U.S. patent application number 13/547176 was filed with the patent office on 2012-11-01 for purification methods.
This patent application is currently assigned to HAMMERSMITH IMANET LIMITED. Invention is credited to ERIK ARSTAD, FRANK BRADY, ALAN CUTHBERTSON, ALEXANDER MARK GIBSON, NICHOLAS TOBY JEFFERY, SAJINDER KAUR LUTHRA, MAGNE SOLBAKKEN, DUNCAN WYNN.
Application Number | 20120275973 13/547176 |
Document ID | / |
Family ID | 32526795 |
Filed Date | 2012-11-01 |
United States Patent
Application |
20120275973 |
Kind Code |
A1 |
LUTHRA; SAJINDER KAUR ; et
al. |
November 1, 2012 |
PURIFICATION METHODS
Abstract
The invention relates to novel processes for the purification of
radiolabelled tracers, using a solid-support bound scavenger group.
The general concept being illustrated by the scheme:
##STR00001##
Inventors: |
LUTHRA; SAJINDER KAUR;
(LONDON, GB) ; BRADY; FRANK; (LONDON, GB) ;
JEFFERY; NICHOLAS TOBY; (CAERPHILLY, GB) ; ARSTAD;
ERIK; (LONDON, GB) ; GIBSON; ALEXANDER MARK;
(BUCKINGHAMSHIRE, GB) ; WYNN; DUNCAN;
(BUCKINGHAMSHIRE, GB) ; CUTHBERTSON; ALAN; (OSLO,
NO) ; SOLBAKKEN; MAGNE; (OSLO, NO) |
Assignee: |
HAMMERSMITH IMANET LIMITED
LONDON
GB
GE HEALTHCARE AS
OSLO
NO
GE HEALTHCARE LIMITED
LITTLE CHALFONT
GB
|
Family ID: |
32526795 |
Appl. No.: |
13/547176 |
Filed: |
July 12, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10560508 |
Jan 29, 2007 |
8221720 |
|
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PCT/GB2005/001796 |
May 11, 2005 |
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13547176 |
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Current U.S.
Class: |
422/554 ;
422/255 |
Current CPC
Class: |
C07B 63/00 20130101;
C07B 2200/11 20130101; C07B 59/00 20130101 |
Class at
Publication: |
422/554 ;
422/255 |
International
Class: |
B01L 3/00 20060101
B01L003/00; B01J 19/00 20060101 B01J019/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 11, 2004 |
GB |
0410448.5 |
Claims
1-12. (canceled)
13. An automated radiosynthesis apparatus comprising a vessel
containing a solid-support bound scavenger selected from the group
consisting of: ##STR00032##
14. A cassette comprising a vessel comprising a solid-support bound
scavenger selected from the group consisting of: ##STR00033##
Description
[0001] The present invention relates to novel processes for the
purification of radiolabelled tracers, in particular for
purification of .sup.18F- and .sup.11C-labelled compounds which may
be suitable for use as Positron Emission Tomography (PET)
radiotracers or for radio-iodinated compounds which may be suitable
for use in PET or SPECT imaging or in radiotherapy. Automated
radiosynthesis apparatus, and disposable or removable cassettes
therefor, adapted to perform the purification processes are also
claimed.
[0002] Radiosynthesis of compounds of clinical interest often
employs non-radioactive organic precursors in amounts which are in
large excess relative to the amount of radiolabelling agent used.
Excess precursors must be removed from the reaction mixture before
the radiolabelled compound can be used clinically, this is
conventionally done by a chromatographic procedure such as high
performance liquid chromatography (HPLC). Given the limited
half-life of most clinically useful radioisotopes, it is desirable
to complete the radiosynthesis and purification as rapidly as
possible. For example, .sup.18F has a half-life of 110 minutes and
.sup.18F-labelled tracers for PET are therefore synthesised and
purified within one hour of clinical use. Therefore, there exists a
need for purification techniques which are rapid and efficient.
[0003] The present invention provides processes for separating
radiolabelled compounds from their precursors rapidly and
chemoselectively.
[0004] According to a general aspect of the invention, there is
provided a process for purifying a radiolabelled product which
comprises use of a solid-support bound scavenger group of formula
(IV):
##STR00002##
wherein Z is a scavenger group and SP is a solid support.
