RADIOFLUORINATION METHOD
Technical Field of the Invention
The present invention relates to a method for radiosynthesis and more specifically a
novel method for the synthesis of 1 F-labelled compounds. The invention also relates to
a novel synthon for use in the inventive method of synthesis.
Description of Related Art
In order to expand the range of applications for positron emission tomography (PET)
there is an interest in developing synthetic methods for new PET tracers, i.e. biologically
useful compounds labelled with C, 1 F or 7 Br. Currently, the most widely-used of
these radiotracers for PET imaging is 1 F.
Typically, the synthesis of a PET tracer including its purification should be completed
within three half-lives of the radiotracer. 1 F has a relatively short half-life of 109.7
minutes and as such methods for its incorporation into a PET tracer demands fast and
high-yielding reactions that can be performed on a small scale and under mild conditions.
Direct labelling is desirable as it introduces 1 F at the last possible step. However, direct
labelling tends only to be possible using [1 F]fluoride in a nucleophilic substitution
reaction can require the presence of activating groups, proton-free conditions and
typically high temperatures of above 100°C. The reader is referred to Coenen ("PET
Chemistry: The Driving Force in Molecular Imaging", Ernst Schering Research
Foundation Workshop 62, Schubiger et al, Eds; Springer 2007 pp 15-50) for more detail
on typical direct labelling reaction conditions.
Alternatively, 1 F can be introduced as part of a synthon. With this approach, an
activated precursor is radiofluorinated, and used in subsequent reactions to prepare the
desired radiofluorinated product. Many classes of synthons are known for the
introduction of an 1 F-labelled aromatic group, e.g. [1 F]fluorobenzaldehydes,
[1 F]fluoroarylketones, [1 F]fluorobenzoic acid, [1 F]fluoronitrobenzene,
[1 F]fluorobenzonitrile, [1 F]fluorosulfonyl arenes, and [1 F]fluorohalobenzenes. These
classes of synthons, methods to obtain them, and how they can be converted into PET
tracers are described in a review by Ermert and Coenen (2010 Current
Radiopharmaceuticals; 3 : 127-160).
1 F-labelled fluoropyridines have found increasing application in PET imaging, and
strategies to obtain these compounds are gaining increasing attention. A review by
Dolle (2005 Curr Pharm Des; 11: 3221-3235) describes how a variety of
[1 F]fluoropyridyl-containing compounds can be obtained by nucleophilic heteroaromatic
substitution at the ortho position with [1 F]fluoride. A specific example of this labelling
strategy is reported by Roger et al (2006 J Label Comp Radiopharm; 49: 489-504), who
describe the synthesis of 2-exo-(2'-[ 1 F]fluoro-3'-(4-fluorophenyl)-pyridin-5'-yl)-7-
azabicyclo[2.2.1]heptane by nucleophilic aromatic substitution of a precursor compound
as follows:
wherein X in the scheme represents CI or Br, with overall radiochemical yields reported
as 8-9%. 4-[ 1 F]fluoropyridyl derivatives can also be obtained using such an approach,
but not feasibly for 3-[ 1 F]fluoropyridyl derivatives where very strongly electronwithdrawing
groups would need to be present, and even then the reaction would likely
be low-yielding.
Abrahim et al (2006 J Label Comp Radiopharm; 49: 345-356) report the synthesis of 5-
[1 F]fluoro-2-pyridinamine and 6-[ 1 F]fluoro-2-pyridinamine. In this approach a
carbonyl was used para to a bromine leaving group to obtain the para radiofluorinated
intermediate in 20-30% radiochemical yields as follows:
In the initial attempts to obtain the 5-[ F]fluoro-2-pyridinamine synthon using a nitro
starting compound, Abrahim reported obtaining 5-bromo-2-[ 1 F]fluoropyridine as an
unwanted side-product and consequently abandoned this approach.
