SYNTHON COMPOSITION
Technical Field of the Invention
The present invention relates to an improved [1 F]labelled synthon composition,
wherein the non-radioactive impurities in said composition have been found to be more
straightforward to remove than with known compositions comprising said [ F]labelled
synthon. The resultant purified [l F]labelled synthon therefore can be used in the
production of a positron emission tomography (PET) tracer having improved properties
for in vivo imaging. The invention also includes methods of imaging and/or diagnosis
using the radiopharmaceutical compositions described.
Description of Related Art
The widespread availability of [1 F]fluoride, its optimal half-life ( 1 0 min) and low
positron energy (0.64 MeV), makes it the isotope f choice for positron emission
tomography (PET) imaging (Snyder & Kilbourn 2003 "Handbook of
Radiopharmaceuticals, Radiochemistry and Applications", Welch & Redvanly, Eds;
Chapter 6: 195-227).
Radiofluorination can be conveniently carried out via direct radiofluorination by
reacting radiofluorine with a suitable precursor compound. A suitable precursor
compound for direct radiofluorination may comprise a group selected for example from
N0 2, trimethylammoniurn (NMe3), CI, Br, I, tosylate (OTs), mesylate (OMs), nosylate
(ONs) and trill ate (OTf). Carroll et al (2005 J Label Comp Radiopharm; 48(7): 519-
520 and 2007 J Fluorine Chem; 128(2): 127-132). Lehmann et al (WO20 10066380)
describe the synthesis of compounds labelled with 1 F by direct labelling of a
sulfonium-derivatised precursor compound.
Although simple to perform, direct radioiodination has disadvantages, especially when
applied to the radioiodination of biomolecules such as proteins. More preferred in this
case are generic radiolabeling strategies using prosthetic groups (also known as
"synthons"). These offer the advantage that a significant part f the radiochemical
process can be standardized and applied to multiple products. The prosthetic group
must be unreactive toward any functional groups found i the product in order to form a
- -
stable bond in a site-specific manner. The aforementioned criteria are met by utilizing
oxime bond formation between an [1 F]aldehyde and an aminooxy-modi ied peptide.
This type of chemoseleetive ligation chemistry has been widely employed using 4-
[ Fjfluorobenzaldehyde as the prosthetic group with acceptable yields being reported
for a range of [18F]labelled peptides (Cuthbertson et al WO2004080492; Poethko et al
2004 J Nuc Med; 45: 892-902; Lee et al 2005 J Label Comp Radiopharm; 48: S288).
Glaser et al (2008 Bioconj Chem; 19(4): 9 1-957) describe the synthesis of
[1 F]labelled aldehydes, including [ F]fiuoroben/aldehyde ([ F]FBA), and their
conjugation to amino-oxy functionalised cyclic ROD peptides. Glaser e al describe
that [ F]FBA is obtained by radiofluorination of 4- V, ,N-trimethylamrnonium
benzaldehyde trifluoromcthanesulfonate as illustrated in the following reaction:
Battle et al (201 1 J Nucl Med; 52(3): 424-430) disclose purification of [ F]FBA by
diluting with water, and trapping on a solid-phase extraction (SPE) cartridge.
Impurities such as precursor, DMSO, Kryptofix-222 and hydrophilic by-products were
said to be eluted to waste, and the [1 F]FBA subsequently eluted with ethanol.
The present inventors have, however, found that using the SPE method of Battle et al
only some of the precursor is eluted to waste, and the remainder co-el utes when the
[ FjFBA is eluted with ethanol. There is therefore still a need for alternative methods
of labelling biological targeting moieties with 1 F.
Summary of the Invention
The present invention relates to a composition comprising an [ F]labelled synthon
wherein impurities which affect imaging in vivo and found in known compositions of
said synthon are not present. Also provided is a radiopharmaceut cat composition
obtained by means of said synthon. The invention also includes methods of imaging
and/or diagnosis using the radiopharmaceutical compositions described.
