Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-07-29
2001-01-09
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018500, C536S122000, C536S124000, C424S001110, C422S105000, C422S105000, C422S105000, C422S159000
Reexamination Certificate
active
06172207
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a new process for synthesising labelled compounds such as 2-[
18
F]fluoro-2-deoxy-D-glucose, more commonly called fluoro-deoxy glucose or FDG.
The invention also relates to a device for synthesising said labelled compounds which relies on this process, making an automatic processing possible, including possibly a single use kit of materials.
BACKGROUND OF THE INVENTION
FDG is a tracer increasingly used in nuclear medical imaging. This molecule, labelled with the radionucleide
18
F, behaves in a way similar to glucose in the first step of its metabolization in the human body and allows to map and quantify this fundamental mechanism. It is indicated for diagnosis of numerous diseases.
The most widely spread synthesis method is the so-called Hamacher method, described by Hamacher K., Coenen H. and Stöcklin G. in “Efficient Stereospecific Synthesis of No-carrier-added-2-[
18
F]fluoro-2-deoxy-D-glucoso Using Aminopolyether Supported Nucleophilic Substitution”, Journal of Nuclear Medicine 27, 235 (1986). Several variations of such method have been developed and are presently used in various Positron Emission Tomography (TEP) laboratories.
The synthesis is substantially based upon the following operating steps:
Preparation of the fluorinating agent
in a first step, the
18
F is activated through “activating” agents such as KRYPTOFIX™ (also called K2.2.2), a trademark used in connection with the compound 4, 7, 13, 16, 21, 24-hexaoxo-1, 10-diazabicyclo-[8.8.8]-hexacosane, so as to make it more reactive. In some publications, they are called “phase transfer agents”. The radionucleide is produced beforehand, generally by irradiation of
18
O enriched water with a proton beam originating from a particle accelerator, as F
−
(for instance H
18
F, in an aqueous solution).
Labelling of the precursor
The fluorinating agent, made totally anhydrous by additions of acetonitrile (CH
3
CN) and dry evaporations, is put in presence of a labelling substrate (precursor), generally the 1,3,4,6-tetra-O-acetyl-2-trifluoromethanesulphonyl-&bgr;-D-mannopyranose (more commonly called “triflate”) solubilized in acetonitrile. A substitution reaction then occurs, where the trifluoromethane sulphonate group of the substrate is replaced by the
18
F atom, resulting in the formation of 2-[
18
F]fluoro-1,3,4,6-tetra-O-acetyl-D-glucose (abbreviated in tetraacetylfluoroglucose or TAFg).
Pre-purification
The reagent residues, particularly the Kryptofix® K2.2.2, are removed by passing the solution through a C18 “Sep-Pak®” on which the TAFg remains trapped. This Sep-Pak® is then rinsed with 10 ml 0.1M HCl. The activity is then desorbed with 2 ml tetrahydrofuran (or THF) towards the reactor where the THF is totally evaporated away.
Deprotection namely hydrolysis
The precursor, namely the TAFg, is converted into FDG by removing its four acetyl groups: these acetyl groups are eliminated by an acid hydrolysis carried out in a hot aqueous solution (2 ml 1M HCl at about 130° C. during 15 min.)
Injectable formulation
The resulting FDG-containing solution is made injectable by passing it through an ion retarding column, which reduces its acidity, followed by alumina and C18 Sep-Pak®, which retain other impurities, and by a filter for sterility. It is made isotonic by adding an appropriate amount of NaCl. It is ready for quality control and others conditioning treatments prior to administration.
This procedure has, however, a number of drawbacks, the main ones of which are:
the duration of such a procedure is about fifty minutes, particularly because of the number of the successive heating and evaporating steps, resulting in a 30% loss of activity just because of the 110 minute half-life of
18
F,
the automation of this procedure requires a quite complicated equipment and makes more difficult the manufacture of a single use device.