[0005] In a further aspect of the invention, there is provided a
process comprising the steps of:
(a) contacting a solution-phase mixture of a radiolabelled product
of formula (III) and excess precursor of formula (I):
##STR00003##
wherein XY is a functional group and R* is a radioisotope or
radiolabelled portion; with a compound of formula (IV):
##STR00004##
wherein Z is a scavenger group; such that the compounds of formulae
(IV) and (I) may form a covalent bond to each other; (b) separation
of purified radiolabelled product of formula (III) in the solution
phase.
[0006] Suitably, the radiolabelled product of formula (III)
contains an .sup.18F-label and is, for example
2-fluoro-2-deoxy-D-glucose ([.sup.18F]-FDG), 6-fluoro-L-DOPA
([.sup.18F]-FDOPA), 3'-deoxy-3'-fluorothymidine
([.sup.18F]-FLT),[.sup.18F]fluorotyrosine,
5-[.sup.18F]fluorouracil, 5-[.sup.18F]fluorocytosine,
2-(1,1-dicyanopropen-2-yl)-6-(2-fluoroethyl)-methylamino)-naphthalene
([.sup.18F]-FDDNP), 2-, 5-, and 6-fluoro
(2(S)-azetinylmethoxy)pyridines,
N-succinimidyl-4-[.sup.18F]fluorobenzoate ([.sup.18F]-SFB), an
.sup.18F-labelled amino acid such as
[.sup.18F]-1-amino-3-fluorocyclobutane-1-carboxylic acid
([.sup.18F]-FACBC), an [.sup.18F]-labelled benzothiazole such as
those described in international patent application WO 02/16333, a
[.sup.18F]fluorotropane such as
2.beta.-carbomethoxy-3.beta.-(4-[.sup.18F]fluorophenyl)tropane
([.sup.18F]CFT) or
N--[.sup.18F]fluoropropyl-2.beta.-carbomethoxy-3.beta.-(4-iodophenyl)nort-
ropane ([.sup.18F]FP-CIT), [.sup.18F]FETNIM, [.sup.18F]dopamine, an
.sup.18F-labelled peptide for example somatostatin analogues, such
as octreotide, bombesin, vasoactive intestinal peptide, chemotactic
peptide analogues, .alpha.-melanocyte stimulating hormone,
neurotensin, Arg-Gly-Asp peptide and its analogues, human
pro-insulin connecting peptide, endothelin, angiotensin and
formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine, more
suitably Arg-Gly-Asp peptide and its analogues, such as those
described in international patent applications WO 01/77415 and WO
03/006491, or a protected derivative of any thereof.
[0007] Alternatively, the radiolabelled product of formula (III)
contains a .sup.11C-label and is, for example,
[.sup.11C]raclopride, [.sup.11C-carboxyl]L-DOPA,
[.sup.11C-carboxyl]5-hydroxytryptophan, [.sup.11C]-WAY-100635,
[.sup.11C]-deprenyl, [.sup.11C]phenylephrine, [.sup.11C]FLB457,
[.sup.11C]SCH23390, [.sup.11C]SCH39166, [.sup.11C]-NNC112,
[.sup.11C]NNC756, [.sup.11C]MDL100907, [.sup.11C]DSAB,
[.sup.11C]PK11195, [.sup.11C]GR205171, [.sup.11C]RTI-32,
[.sup.11C]CIT, [.sup.11C]CFT, [.sup.11C]flumazenil,
[.sup.11C]-diprenorphine, [.sup.11C]-metomidate,
[.sup.11C]SCH442416, [.sup.11C]carfentanil, or a .sup.11C-labelled
benzothiazole such as those described in international patent
application WO 02/16333, or a protected derivative of any
thereof.
[0008] Alternatively, the radiolabelled product of formula (III)
contains a radioiodine label such as .sup.131I, .sup.123I,
.sup.124I, .sup.122I or .sup.125I, and is for example,
2-beta-carbomethoxy-3-beta-(4-iodophenyl)-8-(3-fluoropropyl)-nortropane
or a protected derivative thereof.
[0009] The radiolabelled product of formula (III) comprises a
vector portion being a molecular fragment having with an affinity
for a given biological target (such as a modified drug
pharmacaphore or peptide) and a radioisotope or radiolabelled
portion represented by R*.
[0010] The precursor of formula (I) comprises the same vector
portion as the radiolabelled product of formula (III) but bears a
functional group --XY as described below.