Detailed Description of the Invention
In a first aspect, the present invention provides a composition comprising:
an [1 F]labelled synthon of Formula X:
* -Ar —X (X)
wherein X1is CR'O wherein R 1 s hydrogen or C 6 alkyl; and, Ar is 6-membered
aromatic ring comprising between 0-3 nitrogen heteroatoms;
together with one or more non-radioactive compounds selected from:
(i) compounds of Formula Y :
wherein Ar1is the same as A and Ar2 and Ar3 are the same and are
as defined for Ax; A is a corresponding counter anion to the
sulfonium cation; and, Y is the same as Xs and Y2 and Y3 are the
same and are either hydrogen or -CR'O as defined for Formula X;
and,
compounds of Formula Z:
wherein each of Ar5 and Ar6 is a 6-membered aromatic ring
comprising between 0-3 nitrogen heteroatoms; and, each of Z and
Z2 is hydrogen or -CR'O as defined for Formula X.
The term "a composition comprising" refers to a chemical composition having the
components listed, but that other, unspecified compounds or species may be present in
addition. A preferred subset can therefore be "a composition consisting essentially of ,
which means that the composition has the components listed without other compounds or
species being present.
An F]labelled synthon" also known as an [1 F]labelled prosthetic group, is a small
molecule labelled with F that may be coupled with a non-radioactive precursor compound
to result in the desired [ F]labelled product.
The term "a k l" used either alone or as part another group is defined as any straight,
branched or cyclic, saturated or unsaturated C H2n+i group.
The term "6-membered aromatic ring" refers to an aromatic substitucnt based on benzene
(C H ) comprising 0-3 nitrogen heteroatoms. A "nitrogen hetcroatom" is a nitrogen that
takes the place of a C in the aromatic ring. Examples of 6-membered aromatic rings of
the invention include phenyl, pyridyl, and pyrimidyl.
The term "non-radioactive compounds" refers to any compound that comprises no
radioactive atoms.
The term "counter anion" refers to an anion that accompanies a cationic species in order to
maintain electric neutrality. An "anion" is an ion with more electrons than protons, giving
it a net negative charge. Any anion may be used as the counter anions. Non-limiting
examples include CF3S0 3 , PF , BF , and AsF , S0 4
2 , and N0 3 .
X1is preferably -CR'O wherein R is hydrogen or C i-3 alkyl, and is most preferably -CHO.
Ar1 s preferably phenyl or pyridyl, most preferably phenyl.
Ar2 is preferably phenyl or pyridyl, most preferably phenyl.
Ar3 and Ar4 are preferably both phenyl or both pyridyl, most preferably both phenyl.
Y! is preferably -CR wherein R1is hydrogen or C ., alkyl, and is most preferably -CHO.
Y2 and Y3 are both preferably hydrogen.
Y2 and Y3 are alternatively preferably -CR wherein R is hydrogen or C , alkyl, and is
most preferably - O.
A is preferably selected from CF3S 3 , PF , BF4 , and AsF6 .
Ar5 and Ar6 are preferably either phenyl or pyridyl, most preferably phenyl.
and Z2 are preferably hydrogen or -CHO.
For a preferred compound of Formula X:
is CR wherein R1 is hydrogen; and,
Ar is phenyl or pyridyl and is most preferably phenyl.
For a most preferred compound of Formula X:
X1 is CR wherein R is hydrogen; and,
Ar' is phenyl.
For a preferred compound of Formula Y:
Ar2 is phenyl or pyridyl;
A 3 and Ar4 are the same and are either both phenyl or both pyridyl;
Y1 is CR wherein R is hydrogen;
Y2 and Y3 are the same and are either both hydrogen or both CR wherein R1is hydrogen;
and,
A is selected from CF3SO3 , PF , BF4 , and AsF ,~.
For a most preferred compound of Formula Y:
Ar2 is phenyl;
Ar3 and Ar4 are both phenyl;
Y is C wherein R is hydrogen;
Y2 and Y are both hydrogen; and,
A is selected from CF3SO3 , PF , BF4 , and AsF .
