CLOSED EVAPORATION SYSTEM
Technical Field of the Invention
The present invention relates to the field of radiolabeled compounds and in
particular to their preparation. More specifically, the present invention relates to
systems and methods for evaporation of a radioactive fluid.
Description of Related Art
Evaporation or drying processes typically include an evaporation chamber
submitted to a certain temperature under a reduced pressure and connected to
a vacuum pump. A slight inert gas flow, e.g. nitrogen flow, can be applied in
order to ease the evaporation of the solvent. Such processes are well-known to
the person skilled in the art.
The system illustrated in Figure 1 illustrates a known process for evaporation.
The system includes a heating means 1 for a container of radioactive fluid 2 (as
shown in A) wherein evaporation or drying (as shown in B) of the radioactive
fluid 2 is effected by heating in conjunction with application of a vacuum. Such
a system is extremely efficient when there is no potential radioactive gaseous
material that can be extracted from the solution to be evaporated. Radioactive
gaseous material is released through the vacuum pump into the hot cell or a
chimney in the hot cell, and this radioactive gaseous release is subject to
measurement and regulatory limits. These limits are becoming progressively
lower with time. Therefore there is a need for an evaporation system that limits
the gaseous radioactive release as low as possible.
Summary of the Invention
The present invention provides a system for evaporating a radioactive fluid, a
method for the synthesis of a radiolabeled compound including this system,
and a cassette for the synthesis of a radiolabeled compound comprising this
system. The present invention provides advantages over known methods for
evaporation of a radioactive fluid as it reduces drastically the amount of
radioactive gaseous chemicals that are released in the hot cell. It is gentler and
more secure compared to the known process and provides access to
radiosyntheic processes that may not be acceptable for safety reasons related
to release of volatile radioactive gases during evaporation. In addition, the
process yields are higher because the radioactive volatiles are labelled
intermediate species.
Detailed Description of the Preferred Embodiments
In one aspect the present invention provides a system for evaporating a
radioactive fluid wherein said system comprises:
(i) a fixed volume hot zone which comprises a fixed volume
container and a heating means;
(ii) an expandable volume;
(iv) a 3-way valve which in a first position fluidly connects said fixed
volume container and said an expandable volume and which in a
second position fluidly connects said an expandable volume to
waste.
The "fixed volume hot zone" is essentially an evaporation chamber having a
fixed volume heated using any one of a variety of well-known suitable means,
e.g. a conductive material mantle. This fixed volume hot zone is connected to
the "expandable volume " , which is a condensation chamber that has a variable
volume, e.g. a syringe, which is in a colder, unheated, area.
The "3-wav valve" is any valve that permits selection between (i) fluid
connection of the fixed volume hot zone to the expandable volume and (ii) fluid
connection between the expandable volume and waste. An example of a
suitable such valve is a T-shaped ball valve.
All elements of the system of the invention should be made from radiostable
materials, and at least stable in the presence of the particular radioactive
isotope being used in the system.
The principle of the present invention is that the solution to be evaporated is
heated above its boiling point in order to reach the equilibrium gas/liquid phase.
A variable volume is connected to the system and the expansion of the volume
displaces the equilibrium in favour of the gaseous phase. As the variable
volume is in a cold area, the vapours condense in it. A 3-way valve allows the
condensed vapours in the variable volume to be emptied to waste and then
reconnected to the evaporation chamber. This operation can be repeated
several times until the desired dryness is obtained.
It is intended that system of the invention is used within the confines of a hot
cell due to the radioactive nature of the operations carried out with it. As
compared with known processes, a reduced amount of radioactive volatiles is
released into the hot cell and/or via the hot cell chimney.
Figure 2 illustrates an exemplary system of the present invention and a method
for its use. A volume of radioactive fluid 12 is contained within a fixed volume
hot zone 11 which comprises a fixed volume container 11a and heating means
11b. The fixed volume container 11a is fluidly connected via a 3-way valve 15
to an expandable volume, which as illustrated in Figure 2 is a syringe 13.
