RADIOLABELLING PROCESS
Technical Field of the Invention
The invention relates to a method for the preparation of a radiopharmaceutical
compound, in particular an amino acid derivative useful as a positron emission
tomography (PET) tracer. The method of the invention is especially suitable
when automated and offers advantages over known methods. Particularly, the
invention relates to a method for preparation of [ F]-1 -amino-3-
fluorocyclobutane-1 -carboxylic acid ([ F]-FACBC, also known as [ F]-
fluciclovine).
Description of Related Art
The non-natural amino acid [ F]-1-amino-3-fluorocyclobutane-1-carboxylic
acid ([ F]-FACBC, also known as [ F]-Fluciclovine) is taken up specifically by
amino acid transporters and has shown promise for tumour imaging with
positron emission tomography (PET).
A known synthesis of [ F]-FACBC (EP201 7258) begins with the provision of
the protected precursor compound 1-(N-(f-butoxycarbonyl)amino)-3-
[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-1 -carboxylic acid ethyl ester. This
precursor compound is first labelled with [ F]-fluoride:
II
before removal of the two protecting groups
1
I I III
To then obtain injectable [ F]FACBC drug product the crude [ F]FACBC is
purified and then formulated.
In the current routine process for producing [ F]FACBC the radiolabelling step
(i) is carried out in a reaction vessel followed by transfer of the radiolabeled
compound of Formula I I above to a tC1 8 solid phase extraction column for
removal of the ester protecting group by alkaline hydrolysis. During this time,
the reaction vessel is washed several times with water. The ester-deprotected
compound is then returned to the reaction vessel for the removal of the Boc
protecting group by acid hydrolysis. Despite washing the reaction vessel
several times, the present inventors have determined residual acetonitrile
levels in formulated [ F]FACBC drug product ranging from around 100 pg/ml to
around 600 pg/ml. While these levels are acceptable in terms of permitted
daily exposure and in the context of the acceptance criteria for [ F]FACBC
drug product, the amount and observed variability is less than ideal.
There is therefore scope for the provision of an [ F]FACBC drug product
wherein the levels of acetonitrile are more tightly controlled, and preferably
within a lower concentration range.
Summary of the Invention
The present invention relates to a novel composition comprising 1-amino-3-
[ F]-fluorocyclobutanecarboxylic acid ([ F]-FACBC) wherein said composition
has certain superior properties in comparison with known compositions
comprising [ F]-FACBC. More particularly, the present invention provides an
[ F]FACBC composition that has low and consistent amounts of residual
solvent. Also provided by the invention is a method to obtain said composition.
Detailed Description of Preferred Embodiments
In one aspect the present invention relates to a composition comprising 1-amino-
3-[ F]-fluorocyclobutanecarboxylic acid ([ F]-FACBC) wherein said composition
comprises acetonitrile (MeCN) at a concentration of no greater than 50 pg/mL.
In one embodiment the composition of the present invention comprises MeCN at a
concentration no greater than 20 m /mL.
In one embodiment the composition of the present invention has a radioactive
concentration (RAC) of between 500-5000 MBq/ml, preferably between 1000-5000
MBq/ml. The RAC of the composition of the present invention is preferably the
RAC of the drug product as soon as this is obtained, i.e. immediately following
radiofluorination, deprotection, purification and formulation.
In one embodiment the composition of the present invention has a radiochemical
purity (RCP) of at least 99%.
In one embodiment said [ F]FACBC in the composition of the present invention is
trans-1 -amino-3-[ F]-fluorocyclobutanecarboxylic acid (a 7i/'-[ F]-FACBC):
The composition of the invention is preferably obtainable by the method of the
invention described hereinbelow.
In another aspect, the present invention provides a method to obtain the
composition as defined above wherein said method comprises:
(i) reacting [ F]fluoride with a precursor compound of Formula I :
wherein:
LG is a leaving group;
PG is carboxy protecting group; and
PG2 is an amine protecting group;
wherein said reacting step is carried out in acetonitrile;
to obtain a reaction mixture comprising a compound of Formula II:
wherein:
PG1 and PG2 are as defined for Formula I;
(ii) transferring said compound of Formula II out of said reaction vessel to carry
out removal of PG1 and thereby obtain a compound of Formula III:
wherein PG2 is as defined for Formula I;
(iii) simultaneously to step(ii) applying heat to said reaction vessel;
(iv) transferring said compound of Formula III back into said reaction vessel to
carry out removal of PG2 and thereby obtain [ F]-FACBC.
The method of the invention is largely carried out as described in the art (e.g.