For an alternative most preferred compound of Formula Y:
Ar2 is phenyl;
Ar3 and Ar4 are both phenyl;
Y1 is CR wherein R1 is hydrogen;
Y2 and Y3 are both CR wherein R1 is hydrogen; and,
A is selected from CF3SO , PF , BF , and AsF .
For a preferred compound of Formula Z:
Ar5 and Ar6 are independently either phenyl or pyridyl;
Z1 and Z2 are independently hydrogen or -CHO
Preferably for the composition of the invention defined hereinabove:
said compound of Formula X is a compound of Formula Xa:
said compound of Formula Y is a compound of Formula Ya:
wherein Y are as defined for Formula Y; and,
said compound of Formula Z is a compound of Formula Za:
wherein Z1 and Z2 are as defined for Formula Z.
For the above-defined composition it is preferred that X and Y are both located at the
r -position. In an alternative preferred embodiment, it is preferred that X1 and Y are
both located at the para-position.
The composition of the present invention is advantageous over known compositions that
comprise a compound of Formula X. One well-known compound of Formula X is
[ F]fluorobenzaldehyde ([ F]FBA), which is frequently used for the radiofluorination of
peptides. In the known process described by Battle et al (201 1 J Nucl Med; 52(3): 424-
430) a major chemical impurity is formed:
major chemical impurity
The present inventors have found that this major chemical impurity is not completely
removed following solid-phase extraction (SPE).
In contrast, in the composition of the present invention, the compounds of Formula Y and
Formula Z are very straightforward to remove from the above-described composition f the
present invention to provide pure compound of Formula X. In turn, a compound of
Formula X which does not include the major chemical impurity shown above can be used
to obtain a radiofluorinated product having an improved purity profile.
The above-described composition of the present invention is obtained by the reaction of a
compound of Formula Y with [ F]fluoride. Accordingly, in a second aspect f the present
invention is provided a method to prepare the composition as defined for the first aspect of
the invention wherein said method comprises:
(i) reaction f a non-radioactive compound f Formula Y as defined above
with [, F]fluoride; and,
(ii) purification to result in said composition.
Certain compounds of Formula Y may be obtained by use of methods known in the art.
Crivello & Lam (1978 J Org Chem; 43(15): 3055-3058), Crivello (US4161478) and Yanez
et al (2009 Chem Comm: 827-829) each provide teachings as to how to obtain a variety of
compounds of Formula Y by reaction of a compound of Formula Z with a diaryliodonium
salt of Formula Q as follows:
wherein the features of Formula Y and Formula Z are as defined herein, Q1 and Q2 are as
defined respectively herein for Z1and Z2, and Ar8 and Ar9 are as defined respectively herein
for Ar5 and Ar6. The prior art methods can be adapted in a straightforward manner using
routine skill in the art to obtain any compound falling within the definition of Formula Y.
[1 F]Fluoride used in the method of the second aspect of the invention is normally obtained
as an aqueous solution from the nuclear reaction 1 0(p,n) F. Once t is made reactive by
drying and by the addition of a cationic counterion and the removal f water 1 F can be
reacted with said compound of Formula Y. The step of "drying" [1 F]fluoride comprises
evaporation of water to result anhydrous [18F]fluoride. This drying step are suitably
carried out by application of heat and use of a solvent such as acetonitrile to provide a
lower boiling azeotrope. A "cationic counterion" is a positively-charged counterion
examples of which include large but soft metal ions such as rubidium or caesium,
potassium compiexed with a cryptand, or tctraalkylammonium salts. A preferred cationic
counterion is a metal complex of a cryptand, most preferably wherein said metal is
potassium and wherein said cryptand is Kryptofix 222.
The term "purification " refers to separation of the [1 F]labelled synthon of Formula X
from the non-radioactive compounds of Formula Y and Formula Z comprised the
composition of the first aspect of the invention with the aim of obtaining pure
[ 8FJlabelled synthon of Formula X. The purification step of the method of the
invention is suitably carried out by chromatography or solid-phase extraction (SPE),
wherein said chromatography is preferably high-performance liquid chromatography
(HPLC). Purification is facilitated by virtue o the fact that the non-radioactive
compounds of Formula Y are charged and as such easy to remove by ion exchange, and
also that the non-radioactive compounds of Formula Z are more lipophilic than the
[ F]labelled synthon of Formula and as such they can be removed using differential
lipophilicity to purify using solid-phase extraction (SPE). Purification is even more
straightforward where a symmetrical compound of Formula Y is used i the method as
even fewer non-radioactive compounds are generated i the resultant composition.