LaBeaume et al (2010 Tet Letts; 51: 1906-1909) describe microwave-assisted methods
for direct fluorination of nitro intermediates to obtain fluonnated compounds. A variety
of nitro substrates were fluonnated using the methods described, including 2-bromo-6-
nitropyridine, which was fluorinated with an excess of tetrabutylammonium fluoride
(TBAF), yielding >95% 2-bromo-6-fluoropyridine. LaBeaume highlights that as the
method gives good to excellent yields in less than 10 minutes, it is practical for use in the
preparation of 1 F-labelled ligands for PET imaging. LaBeaume notes that where
conventional heating was tried in place of microwave heating the conversion to
fluorinated product took up to ~4 hours, which would clearly be unsuitable for the
successful production of an 1 F-labelled compound.
As a further alternative, Carroll et al (2007 J Label Comp Radiopharm; 50: 452-454)
suggested diaryliodonium salts as a more generic route to obtain 3-fluoropyridines as
this approach has been shown to place little or no restriction on the aromatic
substituents, allowing it be used much later in the synthetic sequence as compared with
the earlier-reported techniques. Radiochemical yields of 55-63% for 3-
[1 F]fluoropyridine were reported in this paper.
In addition various reports have discussed 1 F-labelled synthons for use in obtaining 1 Flabelled
macromolecules. These are illustrated below:
FPyBrA
Olberg et al (2010 J Med Chem; 53: 1732) report the use of F-Py-TFP (6-
[1 F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester) for peptide coupling reactions.
Dolle et al (2003 J Label Comp Radiopharm; 46: SI 5) report the use of FPyME
([1 F]fluoropyridine maleimide) for linking to thiol groups, in particular on peptides.
Kuhnast et al (2008 J Label Comp Radiopharm; 51: 336) describe FPyKY E (2-
[1 F]Fluoro-3-pent-4-ynyloxy-pyridine) for use in click reactions with macromolecules.
Kuhnast et al (2004 Bioconj Chem; 15: 617) describe the design and use of FPyBrA (2-
bromo-N-[3-(2-[ 1 F]fluoropyridin-3-yloxy)propyl]acetamide), a [1 F]fluoropyridine
based halo-acetamide reagent for the labelling of oligonucleotides. Each of these
synthons is useful for obtaining 1 F-labelled macromolecules, but due to their relative
complexity may change the physicochemical properties of a small molecule if used to
add 1 F.
Alternative means to obtain synthons useful in the synthesis of a broader range of 1 Flabelled
pyridine-containing compounds would be desirable.
Summary of the Invention
Provided by the present invention is a novel method for obtaining an 1 F-labelled
compound wherein said compound comprises an 1 F-labelled pyridyl ring. The method
of the invention is advantageous over the prior art methods as it provides these
compounds in higher radiochemical yields than have been possible with previous
methods. Also provided by the present invention is an 1 F-labelled synthon useful in the
method of the invention.
Detailed Description of the Invention
In one aspect, the present invention provides a method for [1 F] labelling synthesis
comprising reacting a radiolabelling precursor of Formula X:
with [1 F]fluoride to obtain an 1 F-labelled synthon of Formula Y:
The term "synthon" refers to a constituent part of a molecule to be synthesised which is
regarded as the basis of a synthetic procedure.
[1 F]Fluoride used in providing the 1 F-labelled synthon of Formula Y is typically obtained
as an aqueous solution which is a product of the irradiation of an [1 0]-water target.
Various steps are carried out on the aqueous solution to convert [1 F]fluoride into a reactive
nucleophilic reagent, such that it is suitable for use in nucleophilic radiolabelling reactions.
These steps include the elimination of water and the provision of a suitable counterion
(Handbook of Radiopharmaceuticals 2003 Welch & Redvanly eds. ch. 6 pp 195-227).
Suitable counterions include large but soft metal ions such as rubidium or caesium,
potassium complexed with a cryptand such as Kryptofix™, or tetraalkylammonium salts.