Shoup et al 1999 J Labelled Comp Radiopharm; 42: 2 15-225, Svadberg et / 201 1
J Labelled Comp Radiopharm; 55: 97-1 02) with the addition of step (iii).
The "[ F1fluoride" suitable for use in the method of the invention is normally
obtained as an aqueous solution from the nuclear reaction O(p,n) F. In order to
increase the reactivity of fluoride and to reduce or minimise hydroxylated byproducts
resulting from the presence of water, water is typically removed from
[ F]-fluoride prior to the reaction, and fluorination reactions are carried out using
anhydrous reaction solvents (Aigbirhio et al 1995 J Fluor Chem; 70: 279-87). A
further step that is used to improve the reactivity of [ F]-fluoride for
radiofluorination reactions is to add a cationic counterion prior to the removal of
water. Suitably, the counterion should possess sufficient solubility within the
anhydrous reaction solvent to maintain the solubility of the [ F]-fluoride.
Therefore, counterions that are typically used include large but soft metal ions
such as rubidium or caesium, potassium complexed with a cryptand such as
Kryptofix™, or tetraalkylammonium salts, wherein potassium complexed with a
cryptand such as Kryptofix™, or tetraalkylammonium salts are preferred.
A "precursor compound" comprises a non-radioactive derivative of a radiolabeled
compound, designed so that chemical reaction with a convenient chemical form of
the detectable label occurs site-specifically; 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 radiolabeled
compound. Such precursor compounds are synthetic and can conveniently be
obtained in good chemical purity.
A suitable "leaving group" in the context of the present invention is a chemical
group that can be displaced by nucleophilic displacement reaction with fluoride
ion. These are well-known in the art of synthetic chemistry. In some
embodiments the leaving group of the present invention is a linear or branched .
o haloalkyl sulfonic acid substituent, a linear or branched C Oalkyl sulfonic acid
substituent, a fluorosulfonic acid substituent, or an aromatic sulfonic acid
substituent. In other embodiments of the invention the leaving group is selected
from methanesulfonic acid, toluenesulfonic acid, nitrobenzenesulfonic acid,
benzenesulfonic acid, trifluoromethanesulfonic acid, fluorosulfonic acid, and
perfluoroalkylsulfonic acid. In some embodiments the leaving group is either
methanesulfonic acid, trifluoromethanesulfonic acid or toluenesulfonic acid and in
another embodiment the leaving group is trifluoromethanesulfonic acid.
The term "protecting group" refers to 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 in
'Protective Groups in Organic Synthesis', Theorodora W. Greene and Peter G.M.
Wuts, (Fourth Edition, John Wiley & Sons, 2007).
The PG "carboxy protecting group " is preferably linear or branched C O alkyl
chain or an aryl substituent. The term "alkyl " used either alone or as part of
another group is defined as any straight, branched or cyclic, saturated or
unsaturated CnH2n+ group. The term "aryl " refers to any C6- 4 molecular fragment
or group which is derived from a monocyclic or polycyclic aromatic hydrocarbon,
or a monocyclic or polycyclic heteroaromatic hydrocarbon. In one embodiment of
the method of the invention PG1 is selected from methyl, ethyl, t-butyl and phenyl.
In another embodiment of the invention PG1 is methyl or ethyl and in yet another
embodiment PG1 is ethyl.
The PG2 "amine protecting group" suitably prevents reaction between F and the
amino group in the process of providing the compound of Formula II. Examples of
suitable amine protecting groups include various carbamate substituents, various
amide substituents, various imide substituents, and various amine substituents.
Preferably, the amine protecting group is selected from the group consisting of
linear or branched C2-7 alkyloxycarbonyl substituents, linear or branched C3-7
alkenyloxycarbonyl substituents, C7-12 benzyloxycarbonyl substituents that may
have a modifying group, C2-7 alkyldithiooxycarbonyl substituents, linear or
branched C -6 alkylamide substituents, linear or branched C2-e alkenylamide
substituents, C6- benzamide substituents that may have a modifying group, C4-10
cyclic imide substituents, C6-n aromatic imine substituents that may have a
substituent, linear or branched C -6 alkylamine substituents, linear or branched C2-
6 alkenylamine substituents, and C6-n benzylamine substituents that may have a
modifying group. In some embodiments of the invention PG2 is selected from tbutoxycarbonyl,
allyloxycarbonyl, phthalimide, and N-benzylideneamine. In other
embodiments PG2 is selected from t-butoxycarbonyl or phthalimide. In one
embodiment of the invention PG2 is t-butoxycarbonyl.