A recent study performed by Mulholland G. Keith (Simple Rapid Hydrolysis of Acetyl Protecting Groups in the FDG Synthesis Using Cation Exchange Resins, Nucl. Med. Biol. Vol. 22, No 1, pp. 19-23 (1995)) relating to hydrolysis has shown that the 1M HCl acid could be replaced by a cationic resin with similar functionalities. The sulphonic acid resin (Dowex® 50) in the previously wetted H
+
form, is placed in the hydrolysis reactor before starting synthesis. The tetraacetylfluoroglucose (TAFg) resulting from the previous steps of the synthesis, solubilised in ether, is introduced into the reactor on the resin. The ether is evaporated within a period of 3 to 5 minutes. The reactor is then heated at 100° C. for 8 to 10 minutes. During the last minute, 2 ml water are added onto the resin. The solution extracted from the reactor contains the FDG directly available with a pH of about 4 to 5.5.
Such method, which is not implemented in vivo as far as it is known, shows that the acid hydrolysis can be performed in a dry condition on a solid support. Its main interest is that purification through an ion retarding column is no more needed, since the acidity of the FDG solution obtained is very weak and lies within the injection limits.
However, this method does not save time with respect to the “conventional” hydrolysis method described by Hamacher. The elimination of one reagent (1M HCl) for the hydrolysis is compensated for by the addition of the the resin into the hydrolysis reactor, said resin having moreover to be conditioned before use. This method does not avoid the need for heating and evaporating the solvants.
Another recent study from F. F{umlaut over (u)}chtner et al. (Basic Hydrolysis of 2-[
18
F]fluoro-1,3,4,6-tetra-O-acetyl-D-glucose in the Preparation of 2-[
18
F]fluoro-2-deoxy-D-glucose, Appl. Radiat. Isot., vol. 47, No. 1, pp. 61-66 (1996)) has shown that the hydrolysis, performed usually in acid media, can be performed in basic media much faster and at room temperature.
The solution resulting from the labelling step is dry evaporated, only leaving the TAFg (and other non volatile residues) on the walls of the labelling reactor. An aqueous NaOH solution (preferably 2 ml, 0.3M) is transferred into the unheated reactor. After 2 minutes, the TAFg is hydrolysed into FDG with a yield of about 80%. The main advantage of this process is the reaction rate: 2 minutes instead of 8 to 10 minutes for the acid hydrolysis.
However, in practice, the fact that the reaction can be performed at room temperature is not an advantage in a reactor device, since before (or during) the hydrolysis, it will anyway be necessary to include a heating device to evaporate the acetonitrile (or the ether) originating from the labelling step and which is present together with the TAFg.
AIMS OF THE INVENTION
The present invention aims to provide an improved process allowing to solve the problems and drawbacks above mentioned, and in particular aims to:
reduce the duration and the complexity of the synthesis, and
simplify the device.
The process according to the invention aims in particular to simplify the procedure to make its automation easier and to reduce the time of synthesis to improve its yield, while maintaining, possibly improving, the chemical yield of the synthesis process.
Specific advantages of the process and the device according to the invention are mentioned hereafter, in reference to the description of various alternative embodiments of the present invention.
REFERENCES:
patent: 5264570 (1993-11-01), Johnson et al.
patent: 5312592 (1994-05-01), Andersson
patent: 5415843 (1995-05-01), Andersson
patent: 5436325 (1995-07-01), Johnson et al.
patent: 93306081 (1993-08-01), None
patent: 0 588 480 A1 (1994-03-01), None
patent: PCT/US94/02366 (1994-03-01), None
patent: WO 94/21653 (1994-09-01), None
Mulholland, “Simple Rapid Hydrolysis of Acetyl Protecting Groups iin the FDG Synthesis Using Cation Exhange Resins”, Nuclear Med. Biol. vol. 22, No. 1, pp. 19-23.
Fuchtner et al., “Basis Hydrolysis of 2-[18F] Fluoro-1,3,4,6-tetra-&ogr;-acetyl-D-glucose in the Preparation of 2-[18] Fluoro
Damhaut Philippe E.
Lauricella Benjamin P.
Lemaire Christian F.
Luxen Andre
Monclus Michel
Coincidence S. A.
Knobbe Martens Olson & Bear LLP
Wilson James O.
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