The method of second aspect of the invention is preferably 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 uni 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 arc 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; CT Inc; Ion Beam Applications S.A. (Chemin du Cyclotron 3, B-1 348
Louvain-La- Ncuve, 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 comprises 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 o moving
parts of the synthesizer controls the operation of the cassette from outside the cassette, i.e.
externally. Suitable cassettes comprise a linear array ofvalves, 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- fern ale j nt which interfaces
with a corresponding moving a of the automated synthesis apparatus. External rotation
f the arm thus controls the opening or closing of the valve when th 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 versatile, typically having several positions where reagents can be attached,
and several suitable for attachment of syringe vials f reagents or chromatography
cartridges (e.g. for SPE). The cassette always comprises a reaction vessel. Such reaction
vessels are preferably 0.5 to 0 mL, more preferably 0.5 to 5mL 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 5 to 40 valves in a linear array, most preferably 20 to 30, with
25 being especially preferred. Th 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 fro materials which are
of pharmaceutical grade and ideally also are resistant to radiolysis.
Preferred automated synthesis apparatuses of 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 o 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; prc-run automated diagnostic checking o 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.
a third aspect, the present invention provides a method to prepare a composition
comprising a positron emission tomography ( ET) tracer of Formula V:
,8pA N
/°BTM (V)
wherein Ar is as defined n above for the first aspect of the invention for Ar and
BTM is a biological targeting molecule;
wherein said method comprises the method as defined above for the second aspect
of the invention as well as the additional subsequent step f reacting said
, F]labelled synthon of Formula X with a precursor compound of Formula W:
N BTM W
wherein BTM is as defined for Formula V.
Similarly to the method of the second aspect of th invention , the method of the third
aspect of the invention is preferably carried out on an automated synthesis apparatus.
By the term "biological tarReting molecule " (BTM) is meant a compound which, after
administration, is taken up selectively or localises at a particular site o the mammalian
body in vivo. Such sites may be implicated in a particular disease state or be indicative of
how an organ or metabolic process is functioning. The BTM may be of synthetic or natural
origin, but is preferably synthetic. The term "synthetic" has its conventional meaning, i.e.
man-made as opposed to being isolated from natural sources e.g. from the mammalian
body. Such compounds have the advantage that their manufacture and impurity profile can
be fully controlled. The molecular weight o the BTM is preferably up to 10000 Daltons.
More preferably, the molecular weight is in the range 200 to 9000 Daltons, most preferably
300 to 8000 Daltons, with 400 to 6000 Daltons being especially preferred. When the BTM
s a non-peptide, the molecular weight of the BTM is preferably up to 3000 Daltons, more
preferably 200 to 2500 Daltons, most preferably 300 to 2000 Daltons, with 400 to 500
Daltons being especially preferred. By the term "peptide" is meant a compound comprising
two or more amino acids, as defined below, linked by a peptide bond (i.e. an amide bond
linking the amine of one amino acid to the carboxyl of another). When the BTM is an
enzyme substrate, enzyme antagonist, enzyme agonist, enzyme inhibitor or receptorbinding
compound it is preferably a non-peptide, and more preferably synthetic. By the
term "non-peptide is meant a compound which does not comprise any peptide bonds, i.e.
an amide bond between two amino acid residues.