The term "reacting " refers to bringing two or more chemical substances (typically
referred to in the art as "reactants" or "reagents") together to result in a chemical
change in one or both/all of the chemical substances.
The "removal of PG1" is carried out using a reagent capable of removing the
carboxy protecting group PG1 from the compound of Formula II during step (ii) of
the method of the invention. Suitable such carboxy deprotecting agents are wellknown
to the skilled person (see Greene and Wuts, supra) and may be either an
acid or an alkaline solution. The concentration of the PG1 deprotecting agent is
not limited as long as it is sufficient to remove the carboxy protecting group PG1
and does not have an effect on the final purity or results in an incompatibility with
any container used. Preferably the PG1 deprotecting agent is an alkaline solution.
In certain embodiments the PG1 deprotecting agent is a sodium hydroxide or a
potassium hydroxide solution and in a preferred embodiment is a sodium
hydroxide solution, for example of 0.5-2.0M. The reacting step is enabled by
closing the outlet of the SPE column so that the PG1 deprotecting agent is
retained therein for a specified amount of time. The temperature and the duration
of this reacting step need to be sufficient to permit removal of the PG1 carboxy
deprotecting group. In certain embodiments the reacting step is carried out at
room temperature and for a duration of between 1-5 minutes.
Step (iii) comprises applying heat to the reaction vessel, which may be carried out
using methods well-known to the person skilled in the art and must be suitable for
application to the reaction vessel so that the reaction vessel may be used for the
subsequent step (iv). This step (iii) is carried out "simultaneously " to step (ii),
which is to say at the same time as the carrying out removal of PG1, i.e. after the
compound of Formula II has been transferred out of said reaction vessel. A
suitable temperature for this heating step should be no greater than the tolerance
of the reaction vessel, e.g. for a reaction vessel made from cyclic olefin copolymer
(COC) a temperature of no greater than about 130°C and for a reaction vessel
made from polyetheretherketone (PEEK) a temperature of no greater than about
200°C. For convenience, the temperature used to heat the reaction vessel in step
(iii) may be as close as possible to the temperature used during the labelling step
(i). For radiolablling suitable temperatures that are used are in the range of about
80-1 40°C, in other cases 85-1 30°C.
The "removal of PG2" is carried out with a reagent capable of removing the amine
protecting group PG2 from the compound of Formula III during the step (iv) of the
method of the invention. Suitable such amine deprotecting agents are well-known
to the skilled person (see Greene and Wuts, supra) and may be either an acid or
an alkaline solution. The concentration of the PG2 deprotecting agent is not
limited as long as it is sufficient to remove the carboxy protecting group PG2.
Preferably the PG2 deprotecting agent is an acid solution. A suitable acid
preferably includes an acid selected from inorganic acids such as hydrochloric
acid, sulfuric acid and nitric acid, and organic acids such as perfluoroalkyl
carboxylic acid, e.g. trifluoroacetic acid. In certain embodiments, the PG2
deprotecting agent is hydrochloric acid, and in other embodiments when HCI is
used as PG2 deprotecting agent it is at a concentration of 1.0-4.0M. Step (iv) is
preferably carried out with heat to allow the removal of PG2 reaction to proceed
more rapidly. The reaction time depends on the reaction temperature or other
conditions. For example, when step (iv) is performed at 60°C, a sufficient reaction
time is 5 minutes.
Precursor compounds of Formula I may be obtained by following or adapting
methods known in the art, such as for example described by McConathy et al
(2003 Appl Radiat Isotop; 58: 657-666) or by Shoup and Goodman ( 1999 J Label
Comp Radiopharm; 42: 215-225).
In a preferred aspect, the [ F]-FACBC is trans-1 -amino-3-[ F]-
fluorocyclobutanecarboxylic acid (a/?i/-[ F]-FACBC):
said compound of Formula I is a compound of Formula la:
said compound of Formula I I is a compound of Formula lla:
said compound of Formula III is a compound of Formula Ilia:
wherein PG1 and PG2 are as described hereinabove.
In one embodiment, the method of the present invention is automated. Preferably,
the method of the invention is carried out on an automated synthesis 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. They are commercially available
from a range of suppliers (Satyamurthy et al, above), including: GE Healthcare;
CTI Inc; 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 also 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. 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. 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 ideally also
are resistant to radiolysis.
Preferred automated synthesis apparatuses for use with the present invention
comprise a disposable or single use cassette which comprises all the reagents,
reaction vessels and apparatus necessary to carry out the preparation of a given
batch of radiofluorinated 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 s the synthesis
to be carried out; reagent traceability; single-use and hence no risk of crosscontamination,
tamper and abuse resistance.
