsorbed on the strong cation exchanger (30) during the
step of feeding (step b) the diluted solution into the strong
cation exchanger (30). When one dilutes the irradiated solution
with a lower volume times, adsorption of .sup.68Gallium into the
strong cation exchanger is reduced, and the overall yield of the
process is therefore lower.
[0044] Once the irradiated target is diluted in water, the diluted
solution (20) is afterwards fed (step b) into a strong cation
exchanger (30) where the .sup.68Gallium isotope is adsorbed (or
trapped) on the strong cation exchanger (also known as SCX) (30).
By fed, it must be understood that, for example, the diluted
solution (20) is passed through the exchanger (30). The exchanger
(30) may be a strong cationic column loaded with a strong acid
cation resin containing DVB (divinylbenzene). For example
commercial resin DOWEX 50WX8 (Dow Chemical Co., Midlands, Mich.,
USA) or AG 50W-X8 (BioRad Laboratories, Hercules, Calif., USA) and
the likes may be used. The strong cation exchanger (30) may be
preconditioned firstly with 3M hydrochloric acid solution and then
by washing the exchanger with water. For example, for about 1400 mg
of resin exchanger, between 3 mL and 10 mL, preferentially about 5
mL, of hydrochloric acid 3M solution followed by between 5 mL and
15 mL, preferentially about 10 mL, of water may be used during the
preconditioning of the exchanger (30), eventually followed by air
in order to dry the exchanger. Of course, a greater volume of water
may be used when preconditioning the exchanger.
[0045] After adsorption of .sup.68Gallium isotope on the strong
cation exchanger (30), the exchanger is washed (step c). In a
preferred embodiment, the exchanger is washed with water (100), and
more preferentially with chelexed water to avoid the presence of
any undesirable contaminants. This washing step allows removing
certain type of contaminants, like .sup.11C and .sup.13N isotopes.
The volume of the washing solution may be dependent from the volume
of the irradiated target (10) and/or the weight of the exchanger
(30). For example, when the weight of the exchanger (30) is about
1400 mg, about 5 mL of water may be used to wash the strong cation
exchanger (30). Of course, a greater volume may be used. It should
also be understood that a plurality of washing steps may be
performed.
[0046] After this washing step, Zinc isotopes are eluted (step d)
from the strong cation exchanger. The Zinc isotopes may be
recovered in a vial for optional Zn purification and reuse. The
Zinc elution solution (200) used for this step should comprise
acetone. In a more preferred embodiment, the Zn elution solution
(200) is 80% acetone, and in a more preferred embodiment, the Zn
elution solution (200) is 0.5 M hydrobromic acid (HBr) in 80%
acetone solution. The volume of the Zn elution solution (200)
needed to perform this washing step may be dependent from the
volume of the irradiated target (10) and/or the weight of the
strong cation exchanger (30) and/or the molarity of the acetone
solution (300). For example, when the weight of the exchanger is
about 1400 mg and the solution is 80% acetone, between 10 mL and 50
mL, preferentially about 30 mL, of the Zn elution solution (200)
may be used. Of course, greater volume of the Zn elution solution
may be used.
[0047] After the step of elution of Zinc, a further step of washing
(step e) the strong cation exchanger is performed. This step may be
performed with water or chelexed water, like the first washing step
described above. The purpose of this step is to remove traces of
acetone and eventually HBr when the Zn elution solution (200) is
hydrobromic acid in 80% acetone solution.
[0048] After the step d) of elution of the Zinc from the strong
cation exchanger (30) and the step of washing the SCX, a step of
elution (step f) of the .sup.68Gallium from the strong cation
exchanger (30) is performed to obtain an eluted solution (40). A
hydrochloric acid solution (300) should be used when performing
this step of the process. In a preferred embodiment, the
hydrochloric acid solution (300) has a molarity comprised between 1
M and 5 M, preferentially between 2 M and 4 M, and more
preferentially between 2.8 M and 3.2 M, and still more
preferentially a molarity about 3 M. The volume of the hydrochloric
acid solution (300) may be dependent from the weight of the strong
cation exchanger (30) and/or the molarity of the hydrochloric acid
solution (300). For example, when the weight of the strong cation
exchanger (30) is about 1400 mg and the molarity of the
hydrochloric acid solution (300) is about 3 M, between 5 mL and 10
mL, preferentially about 7 mL, of hydrochloric acid solution may be
used when performing this step of the process. Of course, greater
volume of hydrochloric solution may be used when one performs this
step of the process. The eluted solution (40) is collected into a
collection vial or reservoir.