Heating of the radioactive fluid 12 in the fixed volume container 11a above its
boiling point causes it to vaporise and move into syringe 13 when valve 15 is in
a first position. The plunger of syringe 13 becomes displaced by the movement
of vaporised radioactive fluid from the fixed volume container 11a . When the
vaporised radioactive fluid enters the syringe 13 it condenses due to the drop in
temperature to form a volume of radioactive fluid 14 in the syringe. When the
syringe 13 is full the radioactive fluid 14 can be sent to waste by moving valve
15 into a second position and pushing down the plunger of the syringe 13 as
shown in Figure 2B. Once syringe 13 is empty the process can be repeated to
evaporate further radioactive fluid 12 from the fixed volume hot zone.
In one embodiment of the system of the invention the fixed volume container of
the system of the invention is a reaction vessel, i.e. the vessel in which the
radiolabelling reaction is carried out.
In one embodiment of the system of the invention the expandable volume of the
system of the invention is a syringe.
In another aspect the present invention provides a method for the synthesis of a
radiolabeled compound wherein said method comprises:
(i) radiolabelling a protected precursor compound to obtain a
protected radiolabeled compound;
(ii) deprotecting the protected radiolabeled compound obtained from
radiolabelleing step (i) to obtain said radiolabeled compound
wherein said deprotection is effected using a hydrolysis medium;
and,
(iii) evaporating the hydrolysis medium following deprotection step (ii)
wherein said evaporating is carried out using the system as
defined hereinabove.
The term "radiolabeled compound " refers to a compound that comprises a
radioactive atom.
The term "radiolabelling " refers to the radiochemical process by which a
radioactive atom is incorporated into a non-radioactive compound to obtain a
radiolabeled compound.
The term "precursor compound " refers to a non-radioactive compound a no n
radioactive derivative of a radiolabeled compound, designed so that chemical
reaction with a convenient chemical form of the detectable label occurs sitespecifically;
can be conducted in the minimum number of steps (ideally a single
step); and without the need for significant purification (ideally no further
purification), to give the desired in vivo imaging agent. Such precursor
compounds are synthetic and can conveniently be obtained in good chemical
purity.
The term "protected " refers to wherein one or more protecting groups are
included in a chemical compound in order to direct chemical reaction to a
particular site on that compound. By the term "protecting group " is meant a
group which inhibits or suppresses undesirable chemical reactions, but which is
designed to be sufficiently reactive that it may be cleaved from the functional
group in question to obtain the desired product under mild enough conditions
that do not modify the rest of the molecule. Protecting groups are well known to
those skilled in the art and are described by Theorodora W. Greene and Peter
G. M. Wuts in "Protective Groups in Organic Synthesis" (Fourth Edition, John
Wiley & Sons, 2007).
The term "protected radiolabeled compound " refers to a radiolabeled
compound comprising protecting groups.
The term "deprotecting " refers to the process of removing any protecting groups
form a protected chemical compound. Deprotection is typically carried out
using processes well-known to the skilled person (as described in Greene and
Wuts, supra), e.g. by hydrolysis using an acidic or an alkaline solution. A
"hydrolysis medium" is a solution suitable for effecting deprotection and is
typically an acidic or an alkaline solution.
For said evaporating step, the identically-named embodiments described
hereinabove for the system of the invention are equally applicable.
In one embodiment of the method of the invention said radiolabeled compound
is a radiopharmaceutical. The term "radiopharmaceutical " refers to a
radiolabeled compound suitable for use in a diagnostic or therapeutic method.
There are many radiopharmaceuticals well-known to those of skill in the art. Of
particular interest in the context of the present invention are
radiopharmaceuticals that are diagnostic radiopharmaceuticals. The reader is
directed to "Handbook of radiopharmaceuticals: radiochemistry and
applications" (Wiley 2003; Welch and Redvanly, Eds.) for more detail.
In one embodiment of the method of the invention said radiolabeled compound
is a diagnostic radiopharmaceutical that is either a single photon emission
tomography (SPECT) tracer or a positron emission tomography (PET) tracer.
