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Method of tumour imagingMethod of tumour imaging description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080095713, Method of tumour imaging. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001]The invention relates to a method of producing a composition comprising hyperpolarised .sup.13C-pyruvate, the composition and its use as an imaging agent for MR imaging. [0002]Magnetic resonance (MR) imaging (MRI) is a imaging technique that has become particularly attractive to physicians as it allows for obtaining images of a patients body or parts thereof in a non-invasive way and without exposing the patient and the medical personnel to potentially harmful radiation such as X-ray. Because of its high quality images, MRI is the favourable imaging technique of soft tissue and organs and it allows for the discrimination between normal and diseased tissue, for instance tumours and lesions. [0003]MR tumour imaging may be carried out with or without MR contrast agents. On an MR image taken without contrast agent, tumours from about 1-2 centimetres in size and larger will show up fairly clearly. However, contrast-enhanced MRI enables much smaller tissue changes, i.e. much smaller tumours to be detected which makes contrast-enhanced MR imaging a powerful tool for early stage tumour detection and detection of metastases. [0004]Several types of contrast agents have been used in MR tumour imaging. Water-soluble paramagnetic metal chelates, for instance gadolinium chelates like Omniscan.TM. (Amersham Health) are widely used MR contrast agents. Because of their low molecular weight they rapidly distribute into the extracellular space (i.e. the blood and the interstitium) if administered into the vasculature. They are also cleared relatively rapidly from the body. Gadolinium chelates have been found to be especially useful in increasing the detection rate of metastases, small tumours, and improving tumour classification, the latter by allowing the differentiation of vital tumour tissue (well perfused and/or impaired blood-brain-barrier) from central necrosis and from surrounding oedema or macroscopically uninvolved tissue (see for instance C. Claussen et al., Neuroradiology 1985; 27: 164-171). [0005]Blood pool MR contrast agents on the other hand, for instance superparamagnetic iron oxide particles, are retained within the vasculature for a prolonged time. They have proven to be extremely useful to enhance contrast in the liver but also to detect capillary permeability abnormalities, e.g. "leaky" capillary walls in tumours for example as a result of angiogenesis. [0006]Despite the undisputed excellent properties of the aforementioned contrast agents their use is not without any risks. Although paramagnetic metal chelate complexes have usually high stability constants, it is possible that toxic metal ions are released in the body after administration. Further, these type of contrast agents show poor specificity. [0007]WO-A-99/35508 discloses a method of MR investigation of a patient using a hyperpolarised solution of a high T.sub.1 agent as MR imaging agent. The term "hyperpolarisation" means enhancing the nuclear polarisation of NMR active nuclei present in the high T.sub.1 agent, i.e. nuclei with non-zero nuclear spin, preferably .sup.13C- or .sup.15N-nuclei. Upon enhancing the nuclear polarisation of NMR active nuclei, the population difference between excited and ground nuclear spin states of these nuclei are significantly increased and thereby the MR signal intensity is amplified by a factor of hundred and more. When using a hyperpolarised .sup.13C- and/or .sup.15N-enriched high T.sub.1 agent, there will be essentially no interference from background signals as the natural abundance of .sup.13C and/or .sup.15N is negligible and thus the image contrast will be advantageously high. A variety of possible high T.sub.1 agents suitable for hyperpolarisation and subsequent use as MR imaging agents are disclosed including but not limited to non-endogenous and endogenous compounds like acetate, pyruvate, oxalate or gluconate, sugars like glucose or fructose, urea, amides, amino acids like glutamate, glycine, cysteine or aspartate, nucleotides, vitamins like ascorbic acid, penicillin derivates and sulfonamides. It is further stated that intermediates in normal metabolic cycles such as the citric acid cycle like fumaric acid and pyruvic acid are preferred imaging agents for the imaging of metabolic activity. [0008]It has to be stressed that the signal of a hyperpolarised imaging agent decays due to relaxation and--upon administration to the patient's body--dilution. Hence the T.sub.1 value of the imaging agents in biological fluids (e.g. blood) must be sufficiently long to enable the agent to be distributed to the target site in the patient's body in a highly hyperpolarised state. Apart from the imaging