In a most preferred embodiment, the synthon of Formula Y is either of the following:
The relevant dibromo-substituted pyridines are commercially-available. For example, 2-
Bromo-6[ 1 F]-fluoropyridine, can be readily prepared from 2,6-dibromopyridine. The
present inventors have done so in 10 minutes at an end of synthesis (EOS) non-decay
corrected yield of 53%.
In a preferred embodiment, the method of the present invention further comprises the step:
(ii) coupling the 1 F-labelled synthon of Formula Y as defined herein with a
cross-coupling partner in a transition metal-mediated coupling reaction to
obtain an 1 F-labelled product.
The term "cross-coupling partner" refers to a compound that can react with the synthon of
Formula Y with the elimination of the synthon bromo leaving group to result in a desired
1 F-labelled product. The cross-coupling partner therefore suitably comprises a chemical
group that effects nucleophilic displacement of the bromo of the synthon. Non-limiting
examples of such chemical groups include terminal alkene, amino, terminal alkyne, boronic
acid, and organotin.
By the term "terminal alkene" is meant a double bond at the terminal end of a substituent. A
preferred cross-coupling partner comprising a terminal alkene is a compound of Formula la
as defined below.
The term "amino" refers to the group NR2 wherein each R is hydrogen or a monovalent
aliphatic or aromatic hydrocarbon substituent, as defined below. Preferably at least one R is
hydrogen. A preferred cross-coupling partner comprising an amine is a compound of
Formula Ie as defined below.
The term "terminal alkyne" refers to a triple bond at the terminal end of a substituent. A
preferred cross-coupling partner comprising a terminal alkyne is a compound of Formula Ic
as defined below.
The term "boronic acid" refers to the group -B(OH2) . A preferred cross-coupling partner
comprising boronic acid is a compound of Formula Id as defined below.
The term "organotin " refers to a chemical group comprising tin and hydrocarbon
substituents. Organotin compounds are also referred to as stannanes. A preferred crosscoupling
partner comprising an organotin is a compound of Formula lb as defined below.
The coupling reaction of step (ii) of the preferred embodiment of the invention is preferably
site-specific and may consequently require the presence of one or more protecting groups
on the cross-coupling partner. 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 in 'Protective
Groups in Organic Synthesis', Theorodora W. Greene and Peter G. M. Wuts, (Fourth
Edition, John Wiley & Sons, 2007).
The term "transition metal" includes palladium, platinum, gold, ruthenium, rhodium, and
iridium. The most typically used transition metal for the coupling reactions encompassed by
step (ii) of the method of the invention is palladium. Typical forms of palladium for use as a
catalyst include palladium acetate, tetrakis(triphenylphosphine)palladium(0),
bis(triphenylphosphine)palladium(II) dichloride, [1,1 -
bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and palladium on carbon (Pd/C).
Preferably, the 1 F-labelled product obtained in step (ii) is a tracer suitable for PET imaging
and preferably has a molecular weight <1500 Daltons; preferably <1000 Daltons. Where
the 1 F-labelled product is intended to be a PET tracer for imaging the central nervous
system, the molecular weight is preferably <500, which is optimal for blood-brain barrier
penetration.
As reported by Ermert and Coenen (2010 Current Radiopharmaceuticals; 3 : 127-160),
[1 F]fluorohalobenzenes can be converted into a range of different target 1 F-labelled
molecules by means of transition metal-mediated coupling reactions, as illustrated in
Scheme 1 below:
In Scheme 1, X represents bromo, chloro or iodo, and A-E represent:
(A) Heck reaction between an alkene and an aryl halides;
(B) Hartwig-Buchwald amination of an aryl halide with an amine;
(C) Sonogashira coupling between an aryl halide and an alkyne, with copper(I)iodide as
a co-catalyst;
(D) Suzuki reaction between an aryl halide and boronic acid; and,
(E) Stille reaction of an organohalide and an organotin.