There are a variety of well-known SPECT and PET tracers wherein at least one
method for their preparation involves an evaporation step and would therefore
benefit from the present invention. The reader is referred to "Molecular
Imaging: Radiopharmaceuticals for PET and SPECT" (Springer-Verlang 2009;
Vallabhajosula, Ed.) for more detail.
PET tracers are of particular interest, especially those that are 1 1C-labelled or
1 F-labelled. A number of PET tracers are well known in the art and the reader
is referred in this regard to Chapter 6 of "Basic Sciences of Molecular Medicine"
(Springer-Verlang 201 1; Khalil, Ed.) and to Chapter 8 of "Basics of PET
Imaging: Physics, Chemistry and Regulations" (Springer 2010; Saha, Ed.).
In one embodiment of the method of the present invention the radiolabeled
compound is an [1 F]-labelled PET tracer. Non-limiting examples of such [1 F]-
labelled PET tracers include [1 F]fluorodeoxyglucose ([1 F]FDG),
[1 F]fluorothymidine ([1 F]FLT), anf -amino-3-[ 1 F]fluorocyclobutyl-1 -carboxylic
acid ([1 F]FACBC), [1 F]fluoromisonidazole ([1 F]FMISO), [1 F]fluoro-L-DOPA
([1 F]DOPA), O-(-2-[ 1 F]fluoroethyl)-L-tyrosine ([1 F]FET), 6a-[ 1 F]fluoro-1 7 -
estradiol ([1 F]FES) and [1 F]-1-(5-fluoro-5-deoxy-a-aribinofuranosyl)-2-
nitroimidazole ([1 F]-FAZA). [1 F]FDG, [1 F]FLT, [1 F]FACBC and [1 F]FMISO
are of particular interest.
To demonstrate the advantages of the present invention, it has been applied to
the synthesis of [1 F]FLT. Since the method of the invention is not concerned
with the radiochemistry for any particular tracer, these advantages would also
be reasonably expected if the method of the invention were to be applied to any
radiosynthetic process comprising an evaporation step.
[1 F]FLT may be synthesized from a protected precursor compound such as 5'-
O-(4',4'-dimethoxytrityl) thymidine by nucleophilic substitution (with inversion of
stereo chemistry) at the 3' position using 1 F as illustrated in Scheme 1:
Scheme 1
In Scheme 1 DMTr is dimethoxytrityl, Ns is nosyl, and Boc is f-butyloxycarbonyl.
The protected precursor compound is labelled with 1 F using [1 F]fluoride, which
displaces the nosyl leaving group. An exemplary method is described by
Grierson and Shields (2000 Nuc Med Biol; 27(2): 143-56). Following
radiofluorination the protecting groups can be removed by hydrolysis, e.g. using
a hydrolysis medium comprising acetonitrile/water/H 3PO4. The hydrolysis
medium is evaporated following hydrolysis. This evaporation under classical
method conditions generates radioactive volatiles that end up in the hot cell. In
experiments carried out by the present inventors it has been demonstrated that
the activity balance shows an activity loss of 10 to 15% in classical conditions,
where the closed evaporation system show a loss of activity lower than 5%.
The present inventors believe that this effect is not tracer-dependent and
anticipates that a similar advantage would be obtainable for any radioactive
compound prepared under similar conditions, and in particular the [1 F]-labelled
PET tracers mentioned herein.
In one embodiment, the method of the invention is automated. [1 F]-labelled
PET tracers in particular are often now prepared in an automated fashion by
means of an automated radiosynthesis apparatus. By the term "automated
synthesis apparatus " is meant an automated module based on the principle of
unit operations as described by Satyamurthy et al (1999 Clin Positr Imag; 2(5):
233-253). The term "unit operations " means that complex processes are
reduced to a series of simple operations or reactions, which can be applied to a
range of materials. Such automated synthesis apparatuses are preferred for
the method of the present invention especially when a radiopharmaceutical
composition is desired. Automated synthesis apparatuses are commercially
available from a range of suppliers including: GE Healthcare (Chalfont St Giles,
UK); CTI Inc (Knoxville, USA); Ion Beam Applications S.A. (Chemin du
Cyclotron 3, B-1 348 Louvain-La-Neuve, Belgium); Raytest (Germany) and
Bioscan (USA).