The method of the third aspect is preferably carried out i a sterile manner, such that a
pharmaceutical composition comprising said PET tracer of Formula V s obtained. The
radiopharmaceutical compositions of the present invention may be prepared by various
methods:
(i) aseptic manufacture techniques i which the 1 F-radiolabelling step is carried out in
a clean room environment;
(ii) terminal sterilisation, in which the F-radiolabelling is carried out without using
aseptic manufacture and then sterilised at the last step [e.g. by gamma
irradiation, autoclaving dry heat or chemical treatment (e.g. with ethylene
oxide)];
kit methodology in which a sterile, non-radioactive kit formulation
comprising a suitable precursor and optional excipients is reacted with a
suitable supply of F;
(iv) aseptic manufacture techniques which the 1 F-radiolabelling step is carried out
using an automated synthesizer apparatus.
Method (iv) is preferred.
The term "pharmaceutical composition" refers to a composition comprising said PET tracer
of Formula V together with a biocompatible carrier in a form suitable for mammalian
administration.
B the phrase "in a form suitable for mammalian administration " is meant a composition
which is sterile, pyrogen- free, lacks compounds which produce toxic or adverse effects, and
is formulated at a biocompatible pH (approximately p 4.0 to 10.5). Such compositions
lack particulates which could risk causing emboli in vivo, and are formulated so that
precipitation does not occur on contact with biological fluids (e.g. blood). Such
compositions also contain only biologically compatible excipients, and are preferably
isotonic.
The "biocompatible carrier" is a fluid, especially a liquid, n which the PET tracer of
Formula V can be suspended or preferably dissolved, such that the composition is
physiologically tolerable, i.e. can be administered to the mammalian body without toxicity
or undue discomfort. The biocompatible carrier is suitably an injectable carrier liquid such
as sterile, pyrogen-free water for injection; an aqueous solution such as saline (which may
advantageously b balanced so that the final product for injection is isotonic); an aqueous
buffer solution comprising a biocompatible buffering agent (e.g. phosphate buffer); an
aqueous solution f one or more tonicity-adjusting substances (e.g. salts ofplasma cations
with biocompatible counterions), sugars (e.g. glucose or sucrose), sugar alcohols (e.g.
sorbitol or mannitol), glycols (e.g. glycerol), or other non-ionic polyol materials (e.g.
polyethyleneglycols, propylene glycols and the like). Preferably the biocompatible carrier
is pyrogen-free water for injection, isotonic saline or phosphate buffer.
In a fourth aspect the present invention provides a cassette for carrying out the method of
the second aspect of the invention on a automated synthesis apparatus, said cassette
comprising
(i) a vessel containing the compound o Formula Y as defined above for the
first aspect of the invention; and
(ii) means for eluting the vessel with a suitable source of [ F]fluoride; and
optionally,
(iii) an ion-exchange cartridge for removal of excess [ F ]fluoride.
a fifth aspect the present invention provides a cassette for carrying out the method of the
third aspect of the invention on an automated synthesis apparatus, said cassette comprising
the features of the cassette as defined for the fourth aspect of the invention in addition to
(iv) a vessel containing said compound of Formula W as defined for the third aspect of the
invention
A sixth aspect of the present invention i a pharmaceutical composition as defined
hereinabove comprising the PET tracer of Formula V as defined for the third aspect of the
invention wherein said pharmaceutical composition is obtained according to the method of
the third aspect of the invention.
I a seventh aspect, the present invention provides a method of imaging the human or
animal body which comprises generating a PET image of at least a part f said body to
which the pharmaceutical composition of the sixth aspect of the invention has distributed.
In a preferred embodiment, said method of imaging is carried out repeatedly to monitor the
effect treatment f a human or animal body with a drug, said imaging being effected
before and after treatment with said drug, and optionally also during treatment with said
drug.
Alternatively, said method of the seventh aspect of the invention can be understood as
wherein said pharmaceutical composition has been previously administered to said body.
In an eighth aspect, the present invention provides a method of diagnosis of the human or
animal body which comprises the imaging method o the seventh aspect of the invention.
Alternatively said eighth aspect can be understood to be the pharmaceutical composition of
the sixth aspect of the invention for use in said method of diagnosis.
The invention is illustrated by the non-limiting Example detailed below.
Brief Description of the Examples
Example 1 describes the synthesis f an asymmetrical sulfonium precursor compound
of the present invention.