Each of these transition-metal catalysed reactions are well-known to the skilled person and
are described e.g. in "March's Advanced Organic Chemistry: Reactions, Mechanisms, and
Structures (6th Edition Wiley 2007, Smith and March, Eds.); see page 792 for the Stille
reaction, page 875 for Hartwig-Buchwald N-arylation, page 904 for the Sonogashira
reaction and page 899 for Suzuki coupling. The [1 F]-fluorobromopyridine synthon
provided in step (i) of the method of the present invention can therefore be converted into a
range of 1 F-labelled products using these same reactions. The method of the present
invention therefore allows for the synthesis of a wide range of 1 F-labelled heteroaromatic
PET tracers.
In one preferred embodiment of the method of the invention, said transition metal coupling
reaction comprises reaction of the 1 F-labelled synthon of Formula Y with a compound of
Formula la:
(la)
wherein R1 is a monovalent aliphatic or aromatic hydrocarbon group;
to obtain an 1 F-labelled product of Formula Ila:
The term "monovalent aliphatic hydrocarbon group " used here and elsewhere in the
specification is intended to encompass substituted or unsubstituted linear, branched or cyclic
alkyl, alkenyl, or alkynyl radicals, wherein one or more of the carbons in the chain is
optionally a heteroatom selected from O, S and N. The term "alkyl" refers to monovalent
radical having the general formula CnH2n+i, the term "alkenyl" refers to an alkyl comprising
one or more double bonds, and the term "alkynyl" refers to an alkyl comprising one or more
triple bonds. The term "aliphatic" relates to those parts of the radical arranged in straight or
branched chains, and not containing aromatic rings.
The term "monovalent aromatic hydrocarbon group " used here and elsewhere in the
specification is intended to encompass substituted or unsubstituted radicals containing one
or more six-carbon rings characteristic of the benzene series and related organic groups,
wherein one or more of the carbons is optionally a heteroatom selected from O, S and N.
The term also includes radicals comprising aliphatic elements in addition, wherein the
aliphatic elements can be monovalent aliphatic hydrocarbon groups as defined above, or
divalent derivatives thereof, provided that the designated atom's normal valency under the
existing circumstances is not exceeded.
The term "substituted" as used throughout the specification means that one or more
hydrogens on a designated atom is replaced with a substituent, provided that the designated
atom's normal valency under the existing circumstances is not exceeded, and that the
substitution results in a stable compound. Combinations of substituents and/or variables are
permissible only if such combinations result in stable compounds. The term "stable
compound" is meant a compound that is sufficiently robust to survive isolation to a useful
degree of purity from a reaction mixture.
Non-limiting examples of "substituents" include, halo groups, hydroxy groups, oxo groups,
mercapto groups, amino groups, carbamoyl groups, carboxyl groups, cyano groups, nitro
groups, acyl groups, phosphate groups, sulfamyl groups, sulfonyl groups, sulfinyl groups,
and combinations thereof. A substituent can also be a substituted or unsubstituted
monovalent aliphatic or aromatic hydrocarbon group as defined above.
As used herein, the term "halo" or "halogen" means refers to chlorine, bromine, fluorine or
iodine.
The term "oxo" refers to the group =0.
The term "mercapto " refers to the group -SH, which is also known as thiol or sulfhydryl.
The term "carbamoyl" refers to the group -C(=0)NH 2.
The term "carboxyl" refers to the group -C(=0)OH.
The term "cyano" refers to the group -CºN.
The term "nitro" refers to the group -N0 2.
The term "acyl" refers to the group -C(=0)-alkyl wherein alkyl is as defined above.
The term "phosphate " refers to the group -0-P(OH) .
The term "sulfamyl" refers to the group -S(=0) 2-amino wherein amino is as defined above.
The term "sulfonyl" refers to the group -S(=0) 2-alkyl wherein alkyl is as defined above.
The term "sulfinyl" refers to the group -S(=0)-alkyl wherein alkyl is as defined above.