A commercial automated synthesis apparatus provides suitable containers for
the liquid radioactive waste generated as a result of the radiopharmaceutical
preparation. Automated synthesis apparatuses are not typically provided with
radiation shielding, since they are designed to be employed in a suitably
configured radioactive work cell (also referred to herein as a "hot cell"). The
radioactive work cell provides suitable radiation shielding to protect the operator
from potential radiation dose, as well as ventilation to remove chemical and/or
radioactive vapours. With the present invention the amount of radioactive
vapours to be removed is reduced. The automated synthesis apparatus
preferably carries out the radiosynthesis by means of a cassette. By the term
"cassette" is meant a piece of apparatus designed to fit removably and
interchangeably onto an automated synthesis apparatus, in such a way that
mechanical movement of moving parts of the synthesizer controls the operation
of the cassette from outside the cassette, i.e. externally. Suitable cassettes
comprise a linear array of valves, each linked to a port where reagents or vials
can be attached, by either needle puncture of an inverted septum-sealed vial,
or by gas-tight, marrying joints. Each valve has a male-female joint which
interfaces with a corresponding moving arm of the automated synthesis
apparatus. External rotation of the arm thus controls the opening or closing of
the valve when the cassette is attached to the automated synthesis apparatus.
Additional moving parts of the automated synthesis apparatus are designed to
clip onto syringe plunger tips, and thus raise or depress syringe barrels. The
cassette is versatile, typically having several positions where reagents can be
attached, and several suitable for attachment of syringe vials of reagents or
chromatography cartridges (e.g. for SPE). The cassette always comprises a
reaction vessel. Such reaction vessels are preferably 0.5 to 10 ml_, more
preferably 0.5 to 5 ml_ and most preferably 0.5 to 4 ml_ in volume and are
configured such that 3 or more ports of the cassette are connected thereto, to
permit transfer of reagents or solvents from various ports on the cassette.
Preferably the cassette has 15 to 40 valves in a linear array, most preferably 20
to 30, with 25 being especially preferred. The valves of the cassette are
preferably each identical, and most preferably are 3-way valves. The cassettes
are designed to be suitable for radiopharmaceutical manufacture and are
therefore manufactured from materials which are of pharmaceutical grade and
also resistant to radiolysis.
A disposable or single use cassette comprises all the reagents, reaction
vessels and apparatus necessary to carry out the preparation of a given
radiopharmaceutical. The cassette means that the automated synthesis
apparatus has the flexibility to be capable of making a variety of different
radiopharmaceuticals with minimal risk of cross-contamination, by simply
changing the cassette. The cassette approach also has the advantages of:
simplified set-up hence reduced risk of operator error; improved GMP (Good
Manufacturing Practice) compliance; multi-tracer capability; rapid change
between production runs; pre-run automated diagnostic checking of the
cassette and reagents; automated barcode cross-check of chemical reagents
vs the synthesis to be carried out; reagent traceability; single-use and hence no
risk of cross-contamination, tamper and abuse resistance.
In yet another aspect the present invention provides a cassette for the
synthesis of a radiopharmaceutical wherein said cassette comprises:
(i) a vessel containing a protected precursor compound;
(ii) means for eluting the vessel of step (i) with a suitable source of a
radiolabel; and,
(iii) the system of the invention as defined hereinabove.
The term "cassette " is as defined hereinabove.
The term "radiopharmaceutical " is as defined hereinabove.
The term "protected precursor compound " is as defined hereinabove.