Example 2 describes 1 F labelling f an asymmetric sulfonium precursor compound of
the present invention.
List of Abbreviations used in the Examples
[1 F]FBA [1 F]fluorobenzadehyde
HPLC high-performance liquid chromatography
min minute(s)
QMA quaternary methylammoniu
RP reverse phase
SPE solid phase extraction
UV ultraviolet
Example 1: Preparation of (4-formvlphenvQ diphenvlsulfonium
hexafluorophosphate
In a 5 mL glass reaction vessel 4-phenylthiobenzaIdehyde ( 1g, 4.67 mmol),
diphenyliodonium hexafluoro phosphate (4 g, 9.39 mmol) and copper(ll) benzoate
(0.1 2g) were mixed in the dark in chlorobenzene (2 mL) under N2 atmosphere. The
resulting mixture was heated to 125°C for 5 min under microwave. Upon completion
o reaction the solvent was evaporated under vacuum and isolated the crude product as a
dark yellow residue. Purified the crude product using reversed phase chromatography:
Zorbax SB-C1 8, 9.4X 50mm, 5 column, Gradient: Solvent A: Water, Solvent B:
Acetonitrile; flow 1Oml/min, gradient : 98/2(A/B) isocratic for 2 min, 20/80 over 8 min,
isocratic for 2 min,98/2 in min. Isolated the 98.8% pure material as a white solid (0.5
g).
NMR (500 MHz, acetone-d6): 0.24 ( 1 H, s), 8.34(2H, d, 9 Hz), 8. 15 (2H, d, J= 9
Hz,), 8.08 (6H, m), 7.9 (411, t, J= 9Hz)
m/z calculated for : 291.08; found, 291 .4
Example 2 : F labelling of (4-formylphenvl) diphcnvlsulfonium 2,2,2-
trifluoroacetate
[1 F]fluoride (370 MBq) was diluted with water ( 1 mL) and trapped a Waters QMA
carb. Cartridge. The | F] fluoride was eluted into a TRACERlab™ reaction vessel with
a solution containing tetrabutylammonium carbonate in acetonitrile/water. The
1 F]fluoride solution was dried under vacuum and with a stream o nitrogen. (4-
formylphenyl)diphenylsulfonium 2,2,2-trifluoroacetate (8.5 mg) in dimethylsulfoxide ( 1
ml) was added to the resultant [1 F]tetrabutylammonium fluoride residue and heated in
the sealed reactor for 5 minutes at 130°C.
The contents of the reactor were then cooled to 50°C and diluted with 70:30
watendimethylsulfoxide. A sample of the clear-yellow crude product solution was
submitted to analytical RP HPLC (A= water, B=acetonitrile, 30% B for 15 minutes to
95% B) and an incorporation of -78% was determined with ' Fjfluorobenzaldehyde
([ 1 F]-FBA) eluting in 10.478 minutes (see Figure 1 wherein the radioactive trace is top
and the UV trace is bottom). The early peaks in the UV are charged species from the
reaction mixture and the species eluting during the 95% B wash are more lipophilic b y
products, probably diphenylsulfane and 4-(phenylthio)benzaldchydc. The HPLC shows
that [ F]FBA is separated from any UV impurities and those than run close are minor
in comparison to the bulk chemical in the crude product.

Claims
A composition comprising:
an [ F]labelled synthon of Formula X:
F—Ar1- X (X)
wherein X is -CR'O wherein is hydrogen or C1-6 alkyl; and, Ar' is 6-membered
aromatic ring comprising between 0-3 nitrogen heteroatoms;
together with one or more non-radioactive compounds selected from:
(i) compounds of Formula Y:
wherein Ar2 is the same as A1and Ar3 and Ar4 are the same and are
as defined for A1; A is a corresponding counter anion to the
sulfonium cation; and, Y is the same as X' and Y and YJ are the
same and are either hydrogen or CR O as defined for Formula X;
and,
(ii) compounds of Formula Z:
wherein each f Ar5 and Ar6 is a 6-membered aromatic ring
comprising between 0-3 nitrogen heteroatoms; and, each of Z1 and
Z2 is hydrogen or -CR'O as defined for Formula X.