[0049] In a preferred embodiment of the process, an optional
additional step of complementing the eluted solution (40) with
another hydrochloric acid solution (350) is performed before
feeding the eluted solution (40) into the strong anion exchanger
(also known as SAX) (50). This hydrochloric acid solution (350) may
be about 12 M. The purpose of the complementation is to
decrease/adjust the pH of the eluted solution (40). In a more
preferred embodiment, hydrochloric acid is added to the eluted
solution (40) until the molarity of the hydrochloric acid in the
complemented solution is comprised between 7 M and 10 M,
preferentially between 7.5 M and 9 M, more preferentially between
7.5 M and 8.5 M, and most preferentially about 8 M.
[0050] The eluted solution (40) or the complemented solution
comprising .sup.68Gallium is thereafter fed (step g) into a strong
anionic exchanger (SAX) (50). For example, this exchanger (50) may
be a strong anionic column loaded with a strong anion resin like
BIORAD AG1X8 (Bio-Rad laboratories, Hercules, Calif., USA) and the
like. The strong anion exchanger (SAX) (50) may be preconditioned
with 8M HCl before feeding (step g) the eluted solution (40) or the
complemented solution into the strong anion exchanger (SAX) (50).
In a preferred embodiment, the strong anion exchanger (SAX) (50) is
preconditioned with chelexed water followed by hydrochloric acid
solution with a molarity comprised between 7 M and 10 M,
preferentially between 7.5 M and 9 M, more preferentially between
7.5 M and 8.5 M, and most preferentially about 8 M.
[0051] Then, the strong anion exchanger (SAX) (50) is washed (step
h) in order to elute impurities like traces of hydrochloric acid
and/or to ensure correct pH of the final solution (60). The washing
solution used in this step (step h) may be water. In a preferred
embodiment, this step is performed with ethanol solution, like 95%
ethanol (400). The volume of the washing solution may be dependent
on the mass of the strong anion exchanger and/or the molarity of
the ethanol solution. For example, when the mass of the strong
anion exchanger is about 400 mg, between 0.5 mL and 2 mL,
preferentially about 1 ml, of 95% ethanol solution may be used to
perform the washing step (step h).
[0052] Following this washing step, the .sup.68Gallium isotope is
finally eluted (step i) from the strong anion exchanger (50). A
solution of hydrochloric acid (400) is used to perform this step.
In a preferred embodiment, the molarity of the hydrochloric acid
solution (400) is comprised between 0.08 M and 1.2 M, more
preferentially about 0.1 M. The final solution (60) comprises
highly purified and concentrated .sup.68Gallium isotope,
preferentially in 0.1 M hydrochloric acid, and is ready to use for
a further incorporation of .sup.68Ga isotope into tracers
molecules, like DOTA-TOC, DOTA-NOC, DOTA-TATE, PSMA-H BED-CC. The
.sup.68Ga isotope may be incorporated into tracer molecules that
comprise a chelator selected among DOTA, PSMA, NOPO, TRAP, THP
(trishydroxy-pyrydinones), PCTA, AAZTA, DATA, dedpa, FSC, NODAGA
and the like.
[0053] The overall time to perform the process according to the
invention is about 45 min. With the present process, highly pure
and concentrated .sup.68Ga isotope in 0.1 M hydrochloric acid
solution is obtained. For example, when the weight of .sup.68Zn in
solution used is around 200 mg in Zinc-68 nitrate form, with a 30
min proton beam irradiation at a beam of current of 20 .mu.A, the
process according to the invention achieves more than 100 mCi of
pure .sup.68Ga. The final solution is ready to be used on labelling
peptides.
[0054] The .sup.68Ga isotope purified and concentrated according to
the process of the invention may be incorporated into tracer
molecules according to the following steps: [0055] reacting the
final solution (60) comprising .sup.68Ga isotope with a required
amount of a peptide dissolved in a suitable buffer at a pH
comprised between 3.5 and 3.9 to obtain a radiolabelled-peptide,
[0056] cooling the mixture comprising .sup.68Ga and said peptide to
a temperature below 40.degree. C., [0057] purifying the
radiolabelled-peptide on a C18 cartridge.
[0058] For example, the solution comprising highly purified and
concentrated .sup.68Gallium (in 0.1 M HCl) is fed into a
pre-conditioned (1 mL of 4 M HCl, 10 mL of H2O) cation exchange SCX
column. The column is dried with a stream of N2 to remove any
traces of HCl. Thereafter, .sup.68Ga is eluted. The elution
solution should comprise acetone. In a more preferred embodiment,
the elution solution is 98% acetone, and in a more preferred
embodiment, the elution solution is 0.02M hydrochloric acid (HCl)
in 98% acetone solution. The volume of the elution solution needed
to perform this washing step may be dependent from the weight of
the strong cation exchanger. For example, when the weight of column
used is around 100 mg, about 1 mL of a mixture of acetone (98%)/NCl
0.02 M is fed directly into the reaction vial pre-loaded with the
required amount of peptide dissolved in 1 mL of suitable buffer at
pH comprised between 3.5 and 3.9. The total reaction volume is
about 2 mL. The reaction mixture is then heated at 95.degree. C.