The term "suitable source of a radiolabel " refers to the radiolabel in a form
suitable for chemical reaction with the protected precursor compound leading to
the formation of the corresponding protected radiolabeled compound. For
example, when the radiolabel is 1 F one suitable form is [1 F]fluoride ion (1 F )
obtained as an aqueous solution from the nuclear reaction 1 O(p,n) 1 F and
typically made reactive by the addition of a cationic counterion and the
subsequent removal of water. This form of 1 F can displace a leaving group in
the protected precursor compound to form an 1 F-labelled protected precursor
compound.
The present inventors have demonstrated herein that using the system of the
present invention as part of the FASTlab™ manufacture of [1 F]FLT results in a
reduction in losses of radioactivity to less than 5%.
Figure 3 illustrates a FASTlab™ cassette suitable for the synthesis of [1 F]FLT.
The cassette comprises the system of the invention for evaporation of
radioactive fluid. Figure 3A shows a fixed volume hot zone which is a COC
reaction vessel 2 1, a 6ml syringe 23, a tube connection 26 between the
reaction vessel 2 1 and the syringe 23, 3-way valve 25 that connects the
reaction vessel 2 1 to either the syringe 23 or a waste container. Figure 3B
shows the same elements as Figure 3A except that the plunger of syringe 23 is
raised as it would be when radioactive fluid passes into it from the reaction
vessel 2 1.
The drying process of the invention is gentler and more secure compared to the
known process. Due to the volatiles condensing in the colder part of the
system, the system of the invention reduces drastically the amount of
radioactive gaseous chemicals that are released in the hot cell. The gaseous
radioactive material release during a PET tracer synthesis can be problematic
and acceptable limits are becoming more and more stringent. The evaporation
system of the invention will give access to processes that may not been
acceptable for safety reasons related to release of volatile radioactive gases
during evaporation. On top of the safety concerns, the overall process yields
are higher as well because the radioactive volatiles are labelled intermediate
species.
Brief Description of the Figures
Figure 1 illustrates a known process for evaporation or drying.
Figure 2 illustrates an exemplary system of the present invention.
Figure 3 illustrates a FASTlab™ cassette for the synthesis of [1 F]FLT.
Brief Description of the Examples
Example 1(i) describes synthesis of non-radioactive FLT using FASTlab™ to
assess acetonitrile residual content.
Example 1(ii) describes synthesis of [1 F]FLT using FASTlab™ to assess the
amount of volatile radioactive material generated.
List of Abbreviations used in the Examples
FLT fluorothymidine
sec second(s)
mBar millibar(s)
ppm parts per million
Examples
Example 1: Comparative View of Classical vs. Inventive Evaporation
Systems
• Classical evaporation: 110°C, for 450 sec, -600mBar (vacuum pump set
point), N2 pressure - low flow valve
• Closed evaporation system: 110°C, for 450 sec, the 6ml syringe is
emptied 3 times
Example 1(i) and Example 1(ii) below both use FASTlab™ and a cassette
designed for the production of FLT.
Mean
Classical evaporation 73663
Closed evaporation system 2232
Conclusions: the closed evaporation systems results in a lower amount of
acetonitrile as compared with the known evaporation method.
Conclusions: the closed evaporation system reduces the amount of volatiles
generated during the drying step.

claims
A system for evaporating a radioactive fluid wherein said system
comprises:
(i) a fixed volume hot zone ( 1 1) which comprises a fixed volume
container ( 1 1a) and a heating means ( 1 1b);
(ii) an expandable volume ( 13);
(iv) a 3-way valve (15) which in a first position fluidly connects said
fixed volume container ( 1 1a) and said an expandable volume ( 13)
and which in a second position fluidly connects said an
expandable volume ( 13) to waste.
The system as defined in Claim 1 wherein said fixed volume container
( 1 1a) is a reaction vessel.
The system as defined in Claim 1 or Claim 2 wherein said heating
means ( 1 1b) can heat said radioactive fluid to above its boiling point to
reach the equilibrium gas/liquid phase of said radioactive fluid.
The system as defined in any of Claims 1-3 wherein said expandable
volume ( 13) is a syringe (23).