In another preferred embodiment, in the method of the invention, said transition metal
coupling reaction comprises reaction of the 1 F-labelled synthon of Formula Y with a
compound of Formula lb:
Bu SnR2 (lb)
wherein Bu stands for butyl, and R2 is a monovalent aliphatic or aromatic
hydrocarbon group wherein both terms are as defined above;
to obtain an 1 F-labelled product of Formula lib:
In a further preferred embodiment, in the method the invention said transition metal
coupling reaction comprises reaction of the 1 F-labelled synthon of Formula Y with a
compound of Formula Ic:
R (IC)
wherein R is a monovalent aliphatic or aromatic hydrocarbon group wherein both
terms are as defined above:
to obtain an 1 F-labelled product of Formula lie:
In another further preferred embodiment, in the method the invention said transition metal
coupling reaction comprises reaction of the 1 F-labelled synthon of Formula Y with a
compound of Formula Id:
HO R4
B
OH (id)
wherein R4 is a monovalent aliphatic or aromatic hydrocarbon group wherein both
terms are as defined above;
to obtain an 1 F-labelled product of Formula lid:
wherein R4 is as defined for Formula Id.
Example 4 describes such a reaction.
In a yet further preferred embodiment, in the method the invention said transition metal
coupling reaction comprises reaction of the 1 F-labelled synthon of Formula Y with a
compound of Formula Ie:
V
H (Ie)
wherein R5 and R6 are independently hydrogen or a monovalent aliphatic or
aromatic hydrocarbon group, wherein both terms are as defined above, or together
with the nitrogen to which they are attached form a nitrogen-containing aliphatic or
aromatic ring;
to obtain an F-labelled product of Formula He:
Example 2 describes such a reaction.
In the case of each of the 1 F-labelled products of Formulas Ila-IIe, the suitable and
preferred positions for 1 F and for each substituent are as defined respectively for 1 F and Br
in the synthon of Formula Y.
The term "nitrogen-containing aliphatic or aromatic ring" refers to any substituted or
unsubstituted cyclic substituent that comprises at least one nitrogen heteroatom, preferably
having between 4-7 carbon atoms, most preferably between 4-5 carbon atoms. It is
preferred that such rings have between 1-3, and most preferably between 1-2 nitrogen
heteroatoms.
In an even further preferred embodiment, in the method the invention said transition metal
coupling reaction comprises reaction of the 1 F-labelled synthon of Formula Y with the
above-defined compound of Formula Ie in the presence of a source of carbon monoxide to
obtain an 1 F-labelled product of Formula Ilf:
wherein R7 and R8 are as defined above for R5 and R6, respectively.
Example 3 relates to such a reaction.
The alternative known synthetic routes to form the above specific classes of compounds are
relatively low-yielding as compared with the method of the present invention. For example,
to obtain the compound of Formula Ilf, one known method is via direct labelling, although
this can be prohibitively low yielding in unactivated substrates. An alternative known
method is a multi-stage activated ester strategy which is not straightforward to implement.
In a preferred embodiment, the method of the invention is automated, preferably on an
automated synthesiser. [1 F]-radiotracers are now often conveniently prepared on an
automated radiosynthesis apparatus. There are several commercially-available examples of
such apparatus, including Tracerlab™ and Fastlab™ (both from GE Healthcare Ltd). Such
apparatus commonly comprises a "cassette ", often disposable, in which the radiochemistry is
performed, which is fitted to the apparatus in order to perform a radiosynthesis. The
cassette normally includes fluid pathways, a reaction vessel, and ports for receiving reagent
vials as well as any solid-phase extraction cartridges used in post-radiosynthetic clean up
steps. The present invention therefore provides in another aspect a cassette for carrying out
the automated method of the invention wherein said cassette comprises:
i) a vessel containing a precursor compound of Formula X as defined above,
ii) means for eluting the vessel of step (i) with [1 F]fluoride.
The cassette preferably also comprises:
iii) a vessel comprising a compound of any one of Formula Ia-e as defined
above.