for 10 minutes. After the reaction, the mixture is cooled by
dilution with 5 mL of sterile water and with a steam of compressed
air outside of reactor, before being loaded into the C18 SPE
cartridge to a quantitative adsorption of the peptide on the
column. A C18 column (or C18 cartridge) is a HPLC (high performance
liquid chromatography) columns that use a C18 substance as the
stationary phase. The inventors found that cooling the
.sup.68Ga-peptide mixture is critical as it reduces substantially
the radiolabelled peptide losses during purification. After a
washing step with 5 mL of sterile water the .sup.68Ga-peptide
complex is eluted from the cartridge with 1 mL of 75% ethanol
followed by 9 mL of saline solution to obtain the very pure
.sup.68Ga-peptide. The product is then sterilized by filtration
through a 0.22 .mu.m membrane filter and transferred to the final
vial. The final product is ready to use in a PET method.
[0059] Alternatively, the .sup.68Ga isotope purified and
concentrated according to the process of the invention may be
incorporated into tracers molecules according to the following
steps: [0060] feeding the final solution (60) into a strong cation
exchanger, [0061] drying the strong cation exchanger, [0062]
eluting .sup.68Gallium isotope from the strong cation exchanger
with a mixture of acetone and hydrochloric acid to obtain a
reaction solution comprising .sup.68Gallium isotope, i [0063]
reacting the reaction solution comprising .sup.68Ga isotope with a
required amount of a peptide dissolved in a suitable buffer at a pH
comprised between 3.5 and 3.9 to obtain a radiolabelled-peptide,
[0064] cooling the mixture comprising .sup.68Ga and said peptide to
a temperature below 40.degree. C., [0065] purifying the
radiolabelled-peptide on a C18 cartridge.
[0066] The strong cation exchanger may be a strong cationic column
loaded with a strong acid cation resin containing DVB
(divinylbenzene). For example commercial resin DOWEX 50WX8 (Dow
Chemical Co., Midlands, Mich., USA) or AG 50W-X8 (BioRad
Laboratories, Hercules, Calif., USA) and the likes may be used. The
mixture of acetone and hydrochloric acid may be a acetone
(98%)/Hydrochloric acid 0.02 N solution. About 1 mL of the mixture
may be used to elute .sup.68Gallium isotope.
[0067] The invention also concerns a disposable cassette able to
perform the dilution, purification and concentration steps
according to the method of the invention. A disposable cassette
according to a first embodiment of the invention is illustrated on
FIG. 2.
[0068] This disposable cassette comprises a dilution vial (505)
connected by a fifth conduit (650) to a bottle (651) containing
water. The disposable cassette (500) is furthermore characterized
in that the dilution vial (505) is connected by a sixth conduit
(660) to the outlet (661) of the .sup.68Zn target. The disposable
cassette (500) is furthermore characterized in that the first
conduit (610) comprises a second end connected to the dilution vial
(505).
[0069] By disposable cassette, it should be understood that the
cassette may be plugged in and out of a device for synthesis of
radiopharmaceuticals products from chemical reagents. The device
for synthesis of radiopharmaceuticals may be a device that is able
to perform the above described incorporation of .sup.68Ga isotope
into tracer molecules. The disposable cassette is dedicated to
operate with different type of synthesizers driven by an automated
controller. For example, the synthesizer may be the SYNTHERA.RTM.
platform sold by ION BEAM APPLICATION, Louvain-La-Neuve, Belgium.
The device may also be the one described in the patent EP1343533.
This device enables the different chemical compounds for carrying
out the synthesis of radiopharmaceutical compounds to be brought
into contact during reaction and allows purification of the
product. The device for synthesis of radiopharmaceutical compounds
and the disposable cassette (500) when plugged to the device may be
linked to an automaton which controls the various operations
enabling the performance of the purification and concentration of
.sup.68Ga, and the synthesis of pharmaceutical compounds. Pump
means may be located on the disposable cassette (500) and/or on the
synthesizer. For example, the pump means may be syringe pumps
connected to at least some of the conduits to draw and pump fluid
through the conduits. A man skilled in the art is able to determine
where such syringe pumps may be implanted on the disposable
cassette. For example, a syringe pump may be implanted on each
conduit. An automated controller is programmed to operate pumps and
valves, and control the provisions of the various chemical reagents
for a correct purification and concentration of the Gallium-68. For
example, the liquid is pumped through the conduits by a vacuum or
by a syringe pump. When a defined volume of the chemical reagent
has reached to desired location (for example one of the cationic
exchanger), a 3-way valve is actioned and the liquid is therefore
pumped to a disposable vial (or waste vial) when the liquid is a
washing liquid, or a liquid comprising impurities. When the liquid
comprises the Gallium-68, the 3-way valve is activated allowing
pumping the liquid to the elution vial or to the final solution
vial. The disposable cassette (500) may comprise securing means
which enable it to be fixed to the synthesizer. The securing means
can take the form of fasteners arranged according to a precise
configuration. It should be understood that, when the disposable
cassette is connected to the synthesizer, both devices are in fluid
communication through an outlet (999) of the cassette. The cassette
is removable from the synthesizer. For example, the disposable
cassette is cooperatively engaged with the synthesizer to drive the
fluids from the output line of a cyclotron to the synthesizer. The
steps of purification and concentration of the Gallium-68 are
performed within the disposable cassette, while the incorporation
of the Gallium-68 into radiopharmaceuticals is performed within the
synthesizer. The disposable cassette (500) is removed after the
synthesis run and may be replaced by a fresh cassette.