The following example serves to further illustrate the invention.
Brief Description of the Examples
Example 1 describes a known method to obtain [ F]FACBC.
Example 2 describes the method to obtain [ F]FACBC according to the
present invention.
List of Abbreviations used in the Examples
BOC tert-Butyloxycarbonyl
DP drug product
HLB hydrophobic-lipophilic balance
K222 Kryptofix 222
MeCN acetonitrile
QMA quaternary methyl ammonium
RAC radioactive concentration
Examples
Comparative Example 1: Prior Art Synthesis of I F1FACBC
1 ) FASTlab Cassette
All radiochemistry was performed on a commercially available GE FASTlab™
with single-use cassettes. Each cassette is built around a one-piece-moulded
manifold with 25 three-way stopcocks, all made of polypropylene. Briefly, the
cassette includes a 5 ml reactor (cyclic olefin copolymer), one 1 ml syringe and
two 5 ml syringes, spikes for connection with five prefilled vials, one water bag
( 00 ml) as well as various SPE cartridges and filters. Fluid paths are
controlled with nitrogen purging, vacuum and the three syringes. The fully
automated system is designed for single-step fluorinations with cyclotronproduced
[ F]fluoride. The FASTlab was programmed by the software
package in a step-by-step time-dependent sequence of events such as moving
the syringes, nitrogen purging, vacuum, and temperature regulation. Vial A
contained K222 (58.8 mg, 156 mhhoI ) , K2CO3 (8.1 mg, 60.8 mhhoI ) in 79.5% (v/v)
eCN q ( 1 105 m I) . Vial B contained 4M HCI (2.0 ml). Vial C contained MeCN
(4.1 ml). Vial D contained the precursor (48.4 mg, 123.5 mi o I) in its dry form
(stored at -20°C until cassette assembly). Vial E contained 2 M NaOH (4.1 ml).
The 30 ml product collection glass vial was filled with 200 mM trisodium citrate
(10 ml).
1(H) Production of [18FlFluoride
No-carrier-added [1 F]fluoride was produced via the 1 O(p,n) F nuclear
reaction o n a GE PETtrace 6 cyclotron (Norwegian Cyclotron Centre, Oslo).
Irradiations were performed using a dual-beam, 30mA current o n two equal Ag
targets with HAVAR foils using 16.5 MeV protons. Each target contained 1.6
ml of > 96% [ O]water (Marshall Isotopes). Subsequent to irradiation and
delivery to a hotcell, each target was washed with [ 6O]water (Merck, water for
GR analysis). Aqueous [ F]fluoride was passed through the QMA and into the
O-H 2O recovery vial. The QMA was then flushed with MeCN and sent to
waste.
7 ( /7) 8FlFluoride Labelling
The trapped [ F]fluoride was eluted into the reactor using eluent from vial A
and then concentrated to dryness by azeotropic distillation with acetonitrile
(vial C). MeCN was mixed with precursor in vial D from which the dissolved
precursor was added to the reactor and heated to 85°.
1(iv) Removal of Ester Protecting Group
The reaction mixture was diluted with water and sent through the tC18
cartridge. Reactor was washed with water and sent through the tC1 8 cartridge.
The labelled intermediate, fixed on the tC 8 cartridge was washed with water,
and then incubated with 2M NaOH after which the 2M NaOH was sent to
waste.
1(v) Removal of BOC Protecting Group
The labelled intermediate (without the ester group) was then eluted off the
tC1 8 cartridge into the reactor using water. The BOC group was hydrolysed by
adding 4M HCI and heating the reactor.
1(vi) Purification
The reactor content with the crude [1 F]FACBC was sent through the HLB and
Alumina cartridges and into the 30 ml product vial. The HLB and Alumina
cartridges were washed with water and collected in the product vial.
1(vii) Formulation
2M NaOH and water was added to the product vial, giving a purified drug
product (DP) with a total volume of 26 ml.
1(viii) Characterisation
Radioactive concentration (RAC) and concentration of acetonitrile
measured in the DP.
Example 2: Synthesis of I F1FACBC using Inventive Method
The method as defined in Example 1 was used except that during removal of
the ester protecting group, the empty reactor was heated for 5 minutes.