Where the cassette comprises the vessel comprising a compound of any one of Formula
Ia-e, this vessel is eluted with the purified product of the reaction between the precursor
compound of Formula X and [1 F]fluoride, i.e. the synthon of Formula Y as defined
herein. Purification is typically carried out by solid phase extraction on the cassette.
The cassette may also additionally comprise:
iv) an ion-exchange cartridge for removal of excess 1 F.
Brief Description of the Examples
Example 1 describes the Preparation of 2-Bromo-6[ 1 F]-fluoropyridine.
Example 2 describes the preparation of l-benzyl-4-(6-[ 1 F]fluoropyridin-2-yl) piperazine.
Example 3 describes the preparation of N-benzyl-6-[ 1 F]fluoropicolinamide.
Example 4 describes the preparation of 2-[ 1 F]fluoro-6-(p-tolyl)pyridine.
Example 5 describes the preparation of 3-bromo-5-[ 1 F]fluoropyridine.
Example 6 describes the preparation of 3-[ 1 F]fluoro-5-(p-tolyl)pyridine.
List of Abbreviations used in the Examples
Ac acetyl
BINAP 2,2'-bis(diphenylphosphino)-l, -binaphthalene
dba dibenzylideneacetone
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DMF dimethylformamide
DMSO dimethylsulfoxide
FIPLC high performance liquid chromatography
MeCN acetonitrile
Et triethylamine
Ph phenyl
TFIF tetrahydrofuran
UV ultraviolet
Examples
Example 1: Preparation of 2-Bromo-6-[1 Flfluoropyridine
Experiments were undertaken to explore the optimum reaction conditions for preparing
2-bromo-6-[ FJfluoropyridine from 2,6-dibromo pyridine.
All reactions were performed by conventional heating for ten minutes and the resulting
2-bromo-6-[ 1 F]fluoropyridine was purified by semi-preparative HPLC using the
following method:
Column: ACE-5 CI 8 10x100mm
Mobile phase A = H20
Mobile Phase B = MeCN
Flow rate 3 mL/min
Gradient 0-15 min, 5-95%B
In the table below, yields (from fluoride) are of the isolated product after HPLC
purification, with yields in brackets being decay corrected.
The reaction highlighted in bold in the above table resulted in the highest yield.
Example 2: Preparation of l-benzyl-4-(6-f FIfluoropyridin-2-yl) pipemzine
NaO'Bu
MeCN
A Buchwald-Hartwig coupling reaction was tested with 1-benzyl piperazine, using
tris(dibenzylideneacetone) dipalladium(O) and (±)BINAP with sodium t-butoxide in
MeCN. After 25 min heating at 100°C, 49% of the activity was the desired product. The
analytical HPLC using the following method:
Column: Phenomenex Luna C18(2) 3m 4.6 x 50mm
Mobile phase A = 0.8% NEt3 in H20 , corrected to pH -7.5 with H P0 4
Mobile phase B = MeCN
Flow rate = 1 mL/min
0-15 min 40-95%B
15-18 min 95%B
18- 19 min 95-40%B
19-20 min 40%B
The traces are displayed in Figures la-c. Figure l a is a Radio-FTPLC of the reaction
mixture after 25 min heating at 100 °C. Figure l b is a Radio-EfPLC of the product after
semi-preparative F PLC purification. Figure l c is a UV-FTPLC (254 nm) of the
[1 F]standard.
Example 3: Preparation of N-benzyl-6-[1 F/fluoropicolinamide
A reaction using molybdenum(O) hexacarbonyl as CO source was performed. In a
procedure based on that described by Wannberg et al (2003 J Org Chem; 68: 5750),
palladium acetate, molybdenum hexacarbonyl, benzylamine and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) were added and the reaction was heated at
100°C.