[0011] Many radiosyntheses involve radioalkylation such as
[.sup.11C]alkylation, or radiohalogenation such as
[.sup.18F]fluorination or [.sup.18F]fluoroalkylation, of precursors
of formula (I). Treatment of the precursor with a radioisotope or
radiolabelling agent of formula (II) gives rise to a mixture
containing the desired radiolabelled product of formula (III) and
excess unreacted precursor of formula (I). The precursor of formula
(I) therefore contains a functional group --XY which is capable of
reacting with the radioisotope or radiolabelling agent of formula
(II) shown in scheme I. The functional group --XY is suitably a
leaving group such as a sulphonate ester preferably the mesyl,
tosyl, nosyl or is a trimethylammonium salt or is a functional
group which can react site-specifically with a moiety on the
radiolabelling agent of formula (II) to form a stable covalent bond
and is preferably selected from the groups aldehydes, ketones,
aminooxy, hydrazides, hydrazines, alpha-haloacetyl and thiol.
[0012] In the compound of formula (IV), the scavenger group Z is
suitably an isocyanate, isothiocyanate, thiol, hydrazine,
hydrazide, aminooxy, 1,3-dipole, aldehyde or ketone, such as those
described in the more specific aspects of the invention below.
##STR00005##
[0013] In the compounds of formulae (IV) and in the following more
specific aspects of the invention, the solid support represented by
SP, may be any suitable solid-phase support which is insoluble in
any solvents to be used in the process but to which the Linker
and/or scavenger group Z can be covalently bound. Examples of
suitable Solid Support include polymers such as polystyrene (which
may be block grafted, for example with polyethylene glycol),
polyacrylamide, ring-opening metathesis polymerisation (ROMP)
polymer, or polypropylene or glass or silicon coated with such a
polymer. The solid support may also be sepharose based modified
with suitable functional groups or derived from other known
polymeric chromatographic media including ion exchange resins or
C18 reverse-phase media. The solid support may be in the form of
small discrete particles such as beads or pins, or as a coating on
the inner surface of a cartridge or on a microfabricated
vessel.
[0014] In the compounds of formulae (IV) and in the following more
specific aspects of the invention, the "Linker" may be any suitable
organic group which serves to space the scavenger group Z
sufficiently from the solid support structure so as to maximise
reactivity. Suitably, the Linker comprises zero to four aryl groups
(suitably phenyl) and/or a C.sub.1-6 alkyl or C.sub.1-6 haloalkyl
(suitably C.sub.1-6 fluoroalkyl), and optionally one to four
additional functional groups such as an amide or sulphonamide
groups. In a preferred embodiment the linker is a polyethylene
glycol containing moiety.
[0015] Compounds of formula (IV) may be prepared by methods known
to the person skilled in the art (for a review of such methods, see
Stabile-Harris and Ciampoli; Laboratory Automation in the Chemical
Industries, 111-32 (2002)) or are available commercially, for
example from Novabiochem (Merck Biosciences Ltd, Nottingham, UK) or
from Argonaut (Mid Glamorgan, UK)
[0016] The purification may be performed by mixing the
solid-support bound scavenger group of formula (IV) with a
solution-phase mixture comprising a radiolabelled product of
formula (III) in a container and then separating the resulting
solid-phase by filtration. Alternatively, and particularly suitably
when the solid-support bound scavenger group of formula (IV) is
used within an automated synthesis apparatus, the solid-support
bound scavenger group of formula (IV) may be contained in a vessel
through which the solution-phase mixture comprising a radiolabelled
product of formula (III) is passed. The solution-phase mixture
comprising a radiolabelled product of formula (III) may be passed
through the solid-support bound scavenger group of formula (IV) as
a continuous flow, for example at a flow rate of from 0.1 ml/min to
100 ml/min, or in batches, so as to permit sufficient residence
time on the solid-phase for the purification to occur. As would be
understood by the person skilled in the art, the solid-support
bound scavenger group of formula (IV) may be held in any suitable
vessel such as a plastic or metal column, cartridge, or syringe
barrel. The purification is conveniently performed at ambient
temperature, but use of non-extreme elevated temperature (for
example up to 120.degree. C., but preferably up to around
80.degree. C.) can increase efficiency of the extraction. If the
temperature is too high, stability of the solid-support bound
scavenger group of formula (IV) and/or radiolabelled product of
formula (III) may be compromised.