(2) The composition as defined n Clai 1wherein R is hydrogen.
(3) The composition as defined in either Claim 1 or Claim 2 wherein Ar1 is phenyl or
pyridyl.
(4) The composition as defined n Claim 3 wherein Ar 1 is phenyl.
(5) The composition as defined in any one of Claims 1-4 wherein Ar2 and Ar3 are both
phenyl or pyridyl.
(6) The composition as defined in Claim 5 wherein Ar2 and Ar3 are both phenyl.
(7) The composition as defined in any one of Claims 1-6 wherein Y2 and Y3 are both
hydrogen.
(8) The composition as defined in any one of Claims 1-6 wherein Y2 and Y are both
-CHO.
(9) The composition as defined in Claim 1wherein said compound of Formula X is a
compound of Formula Xa:
said compound of Formula Y is a compound of Formula Ya:
wherein Y 3 are as defined for Formula Y; and,
said compound of Formula Z is a compound of Formula Za:
wherein Z and Z2 are as defined for Formula Z.
(10) The composition as defined in any one of Claims 1, 2 and Claim 9 wherein 1 and
Y arc both located at the r -position.
( D The composition as defined in any one f Claims 1, 2 and Claim 9 wherein 1and
Y are both located at the r -position.
(12) The composition as defined in any one of Claims 1-1 1wherein A i selected from
CF3SO3 , PF , BF4 , and AsF .
(13) A method to prepare the composition as defined in any one of Claims 1-12 wherein
said method comprises:
(i) reaction of a non-radioactive compound of Formula Y as defined in any one
of Claims 1, 2 and 5-1 1 with [ F]fluoride; and,
(ii) purification to result in said composition.
(14) The method as defined in Claim 3 wherein said purification is carried out by highperformance
liquid chromatography (HPLC).
(15) The method as defined in Claim 13 wherein said purification is carried out by solidphase
extraction (SPE).
(16) The method as defined in any one of Claims 13-15 which is carried out on an
automated synthesis apparatus.
(17) A method to prepare a composition comprising a positron emission tomography
(PET) tracer of Formula V:
wherein Ar7 is as defined i any one of Claims , 3 and 4 for Ar and BTM is a
biological targeting molecule;
wherein said method comprises the method as defined in any one of Claims 13-16
as well as the additional subsequent step of reacting said [l F]labelled synthon of
Formula X with a precursor compound of Formula W:
H2N BTM (w)
wherein BTM is as defined for Formula V.
( 8) The method as defined in Claim 17 which s carried out on an automated synthesis
apparatus.
(19) A cassette for carrying out the method as defined in Claim 16, said cassette
comprising
(i) a vessel containing the compound of Formula Y as defined in any one of Claims ,
2 and 5-12; and
(ii) means for eluting the vessel with a suitable source f [ F]fluoride; and
optionally,
(iii) an ion-exchange cartridge for removal of excess [i 8F]fluoride.
(20) A cassette for carrying out the method as defined in Claim 18, said cassette
comprising the features f the cassette as defined in Claim 1 i addi tion to (iv) a
vessel containing said compound of Formula W as defined in Claim 17.
(21 A pharmaceutical composition comprising the PET tracer of Formula V as defined
in Claim 7 wherein said pharmaceutical composition is obtained according to the
method defined in Claim 7.
(22) A method of imaging the human r animal body which comprises generating a PET
image of at least a part f said body to which the pharmaceutical composition of
claim 2 1 has distributed.
(23) The method of claim 22, which is carried out repeatedly to monitor the effect of
treatment f a human or animal body with a drug, said imaging being effected
before and after treatment with said drug, and optionally also during treatment with
said drug.
(24) The method of claim 22 or claim 23, wherein said pharmaceutical composition has
been previously administered to said body.
(25) A method of diagnosis of the human or animal body which comprises the imaging
method o any one of claims 22-24.
(26) The pharmaceutical composition as defined in Claim 21 for use in the method f
diagnosis as defined in Claim 25.