Analytical HPLC was carried out using the following method:
Column: Phenomenex Luna C18(2) 3m 4.6 x 50mm
Mobile phase A = 0.8% Et in H20 , corrected to pH -7.5 with H P0
Mobile phase B = MeCN
Flow rate = 1 mL/min
0-15 min 40-95%B
15-18 min 95%B
18-19 min 95-40%B
19-20 min 40%B
Traces of the aminocarbonylation reaction after 5, 15, and 30 min heating are displayed
in Figures 2a-c, respectively. The retention times of [1 F]-2-bromo-6-fluoropyridine and
the desired product are 2.8 min and 3.5 min respectively. 66% of the activity injected
was desired product after 30 min.
Analytical HPLC data a . Radio-HPLC 5 min, b . Radio-HPLC 15 min c . Radio-HPLC 30
min d. UV-HPLC of cold standard.
The absence of any [ F]-Buchwald-Hartwig product in the radiolabelling reaction
(formed without insertion of CO) can be noted, demonstrating the efficiency of the
aminocarbonylation reaction.
Example 4: Preparation of 2-[1 F]fluoro-6-(p-tolyl)pyridine
MeCN/H20
A Suzuki coupling was performed with /?-tolylboronic acid, using tetrakis
(triphenylphosphino) palladium and sodium carbonate in H20-acetonitrile mixture. After
5 min heating at 100 °C, 98% of the activity was the desired product. Analytical HPLC
was carried out using the following method:
Column: Phenomenex Luna C18(2) 3m 4.6 x 50mm
Mobile phase A = 0.8% Et in H20 , corrected to pH -7.5 with H P0
Mobile phase B = MeCN
Flow rate = 1 mL/min
0-15 min 40-95%B
15-18 min 95%B
18- 19 min 95-40%B
19-20 min 40%B
FIPLC traces of the unpurified reaction is shown in the Figures 3a-b. Figure 3a shows a
Radio FIPLC trace of the reaction after 5 min heating at 100 °C. Figure 3b shows a UV
HPLC (254 nm) of the [1 F]standard.
Example 5: Preparation of 3-bromo-5-[1 Flfluoropyridine
Experiments to assess the [ FJfluorine labelling in the 3-position were undertaken.
Several experiments to explore various reaction conditions were performed. Yields given
are after HPLC purification of the synthon (with the exception of entry 1). The HPLC
method was as follows:
Column: ACE5 C18 lOxlOOmm
Mobile phase A = H20
Mobile Phase B = MeCN
Flow rate 3mL/min
0-15 min 5-95%B
* This is the analytical incorporation, by HPLC.
The highest yielding reaction was performed as follows:
3,5-dibromopyridine (3.0 mg) was added to dried [1 F]fluoride/kryptofix/potassium
carbonate in DMSO and subjected to microwave heating (50 W) for 1 min. After
purification by semi-preparative HPLC, the isolated non-decay corrected yield from
fluoride was 16%.
Example 6: Preparation of 3-[1 F]fluoro-5-(p-tolyl)pyridine
Na2C0 3
Pd(PPh3)4
Suzuki coupling of 3-bromo-5[ FJfluoropyridine was performed with /?-tolylboronic
acid, using tetrakis(triphenylphosphino) palladium and sodium carbonate in an
acetonitrile-H 20 mixture. After 5 min heating at 100 °C, 82% of the activity was the
desired product.
Semi-preparative radio-HPLC was carried out as follows:
Column ACE5 CI8 10 x 100mm
A = H20
B = MeCN
Flow rate 3mL/min
0-15min 5-95%B
Analytical FIPLC was carried out as follows:
Column: Phenomenex Luna C18(2) 3m 4.6 x 50mm
Mobile phase A = 0.8% Et in H20 , corrected to pH -7.5 with H P0 4
Mobile phase B = MeCN
Flow rate = 1 mL/min
0-15 min 40-95%B
15-18 min 95%B
18-19 min 95-40%B
19-20 min 40%B
Figure 4a shows the semi-preparative radio-FIPLC trace of the Suzuki coupling reaction
of /?-tolylboronic acid and 3-bromo-5-[ 1 F]fluoropyridine after 5 min at 100 °C. Rt
desired product = 14.1 min. Figures 4b and 4c show the analytical FIPLC traces of
isolated 3-[ 1 F]fluoro-5-(p-tolyl)pyridine. a . Radio-FIPLC of isolated product b. UVFIPLC
of [1 F]standard (254 nm). Rt product = 5 min. The slight shoulder is due to the
age of the column.