FASTlab Run# RAC (MBq/ml) MeCN in DP ( g/ l)
1 3247 16
2 4190 16
3 708 16
4 776 17

Claims
A method to obtain a composition comprising 1-amino-3-[ F]-
fluorocyclobutanecarboxylic acid ([ F]-FACBC) wherein said composition
comprises acetonitrile (MeCN) at a concentration of no greater than 50
g/mL wherein said method comprises:
(i) reacting [ F]fluoride with a precursor compound of Formula I :
wherein:
LG is a leaving group;
PG1 is carboxy protecting group; and,
PG2 is an amine protecting group;
wherein said reacting step is carried out in acetonitrile;
to obtain a reaction mixture comprising a compound of Formula II
wherein:
PG1 and PG2 are as defined for Formula I;
transferring said compound of Formula I I out of said reaction vessel
to carry out removal of PG1 and thereby obtain a compound of
Formula III:
wherein PG2 is as defined for Formula I;
(iii) simultaneously to step(ii) applying heat to said reaction vessel;
(iv) transferring said compound of Formula III back into said reaction
vessel to carry out removal of PG2 and thereby obtain [ F]-FACBC.
(2) The method as defined in Claim 1 wherein said concentration of MeCN in
said composition is no greater than 20 g/mL.
(3) The method as defined in either Claim 1 or Claim 2 wherein said
composition has a radioactive concentration (RAC) of between 500-5000
MBq/ml.
(4) The composition as defined in any one of Claims 1-3 wherein said
composition has a RAC of between 1000-5000 MBq/ml.
(5) The composition as defined in any one of Claims 1-4 wherein said
composition has a radiochemical purity (RCP) of at least 99%.
(6) The composition as defined in any one of Claims 1-5 wherein said
[ 8F]FACBC is trans-1 -amino-3-[ F]-fluorocyclobutanecarboxylicacid (anti-
[ F]-FACBC):
(7) The method as defined in any one of Claims 1-6 wherein LG is a linear or
branched C 0 haloalkyl sulfonic acid substituent, a linear or branched - 0
alkyl sulfonic acid substituent, a fluorosulfonic acid substituent, or an
aromatic sulfonic acid substituent.
(8) The method as defined in Claim 7 wherein LG is methanesulfonic acid,
toluenesulfonic acid, nitrobenzenesulfonic acid, benzenesulfonic acid,
trifluoromethanesulfonic acid, fluorosulfonic acid, and perfiuoroalkylsulfonic
acid.
(9) The method as defined in Claim 7 or Claim 8 wherein LG is
trifluoromethanesulfonic acid.
( 0) The method as defined in any one of Claims 1-9 wherein PG1 is a linear or
branched - 0 alkyl chain or an aryl substituent.
( 1 1) The method as defined in Claim 10 wherein PG1 is methyl, ethyl, t-butyl
and phenyl.
( 12) The method as defined in Claim 11 wherein PG1 is methyl or ethyl.
( 13) The method as defined in Claim 12 wherein PG1 is ethyl.
(14) The method as defined in any one of Claims 1- 13 wherein PG2 is a
carbamate substituent, an amide substituent, an imide substituents or an
amine substituents.
( 15) The method as defined in Claim 14 wherein PG2 is t-butoxycarbonyl,
allyloxycarbonyl, phthalimide, or N-benzylideneamine.
( 16) The method as defined in Claim 15 wherein PG2 is t-butoxycarbonyl.
( 17) The method as defined in any one of Claims 1- 16 wherein said [ F]FACBC
is trans-1-amino-3-[ F]-fluorocyclobutanecarboxylic acid (anf/-[ F]-
FACBC):
said compound of Formula I is a compound of Formula la:
said compound of Formula I I is a compound of Formula lla:
said compound of Formula III is a compound of Formula Ilia:
(Ilia)
wherein LG is as defined in any one of Claims 1 and 7-9, PG1 is as defined
in any one of Claims 1 and 10-1 3, and PG2 is as defined in any one of
Claims 1 and 14-16.
( 18) The method as defined in any one of Claims 1- 17 which is automated.
( 19) A composition comprising 1-amino-3-[ 1 F]-fluorocyclobutanecarboxylic acid
([ F]-FACBC) wherein said composition comprises acetonitrile (MeCN) at
a concentration of no greater than 50 pg/mL.
(20) The composition as defined in Claim 19 wherein said concentration of
MeCN is no greater than 20 m /mL.
(21 ) The composition as defined in either Claim 19 or Claim 20 which has a
radioactive concentration (RAC) of between 500-5000 MBq/ml.
(22) The composition as defined in any one of Claims 19-21 which has a RAC
of between 1000-5000 MBq/ml.
(23) The composition as defined in any one of Claims 19-22 which has a
radiochemical purity (RCP) of at least 99%.
(24) The composition as defined in any one of Claims 19-23 wherein said
[ F]FACBC is trans-1 -amino-3-[ 1 F]-fluorocyclobutanecarboxylic acid (anti-
[1 F]-FACBC):