[0017] In a further aspect of the invention, there is provided a
process for purifying a radiolabelled product which comprises use
of a solid-support bound isocyanate or isothiocyanate scavenger
group. This process comprises the steps of:
(a) contacting a solution-phase mixture of a radiolabelled product
of formula (IIIa) and excess precursor of formula (Ia):
##STR00006##
wherein R.sup.1 is C.sub.1-6 alkyl and R* is
[.sup.11C]--C.sub.1-6alkyl, such as --.sup.11CH.sub.3 or
[.sup.18F]fluoro C.sub.1-6 alkyl or [.sup.18F]fluoro C.sub.6-12
aryl; with a compound of formula (IVa):
##STR00007##
wherein R.sup.2 is oxygen or sulphur such that the compounds of
formulae (IVa) and (Ia) may form a covalent bond to each other; and
(b) separation of purified radiolabelled product of formula (IIIa)
in the solution phase.
[0018] The compounds of formula (IVa) and (Ia) react to form the
corresponding urea or thiourea of formula (Va):
##STR00008##
wherein R.sup.1 and R.sup.2 are as defined for the compounds of
formulae (Ia) and (IVa) respectively.
[0019] The purification process using a compound of formula (IVa)
may be performed at a non-extreme temperature such as 10 to
120.degree. C., suitably at ambient temperature to 80.degree. C.
and using an inert solvent such as xylene, N,N-dimethylformamide
(DMF) or chloroform.
[0020] In this aspect of the invention, the compound of formula
(IIIa) is suitably a .sup.11C-labelled tertiary amine such as
[.sup.11C--CH.sub.3]-2-Pyridin-4-yl-quinoline-8-carboxylic acid
(2-dimethylamino-ethyl)-amide,
[N--.sup.11C-methyl]dimethylphenethylamine, or [.sup.11C]DASB, and
the precursor of formula (Ia) is the corresponding secondary amine
such as 2-pyridin-4-yl-quinoline-8-carboxylic acid
(2-methylamino-ethyl)-amide.
[0021] In a further aspect of the invention, there is provided a
process for purifying a radiolabelled product which comprises use
of a solid-support bound thiol scavenger group. This process
comprises the steps of:
(a) contacting a solution-phase mixture of a radiolabelled product
of formula (IIIb) and excess precursor of formula (Ib):
##STR00009##
wherein either (i) the functional group --X.sup.bY.sup.b in the
compound of formula (Ib) is --OSO.sub.2R.sup.3 wherein R.sup.3 is
C.sub.1-15 alkyl or C.sub.1-10 alkylaryl and R.sup.3 is optionally
substituted by halo (preferably fluoro), for example R.sup.3 is
methyl, para-toluene, trifluoromethyl, and R*.sup.b in the compound
of formula (IIIb) is a radiohalogen such as radiofluoro (for
example .sup.18F) or radioiodo (such as .sup.123I, .sup.124I, or
.sup.125I) or radiobromo (such as .sup.76Br); or (ii) the
functional group --X.sup.bY.sup.b in the compound of formula (Ib)
is --C(O)CH.sub.2Cl and R*.sup.b in the compound of formula (IIIb)
is --S-L.sup.b-.sup.nF wherein L.sup.b is a C.sub.1-30 hydrocarbyl
linker group optionally including 1 to 10 heteroatoms; and .sup.nF
is a radioisotope of fluorine such as .sup.18F; with a compound of
formula (IVb):
##STR00010##
wherein R.sup.4 is hydrogen; such that the compounds of formulae
(IVb) and (Ib) may form a covalent bond to each other; (b)
separation of purified radiolabelled product of formula (IIIb) in
the solution phase.
[0022] The compounds of formula (IVb) and (Ib) react to form the
corresponding compound of formula (Vbi or Vbii):
##STR00011##
[0023] The purification process using a compound of formula (IVb)
may be performed at a non-extreme temperature such as 10 to
120.degree. C., suitably at ambient temperature to 80.degree. C.
and using an inert solvent such as xylene, N,N-dimethylformamide
(DMF), DMSO, acetonitrile or chloroform. Preferably the solvent is
an aqueous buffer or a mixture of acetonitrile and water or alcohol
and water.