Claims
A method for [ F] labelling synthesis comprising reacting a radiolabelling precursor
of Formula X:
with [ FJfluoride to obtain an F-labelled synthon of Formula Y:
The method as defined in Claim 1wherein
said radiolabelling precursor of Formula X has the following chemical structure:
and said F-labelled synthon of Formula Y has the following chemical structure:
The method as defined in Claim 1 wherein
said radiolabelling precursor of Formula X has the following chemical structure:
and said F-labelled synthon of Formula Y has the following chemical structure:
The method as defined in any one of Claims 1-3 which further comprises the step:
(ii) coupling the F-labelled synthon of Formula Y as defined herein with a
cross-coupling partner in a transition metal-mediated coupling reaction to
obtain an 1 F-labelled product.
The method as defined in Claim 4 wherein said transition metal is palladium.
The method as defined in Claim 4 or Claim 5 wherein said coupling step comprises
reaction of said 1 F-labelled synthon of Formula Y with a compound of Formula la:
(la)
wherein R1 is a monovalent aliphatic or aromatic hydrocarbon group;
to obtain an 1 F-labelled product of Formula Ila:
The method as defined in Claim 4 or Claim 5 wherein said coupling step comprises
reaction of the 1 F-labelled synthon of Formula I with a compound of Formula lb:
Bu SnR2 (lb)
wherein R2 is a monovalent aliphatic or aromatic hydrocarbon group;
to obtain an 1 F-labelled product of Formula lib:
N (lib)
The method as defined in Claim 4 or Claim 5 wherein said coupling step comprises
reaction of the 1 F-labelled synthon of Formula I with a compound of Formula Ic:
R (IC)
wherein R is is a monovalent aliphatic or aromatic hydrocarbon group;
to obtain an 1 F-labelled product of Formula Ila:
The method as defined in Claim 4 or Claim 5 wherein said coupling step comprises
reaction of the 1 F-labelled synthon of Formula I with a compound of Formula Id:
HO R4
B
OH (id)
wherein R4 is is a monovalent aliphatic or aromatic hydrocarbon group;
to obtain an 1 F-labelled product of Formula lid:
N (Hd)
The method as defined in Claim 4 or Claim 5 wherein said coupling step comprises
reaction of the 1 F-labelled synthon of Formula I with a compound of Formula Ie:
V
H (Ie)
wherein R5 and R6 are independently hydrogen or a monovalent aliphatic or
aromatic hydrocarbon group, or together with the nitrogen to which they are
attached form a nitrogen-containing aliphatic or aromatic ring;
to obtain an 1 F-labelled product of Formula He:
( 11) The method as defined in Claim 4 or Claim 5 wherein said coupling step comprises
reaction of the 1 F-labelled synthon of Formula I with a compound of Formula Ie as
defined in Claim 10 in the presence of a source of carbon monoxide to obtain an 1 Flabelled
product of Formula Ilf:
wherein R7 and R8 are as defined in Claim 10 for R5 and R6, respectively.
(12) The method as defined in any one of claims 1-1 1 which is automated.
(13) A cassette for carrying out the method as defined in Claim 12 wherein said cassette
comprises:
i) a vessel containing a precursor compound of Formula III as defined in any
one of Claims 1-3; and,
ii) means for eluting the vessel of step (i) with [1 F]fluoride.
(14) The cassette as defined in Claim 13 which further comprises:
iii) a vessel comprising a compound of any one of Formula Ia-e as defined in
Claims 6-10, respectively.