A method for the synthesis of a radiolabeled compound wherein said
method comprises:
(i) radiolabelling a protected precursor compound to obtain a
protected radiolabeled compound;
(ii) deprotecting the protected radiolabeled compound obtained from
radiolabelling step (i) to obtain said radiolabeled compound
wherein said deprotection is effected using a hydrolysis medium;
and,
(iii) evaporating the hydrolysis medium following deprotection step (ii)
wherein said evaporating is carried out using the system as
defined in any one of Claims 1-4.
The method as defined in Claim 5 wherein said radiolabeled compound
is a radiopharmaceutical.
(7) The method as defined in Claim 6 wherein said radiopharmaceutical is a
diagnostic radiopharmaceutical.
(8) The method as defined in Claim 7 wherein said diagnostic
radiopharmaceutical is either a single photon emission tomography
(SPECT) tracer or a positron emission tomography (PET) tracer.
(9) The method as defined in Claim 8 wherein said diagnostic
radiopharmaceutical is a PET tracer.
( 10) The method as defined in Claim 9 wherein said PET tracer comprises a
1 1C-labelled compound or an 1 F-labelled compound.
( 1 1) The method as defined in Claim 10 wherein said 1 F-labelled compound
is selected from [1 F]fluorodeoxyglucose ([1 F]FDG), [1 F]fluorothymidine
([1 F]FLT), an /- 1-amino-3-[ 1 F]fluorocyclobutyl-1 -carboxylic acid
([1 F]FACBC), [1 F]fluoromisonidazole ([1 F]FMISO), [1 F]fluoro-L-DOPA
([1 F]DOPA), O-(-2-[ 1 F]fluoroethyl)-L-tyrosine ([1 F]FET), 16a-[ 1 F]fluoro-
17p-estradiol ([1 F]FES) and [1 F]-1 -(5-fluoro-5-deoxy-aaribinofuranosyl)-
2-nitroimidazole ([1 F]-FAZA).
( 12) The method as defined in Claim 11 wherein said 1 F-labelled compound
is selected from [1 F]FDG [1 F]FLT, [1 F]FACBC and [1 F]FMISO.
( 13) The method as defined in Claim 12 wherein said 1 F-labelled compound
is [1 F]FLT.
(14) A cassette for the synthesis of a radiopharmaceutical wherein said
cassette comprises:
(i) a vessel containing a protected precursor compound;
(ii) means for eluting the vessel of step (i) with a suitable source of a
radiolabel; and,
(iii) the system as defined in any one of Claims 1-4.
( 15) The cassette as defined in Claim 14 wherein said radiopharmaceutical is
a diagnostic radiopharmaceutical.
( 16) The cassette as defined in Clainn 15 wherein said diagnostic
radiopharmaceutical is either a SPECT tracer or a PET tracer.
( 17) The cassette as defined in Claim 16 wherein said diagnostic
radiopharmaceutical is a PET tracer.
( 18) The cassette as defined in Claim 17 wherein said PET tracer comprises
a 1 1C-labelled compound or an 1 F-labelled compound.
( 19) The cassette as defined in Claim 18 wherein said 1 F-labelled compound
is selected from [1 F]fluorodeoxyglucose ([1 F]FDG), [1 F]fluorothymidine
([1 F]FLT), an /'- 1-amino-3-[ 1 F]fluorocyclobutyl-1 -carboxylic acid
([1 F]FACBC), [1 F]fluoromisonidazole ([1 F]FMISO), [1 F]fluoro-L-DOPA
([1 F]DOPA), O-(-2-[ 1 F]fluoroethyl)-L-tyrosine ([1 F]FET), 16a-[ 1 F]fluoro-
17p-estradiol ([1 F]FES) and [1 F]-1 -(5-fluoro-5-deoxy-aaribinofuranosyl)-
2-nitroimidazole ([1 F]-FAZA).
(20) The cassette as defined in Claim 19 wherein said 1 F-labelled compound
is selected from [1 F]FDG [1 F]FLT, [1 F]FACBC and [1 F]FMISO.
(21 ) The cassette as defined in Claim 20 wherein said 1 F-labelled compound
is [1 F]FLT.