Alternatively, some elements of the disposable cassette may be
replaced, like the chemical reagents or the cation exchangers,
while the other elements of the cassette are washed to remove any
trace of the previous run. The disposable cassette (500) may
comprise a rigid portion (e.g. an ABS plate) on which the various
components of the disposable cassette (500) are arranged and
fixed.
[0070] By chemical reagents, it should be understood the reagents
used for purifying and concentrating .sup.68Ga isotope, like water,
acetone, Hydrochloric acid. In a more preferred embodiment, one
first bottle (530a) comprises water; one other first bottle (530b)
comprises acetone; and one other first bottle (530c) comprises
hydrochloric acid. In a complementary embodiment, one second bottle
(540a) comprises water and one other second bottle (540b) comprises
hydrochloric acid.
[0071] The disposable device (500) may comprise a support plate,
for example in ABS, for supporting the elements constituting the
disposable device. The conduits (610, 620, 630, 640, 650, 660) may
be flexible tubes like silicone tubes, channels molded or drilled
in a support plate. The bottles may be pre-metered bottles. The
conduits may be linked to mechanical means acting on the said
conduits and enabling to monitor and control mechanically the
transfer of the chemical reagents, the various solutions
(irradiated solution target, diluted solution, eluted solution,
final solution) between their respective compartments. For example,
such mechanical means may comprise: [0072] pistons for forwarding a
fluid from one vessel, vial or bottle to another, [0073] valves
such as three-way valves for directing a fluid from one conduit to
another conduit, [0074] compressed air or gas or law pressure of
air or gas for forwarding a fluid from one vessel, vial or conduit
to another, [0075] pumps,
[0076] under the control of an automaton or a computer.
[0077] Once the final concentration step has taken place, the pure
product is taken out from the disposable cassette and dispatched to
a synthesizer that will incorporate Gallium-68 into
radiopharmaceuticals.
[0078] In a more preferred embodiment, the disposable cassette
(500) furthermore comprises another optional bottle (550)
containing hydrochloric acid connected directly to the elution vial
(501). This allows for complementation of the eluted solution with
hydrochloric acid before feeding the eluted solution into the
strong anion exchanger (900).
[0079] In a more preferred embodiment, illustrated on FIG. 3, the
first conduit comprises two first 3-way valves (710, 711). One of
the first 3-way valves (710) is connected to at least two bottles
of reagent (530a, 530b). The other first 3-way valve (711) is
connected to a third bottle of reagent (530c). This embodiment
allows the separation of reagents reserved for washing the strong
cation exchanger (800) and removing impurities, like .sup.68Zn,
from the strong cation exchanger (800) on one hand, and the
reagents, like hydrochloric acid, reserved for eluting .sup.68Ga
isotope from the strong cation exchanger (800). The eluted solution
contains less impurity when the disposable cassette (500) according
to this embodiment is used.
[0080] The terms and descriptions used herein are set forth by way
of illustration only and are not meant as limitations. Those
skilled in the art will recognize that many variations are possible
within the spirit and scope of the invention as defined in the
following claims, and their equivalents, in which all terms are to
be understood in their broadest possible sense unless otherwise
indicated. As a consequence, all modifications and alterations will
occur to others upon reading and understanding the previous
description of the invention. In particular, dimensions, materials,
and other parameters, given in the above description may vary
depending on the needs of the application.
[0081] The present invention has been described in terms of
specific embodiments, which are illustrative of the invention and
not to be construed as limiting. More generally, it will be
appreciated by persons skilled in the art that the present
invention is not limited by what has been particularly shown and/or
described hereinabove.
[0082] Reference numerals in the claims do not limit their
protective scope.
[0083] Use of the verbs "to comprise", "to include", "to be
composed of", or any other variant, as well as their respective
conjugations, does not exclude the presence of elements other than
those stated.
[0084] Use of the article "a", "an" or "the" preceding an element
does not exclude the presence of a plurality of such elements.
* * * * *