[0024] In a further aspect of the invention, there is provided a
process for purifying a radiolabelled product which comprises use
of a solid-support bound amino scavenger group. This process
comprises the steps of:
(a) contacting a solution-phase mixture of a radiolabelled product
of formula (IIIc) and excess precursor of formula (Ic):
##STR00012##
wherein the functional group --X.sup.cY.sup.c in the compound of
formula (Ic) is an aldehyde or ketone and R*.sup.c in the compound
of formula (IIIc) is .dbd.N--W-Linker-F where W is C.sub.1-15 alkyl
or C.sub.7-15 aryl, with a compound of formula (IVc):
##STR00013##
wherein Z.sup.c is selected from --NH.sub.2, hydrazine, hydrazide,
aminooxy, phenylhydrazines, semicarbazide, or thiosemicarbazide;
such that the compounds of formulae (IVc) and (Ic) may form a
covalent bond to each other; and (b) separation of purified
radiolabelled product of formula (IIIc) in the solution phase.
[0025] The compounds of formula (IVc) and (Ic) react to form the
corresponding compound of formula (Vc):
##STR00014##
wherein A is hydrogen, C.sub.1-6alkyl or aryl (such as phenyl) and
B is --CO--NH--, --NH--, --O--, --NHCONH--, or --NHCSNH--.
[0026] In this aspect of the invention, compounds of the formula
(IIc) have the formula NH.sub.2--W-Linker-F where W is as described
previously and F is preferably .sup.18F and the compound of formula
(IIIc) is suitably a .sup.18F-labelled compound such as a peptide
or drug substance and the precursor of formula (Ic) is the
corresponding aldehyde or ketone.
[0027] The purification process using a compound of formula (IVc)
may be performed at a non-extreme temperature such as 10 to
120.degree. C., suitably at ambient temperature to 80.degree. C.
and using an inert solvent such as xylene, N,N-dimethylformamide
(DMF), DMSO, acetonitrile, or chloroform. Preferably the solvent is
an aqueous buffer or a mixture of acetonitrile: water or alcohol
and water.
[0028] In a further embodiment of this aspect of the invention, the
functional group --X.sup.cY.sup.c in the compound of formula (Ic)
is --OSO.sub.2R.sup.3 wherein R.sup.3 is C.sub.1-15 alkyl or
C.sub.1-10 alkylaryl and R.sup.3 is optionally substituted by halo
(preferably fluoro), for example R.sup.3 is methyl, para-toluene,
trifluoromethyl; and the purification is effected using a compound
of formula (IVci):
##STR00015##
where W is selected from C.sub.1-15 alkyl or C.sub.7-15 aryl,
--NH--, --NH--CO-- or --O-- and the linker is as described
previously such that compounds of formula (Ic) and (IVci) form a
covalent bond to each other.
[0029] The compounds of formula (IVci) and (Ic) react to form the
corresponding compound of formula (Vci):
##STR00016##
wherein W is as defined for the compound of formula (IVci).
[0030] In a further aspect of the invention, there is provided a
process for purifying a radiolabelled product which comprises use
of a solid-support bound aldehyde or ketone scavenger group. This
process comprises the steps of:
(a) contacting a solution-phase mixture of a radiolabelled product
of formula (IIId) and excess precursor of formula (Id):
##STR00017##
wherein the functional group --X.sup.dY.sup.d in the compound of
formula (Id) is an amine, hydrazine, hydrazide, aminooxy,
phenylhydrazine, or semicarbazide, thiosemicarbazide group and
R*.sup.d in the compound of formula (IIId) is .dbd.CH-Linker-F
where the linker comprises an alkyl, aryl or polyethylene glycol
component; with a compound of formula (IVd):
##STR00018##
wherein Z.sup.d is an aldehyde or ketone moiety; such that the
compounds of formulae (IVd) and (Id) may form a covalent bond to
each other; and (b) separation of purified radiolabelled product of
formula (IIId) in the solution phase.
[0031] The compounds of formula (Id) and (IVd) react to give
compounds of formula (Vd):
##STR00019##
wherein A is hydrogen, C.sub.1-6alkyl or aryl (such as phenyl) and
B is --CO--NH--, --NH--, --O--, --NHCONH--, or --NHCSNH--.
[0032] The purification process using a compound of formula (IVd)
may be performed at a non-extreme temperature such as 10 to
120.degree. C., suitably at ambient temperature to 80.degree. C.
and using an inert solvent such as xylene, N,N-dimethylformamide
(DMF), DMSO, acetonitrile or chloroform. Preferably the solvent is
an aqueous buffer or a mixture of acetonitrile and water or alcohol
and water.