agent having a high T.sub.1 value, it is extremely favourable to achieve a high polarisation level. [0009]Several hyperpolarising techniques are disclosed in WO-A-99/35508 one of them is the dynamic nuclear polarisation (DNP) technique whereby polarisation of the sample is effected by a paramagnetic compound, the so-called paramagnetic agent or DNP agent. During the DNP process, energy, normally in the form of microwave radiation, is provided, which will initially excite the paramagnetic agent. Upon decay to the ground state, there is a transfer of polarisation from the unpaired electron of paramagnetic agent to the NMR active nuclei of the sample. Generally, a moderate or high magnetic field and a very low temperature are used in the DNP process, e.g. by carrying out the DNP process in liquid helium and a magnetic field of about 1 T or above. Alternatively, a moderate magnetic field and any temperature at which sufficient polarisation enhancement is achieved may be employed. The DNP technique is for example described in WO-A-98/58272 and in WO-A-01/96895, both of which are included by reference herein. [0010]The paramagnetic agent plays a decisive role in the DNP process and its choice has a major impact on the level of polarisation achieved. A variety of paramagnetic agents--in WO-A-99/35508 denoted as "OMRI contrast agents"--is known, for instance oxygen-based, sulfur-based or carbon-based organic free radicals or magnetic particles referred to in WO-A-99/35508, WO-A-88/10419, WO-A-90/00904, WO-A-91/12024, WO-A-93/02711 or WO-A-96/39367. [0011]We have now surprisingly found an improved method for producing a liquid composition comprising hyperpolarised .sup.13C- pyruvate which allows for obtaining hyperpolarised .sup.13C- pyruvate with a remarkably high polarisation level. It has further been found that such a composition is especially suitable for in vivo MR tumour imaging. [0012]Thus, viewed from one aspect, the present invention provides a method for producing a liquid composition comprising hyperpolarised .sup.13C-pyruvate said method comprising [0013]a) forming a liquid mixture comprising a radical of formula (1), .sup.13C-pyruvic acid and/or .sup.13C-pyruvate and freezing the mixture; [0013]where [0014]M represents hydrogen or one equivalent of a cation; and [0015]R1 which is the same or different represents a straight chain or branched hydroxylated and/or alkoxylated C.sub.1-C.sub.4-hydrocarbon group [0016]b) enhancing the .sup.13C nuclear polarisation of pyruvic acid and/or pyruvate in the mixture via DNP; [0017]c) adding a buffer and a base to the frozen mixture to dissolve it and to convert the .sup.13C-pyruvic acid into a .sup.13C-pyruvate to obtain a liquid composition or, when only .sup.13C-pyruvate is used in step a), adding a buffer to the frozen mixture to dissolve it to obtain a liquid composition; and [0018]d) optionally removing the radical and/or reaction products thereof from the liquid composition. [0019]The terms "hyperpolarised" and "polarised" are used interchangeably hereinafter and denote a polarisation to a level over that found at room temperature and 1 T. [0020]A radical of formula (I) is used in the method of the invention where [0021]M represents hydrogen or one equivalent of a cation; and [0022]R1 which is the same or different represents a straight chain or branched hydroxylated and/or alkoxylated C.sub.1-C.sub.4-hydrocarbon group. [0023]Hereinafter, the term "radical" is used for the radical of formula (I). [0024]In a preferred embodiment, M represents hydrogen or one equivalent of a physiologically tolerable cation. The term "physiologically tolerable cation" denotes a cation that is tolerated by the human or non-human animal living body. Preferably, M represents hydrogen or an alkali cation, an ammonium ion or an organic amine ion, for instance meglumine. Most preferably, M represents hydrogen or sodium. [0025]In a further preferred embodiment, R1 is the same or different and represents hydroxymethyl or hydroxyethyl. In another preferred embodiment, R1 is the same or different and represents a straight chain or branched alkoxylated C.sub.1-C.sub.4-hydrocarbon group, preferably --CH.sub.2--O--(C.sub.1-C.sub.3-alkyl), --(CH.sub.2).sub.2--O--CH.sub.3 or --(C.sub.1--C.sub.3-alkyl)--O--CH.sub.3. In another preferred embodiment, R1 is the same or different and represents a straight chain or branched alkoxylated C.sub.1-C.sub.4-hydrocarbon group carrying a terminal hydroxyl group, preferably --CH.sub.2--O--C.sub.2H.sub.4OH or --C.sub.2H.sub.4--O--CH.sub.2OH. In a more preferred embodiment, R1 is the same and represents a straight chain alkoxylated C.sub.1-C.sub.4-hydrocarbon group, preferably methoxy, --CH.sub.2--OCH.sub.3, --CH.sub.2--OC.sub.2H.sub.5 or --CH.sub.2--CH.sub.2--OCH.sub.3, most preferably --CH.sub.2--CH.sub.2--OCH.sub.3. [0026]In a most preferred embodiment, M represents hydrogen or sodium