[0033] In this aspect of the invention, the compound of formula
(IIId) is suitably a .sup.18F-labelled compound such as a peptide
or drug and the precursor of formula (Id) is suitably a modified
peptide or drug carrying an aminooxy (NH.sub.2--O--), hydrazide or
hydrazine moiety.
[0034] One particular compound of formula (IVd) which may be useful
in this aspect of the invention, having a high loading of ketone
scavenging group may be based on a ring-opening metathesis
polymerisation (ROMP) polymer backbone. One of the main advantages
of ROMP polymers is that in principle every monomer unit carries a
functional group and should give much higher loading than some
other polymers. ROMP is known for the production of functionalised
polymers for organic synthesis (Barrett et al Chemical Reviews 2002
102 pp 3301-24). Suitable ROMP based polymers of formula (IVd) may
be prepared by condensation of commercially available ketone alkene
with furan followed by polymerisation, as shown in scheme 2:
##STR00020##
[0035] In a further aspect of the invention, there is provided a
process for purifying a radiolabelled product which comprises use
of a solid-support bound dipolar scavenger group. This process
comprises the steps of
(a) contacting a solution-phase mixture of a radiolabelled product
of formula (IIIe) and a by-product (VIIe):
##STR00021##
wherein the by-product (VIIe) contains an unwanted double bond,
formed by an elimination side-reaction, and R*.sup.e in the
compound of formula (IIIe) is radiohalo, particularly
[.sup.18F]fluoro; with a compound of formula (IVe):
##STR00022##
wherein Z.sup.e is a 1,3-dipole such as --N.dbd.N.sup.+.dbd.N.sup.-
or --C.ident.N.sup.+--O.sup.- such that the compounds of formula
(IVe) and (VIIe) may form a covalent bond to each other; and (b)
separation of purified radiolabelled product of formula (IIIe) in
the solution phase.
[0036] This aspect of the invention has particular relevance to
synthesis of 3'-deoxy-3'-fluorothymidine ([.sup.18F]-FLT) (IIIe)
wherein a common by-product (VIIe) is formed by elimination of
[.sup.18F]HF from the sugar ring as shown in scheme 2:
##STR00023##
wherein each PG is hydrogen or a hydroxyl protecting group
(suitably tert-butoxycarbonyl, benzyl, triphenylmethyl, or
dimethoxytriphenylmethyl), and --X.sup.eY.sup.e is a suitable
leaving group such as an alkyl- or aryl-sulphonate ester (for
example trifluoromethane sulphonate, methane sulphonate, or
toluene-para-sulphonate) or halo (such as iodo or bromo).
[0037] Purification using a compound of formula (IVe):
##STR00024##
wherein Z.sup.e is a 1,3-dipole -A-E.sup.+-G.sup.-, such as
--N.dbd.N.sup.+.dbd.N.sup.- or --C.ident.N.sup.+--O.sup.-, gives a
compound of formula (Ve) as shown in scheme 3:
##STR00025##
[0038] In a further aspect of the invention, a scavenger resin such
as a compound of formula (IV) may also be used to react covalently
with any unreacted radiolabelling agent of formula (II) as shown in
scheme 4 to give compounds of formula (VI). This purification
process may be used instead of, or in addition to, processes
described herein for removal of excess precursor.
##STR00026##
[0039] Thus, for example:
(i) A solid-support bound aldehyde or ketone scavenger group, such
as a compound of formula (IVd) may facilitate removal of unreacted
amino functionalised radiolabelling agent, such as a compound of
formula (IIc) from a reaction mixture resulting in a compound of
formula (VId):
##STR00027##
(ii) A solid-support bound amino scavenger group, such as a
compound of formula (IVc) may facilitate removal of unreacted
radiolabelling agent having an aldehyde or ketone functionality
resulting in a compound of formula (VIc).
##STR00028##
wherein A and B are as defined for the compound of formula (Vc).
(iii) A solid-support bound haloacetyl scavenger group, such as
compound of formula (IVf)
##STR00029##
may be used wherein Z.sup.f is Cl--CH.sub.2--CO-- or another
haloacetyl containing moiety for removal of unreacted
radiolabelling agent containing a thiol moiety of formula (II) from
a reaction mixture results in compound of formula (VIf).
##STR00030##
[0040] Radiotracers, such as [.sup.18F]FDG are now often prepared
on an automated radiosynthesis apparatus using nucleophilic
radiofluorination chemistry with .sup.18F.sup.-, based on the
reagent Kryptofix.TM. 2.2.2. There are several examples of such
apparatus commercially available, including Tracerlab MX
(Coincidence Technologies SA) and Tracerlab FX (Nuclear Interface
GmbH). 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 (typically C.sub.18 or alumina) used in
post-radiosynthetic clean up steps. The methods of the present
invention may offer particular advantages in the field of automated
radiosynthesis.
[0041] According to a further aspect of the invention, there is
provided an automated radiosynthesis apparatus comprising a vessel,
such as a cartridge, containing a solid-support bound scavenger
group of formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe), or
(IVf).
[0042] The vessel, such as a cartridge, containing a solid-support
bound scavenger group of formula (IV) may be housed in a disposable
or removable cassette designed for use with the automated
radiosynthesis apparatus. Therefore, the invention further provides
a cassette for an automated radiosynthesis apparatus comprising a
vessel, such as a cartridge, containing a solid-support bound
scavenger group of formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe),
or (IVf).
[0043] The invention will now be illustrated by way of the
following non-limiting examples.
EXAMPLES
Example 1
Use of an Isocyanate Resin for Purification of a
.sup.11C-Tracer
##STR00031##
[0045] In both cases isocyanate resin was conditioned, using the
same solvent as that from which precursor was to be extracted.
Extraction efficiency was determined using HPLC. For studies using
non-radioactive standard solutions, xylene was used as a control
such that adjustments could be made for non-specific extraction and
solvent loss.
Example 1(a)
In Situ Resin Conditioning and Solid Phase Extraction (SPE) at
Elevated Temperatures
[0046] A cartridge (internal volume 0.067 ml) made of 3.2 mm
(1/8'') o.d. steel tubing and circular frits was charged with 25 mg
of dry isocyanate functionalised polystyrene resin (Novabiochem).
Solvent ca 5 ml (dichloromethane (DCM), N,N-dimethylformamide (DMF)
or dimethylsulphoxide (DMSO)) was then passed through the cartridge
and excess solvent removed with compressed air. For studies at
elevated temperature a two-piece heater block, thermocouple and
band heater were fitted around the cartridge and the entire
assembly left ca 10 min to thermally equilibrate. 500 .mu.l of
solution containing precursor 2-Pyridin-4-yl-quinoline-8-carboxylic
acid (2-methylamino-ethyl)-amide (A) 0.5 mg and Xylene 1.3 mg were
then passed through the cartridge using a syringe drive. Using this
method, SPE efficiency was dependent on the solvent used, with
extraction efficiency decreasing in the order DCM (67%), DMF (36%),
and DMSO (<5%) at room temperature.
Example 1(b)
SPE with External Resin Conditioning
[0047] For external conditioning 300 mg of isocyanate resin
(Novabiochem) was suspended in excess solvent ca 9 ml for ca 5 min.
The conditioned resin slurry was then loaded onto a 0.8 ml volume
cartridge made of 6 mm ( 2/8'') steel tubing. Excess solvent was
removed with compressed air. Precursor solutions 300 .mu.l or
reaction mixture from automated preps 300 .mu.l were passed through
the cartridge using a syringe drive. A 1 ml syringe gave flow rates
of 0.4 ml min.sup.-1, equating to a contact time ca 2 min.
Example 1(c)
SPE Purification of
[.sup.11C--CH.sub.3]2-Pyridin-4-yl-quinoline-8-carboxylic Acid
(2-dimethylamino-ethyl)-amide Reaction Mixtures
[0048] Following [.sup.11C]radiolabelling, 300 .mu.l of the
resulting reaction mixture (A+B) was drawn up from the reaction
vial and dispensed (using a syringe drive) at a flow of 444 .mu.l
min.sup.-1 through one of the conditioned isocyanate resin
cartridges detailed in Examples 1(a) and 1(b). The cartridge was
then flushed with 500 .mu.l of chloroform and the combined
solutions analysed by HPLC. The cartridge was then flushed with a
further 3 aliquots of 500 .mu.l chloroform. Cumulative product
recovery after SPE using the external conditioning method of
Example 1(b) was 90% with precursor levels at circa 4% of the
levels found in the non-purified reaction mixture.
* * * * *