and R1 is the same and represents --CH.sub.2--CH.sub.2--OCH.sub.3. [0027]The synthesis of the radicals is known in the art and disclosed in WO-A-91/12024, WO-A-96/39367, WO 97/09633 and WO-A-98/39277. Briefly, the radicals may be synthesized by reacting three molar equivalents of a metallated monomeric aryl compound with one molar equivalent of a suitably protected carboxylic acid derivative to form a trimeric intermediate. This intermediate is metallated and subsequently reacted with e.g. carbon dioxide to result in a tri-carboxylic trityl carbinol which, in a further step, is treated with a strong acid to generate a triarylmethyl cation. This cation is then reduced to form the stable trityl radical. [0028]The isotopic enrichment of the .sup.13C-pyruvic acid and/or .sup.13C-pyruvate used in the method of the invention is preferably at least 75%, more preferably at least 80% and especially preferably at least 90%, an isotopic enrichment of over 90% being most preferred. Ideally, the enrichment is 100%..sup.13C-pyruvic acid and/or .sup.13C-pyruvate may be isotopically enriched at the C1-position (in the following denoted .sup.13C.sub.1-pyruvic acid and .sup.13C.sub.1-pyruvate), at the C2-position (in the following denoted .sup.13C.sub.2-pyruvic acid and .sup.13C.sub.2-pyruvate), at the C3-position (in the following denoted .sup.13C.sub.3-pyruvic acid and .sup.13C.sub.3-pyruvate), at the C1- and the C2-position (in the following denoted .sup.13C.sub.1,2-pyruvic acid and .sup.13C.sub.1,2-pyruvate), at the C1- and the C3-position (in the following denoted .sup.13C.sub.1,3-pyruvic acid and .sup.13C.sub.1,3-pyruvate), at the C2- and the C3-position (in the following denoted .sup.13C.sub.2,3-pyruvic acid and .sup.13C.sub.2,3-pyruvate) or at the C1-, C2- and C3-position (in the following denoted .sup.13C.sub.1,2,3-pyruvic acid and .sup.13C.sub.1,2,3-pyruvate); the C1-position being the preferred one. [0029]Several methods for the synthesis of .sup.13C.sub.1-pyruvic acid are known in the art. Briefly, Seebach et al., Journal of Organic Chemistry 40(2), 1975, 231-237 describe a synthetic route that relies on the protection and activation of a carbonyl-containing starting material as an S,S-acetal, e.g. 1,3-dithian or 2-methyl-1,3-dithian. The dithian is metallated and reacted with a methyl-containing compound and/or .sup.13C0.sub.2. By using the appropriate isotopically enriched .sup.13C-component as outlined in this reference, it is possible to obtain .sup.13C.sub.1-pyruvate, .sup.13C.sub.2-pyruvate or .sup.13C.sub.1,2-pyruvate. The carbonyl function is subsequently liberated by use of conventional methods described in the literature. A different synthetic route starts from acetic acid, which is first converted into acetyl bromide and then reacted with Cu.sup.13CN. The nitril obtained is converted into pyruvic acid via the amide (see for instance S. H. Anker et al., J. Biol. Chem. 176 (1948), 1333 or J . E. Thirkettle, Chem Commun. (1997), 1025). Further, .sup.13C-pyruvic acid may be obtained by protonating commercially available sodium .sup.13C-pyruvate, e.g. by the method described in U.S. Pat. No. 6,232,497. [0030]Whether .sup.13C-pyruvic acid and/or .sup.13C-pyruvate is used in the method of the invention is mainly dependent on the radical employed. If the radical is soluble in .sup.13C-pyruvic acid, then .sup.13C-pyruvic acid is preferably used and a liquid mixture, preferably a liquid solution is formed by the radical and .sup.13C-pyruvic acid. If the radical is not soluble in .sup.13C-pyruvic acid, then .sup.13C-pyruvate and/or .sup.13C-pyruvic acid and at least one co-solvent are used to form a liquid mixture, preferably a liquid solution. It has been found that the success of the polarisation in step b) and thus the level of polarisation is dependent on the compound to be polarised and the radical being in intimate contact with each other. Hence the co-solvent is preferably a co-solvent or co-solvent mixture that dissolves both, the radical and .sup.13C-pyruvic acid and/or .sup.13C-pyruvate. For .sup.13C-pyruvate water is preferably used as a co-solvent. Continue reading about Method of tumour imaging... Full patent description for Method of tumour imaging Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method of tumour imaging patent application. Patent Applications in related categories: 20090297454 - Perfluoroalkyl-containing complexes, process for their production as well as their use - The invention relates to the subjects that are characterized in the claims, namely perfluoroalkyl-containing metal complexes with nitrogen-containing radicals of general formula I, process for their production and their use in NMR and x-ray diagnosis, radiodiagnosis, and radiotherapy, as well as in MRT lymphography and in blood-pool imaging. ... ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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