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Labelled glutamine and lysine analoguesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory Compositions, In An Organic Compound, Attached To Peptide Or Protein Of 2+ Amino Acid Units (e.g., Dipeptide, Folate, Fibrinogen, Transferrin, Sp. Enzymes); Derivative ThereofLabelled glutamine and lysine analogues description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060292075, Labelled glutamine and lysine analogues. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to a class of compounds useful in the diagnosis of sites of venous and arterial thrombosis, embolism or infection, pharmaceutical formulations containing them, their use in the diagnosis of disease and methods for their preparation. BACKGROUND OF THE INVENTION [0002] Prior approaches to thrombus imaging radiopharmaceuticals include radiolabelled fibrinogen or plasminogen; radiolabelled fragment E.sub.1 of human fibrin; radiolabelled plasminogen activators such as tissue plasminogen activator (t-PA) and labelled anti-fibrin antibodies. Methods based on the detection of sites of platelet accumulation such as the administration of radiolabelled platelets (e.g. using .sup.111In oxine) or radiolabelled anti-platelet antibodies have also been described. More recent efforts have focused on radiolabelled peptides or polypeptides such as the cell adhesion motif RGD (where R, G and D are the standard abbreviations for the amino acids arginine, glycine and aspartic acid respectively); platelet factor 4 or fragments thereof or anticoagulant peptides such as disintegrins. [0003] Factor XIII is a plasma glycoprotein which is present in blood and certain tissues in a catalytically inactive (or zymogen) form. Factor XIII is transformed into its active form Factor XIIIa by thrombin in the presence of calcium ions. Factor XIIIa is also known as plasma transglutaminase, fibrinoligase or fibrin-stabilising factor. The final step in the formation of a blood clot is the covalent crosslinking of the fibrin which is formed by the proteolytic cleavage of fibrinogen by thrombin. Fibrin molecules align and the enzyme Factor XIIIa catalyses covalent crosslinking of the NH.sub.2 and CONH.sub.2 groups of lysyl and glutaminyl residues respectively giving structural rigidity to the blood clot. The crosslinking stabilises the fibrin clot structure and confers resistance to fibrinolysis. The crosslink formation is an important facet of normal blood coagulation and wound healing as well as pathological conditions such as thrombosis. As atherothrombotic brain infarctions are a common sub-type of stroke, Factor XIIIa substrates may allow diagnosis of stroke. It may also be implicated in atherosclerosis, inflammatory processes, tumour growth and metastasis. WO 91/16931 discloses that radiolabelled analogues of Factor XIII (in which the active site has been inactivated by amino acid substitution) are useful as thrombus imaging radiopharmaceuticals. [0004] Factor XIIIa is also known to catalyse the incorporation of low molecular weight amines into the .gamma.-glutamine sites of proteins. Similarly Factor XIIIa also catalyses the incorporation of low molecular weight glutamine analogues into lysyl residues. Thus such low molecular weight amines (or glutamine analogues) function as competitive inhibitors of the Factor XIIIa-induced lysyl/glutaminyl crosslinking of proteins. A range of synthetic amines have been described which are competitive inhibitors of the uptake of labelled putrescine (1,4-butanediamine) into N,N'-dimethylcasein catalysed by pig liver transglutaminase [L. Lorand et al., Biochem., 18, 1756(1979)]. [0005] WO 89/00051 (Cytrx Biopool Ltd.) claims a method for targeting fibrin deposits using a labelled compound which is covalently bound to fibrin by Factor XIIIa. The fibrin binding compound is stated to be "any peptide that is a substrate for the blood enzyme commonly known as Factor XIIIa". Preferred peptides are said to include the tetrapeptide sequence -Asn-Gln-Glu-Gln- (or NQEQ in standard amino acid abbreviation notation). Also disclosed is the 12-mer peptide sequence from the NH.sub.2 terminus of the alpha-2 antiplasmin enzyme: NH.sub.2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Leu-Thr-Leu-Thr-Leu-Leu-Lys-OH together with a synthetic analogue: NH.sub.2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr-Thr-Leu-Thr-Leu-Leu-Lys-OH, (denoted NQEQVSPLTLTLLK and NQEQVSPYTLTLLK respectively). The latter was radiolabelled with .sup.125I and shown to be taken up in thrombin clots in vitro. [0006] It has now been discovered that synthetic analogues of lysine and glutamine labelled with a suitable detectable moiety can also function as substrates for the enzyme Factor XIIIa. The use of suitable protecting groups provides compounds which are less susceptible to in vivo metabolism especially by peptidases, and are hence more useful targeting agents. SUMMARY OF THE INVENTION [0007] The present invention provides the following compounds: Y--(CR.sub.2).sub.n--X--NHJ where: [0008] X is C.dbd.O or CR.sub.2; [0009] n is an integer of value 1 to 6; [0010] Y is L(A).sub.m- or R.sup.1R.sup.2CR-- where L is a metal complexing agent, A is --CR.sub.2--, --CR.dbd.CR--, --C.dbd.--C--, --NRCO--, --CONR--, --SO.sub.2NR--, --NRSO.sub.2--, --CR.sub.2OCR.sub.2--, --CR.sub.2SCR.sub.2--, --CR.sub.2NRCR.sub.2--, a C.sub.4-8 cycloheteroalkylene group, a C.sub.4-8 cycloalkylene group, a C.sub.5-12 arylene group, a C.sub.3-12 heteroarylene group or a polyalkyleneglycol, polylactic acid or polyglycolic acid moiety; [0011] m is an integer of value 0 to 10; [0012] where one of R.sup.1 and R.sup.2 is --NH(B).sub.pZ.sup.1 and the other is --CO(B).sub.qZ.sup.2 where [0013] p and q are integers of value 0 to 30, and [0014] each B is independently chosen from Q or an amino acid, [0015] where Q is a cyclic peptide; [0016] Z.sup.1 and Z.sup.2 are protecting groups; [0017] J and each R group are independently chosen from H, C.sub.1-4 alkyl, C.sub.1-4 alkenyl, C.sub.1-4 alkynyl, C.sub.1-4 alkoxyalkyl or C.sub.1-4 hydroxyalkyl; with the provisos that: [0018] (i) the total number of amino acid residues in the R.sup.1 and R.sup.2 groups does not exceed 30; [0019] (ii) when X is CR.sub.2, then Y is --CRR.sup.1R.sup.2 and Z.sup.2 is a metal complexing agent; [0020] (iii) when Y is --CRR.sup.1R.sup.2then at least one of R.sup.1 and R.sup.2 bears at least one detectable moiety. [0021] The invention also includes kits for the preparation of the above compounds labelled with a detectable moiety, and the use of these and related compounds in the diagnosis or therapy of thrombosis, embolism, atherosclerosis, inflammation or cancer. BRIEF DESCRIPTION OF THE FIGURES [0022] FIG. 1 shows imaging with .sup.99mTc-Compound 5 at different dissection time points. [0023] FIG. 2 shows imaging with .sup.99mTc-Compound 5 at 180 min at head, clot and thorax. Continue reading about Labelled glutamine and lysine analogues... Full patent description for Labelled glutamine and lysine analogues Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Labelled glutamine and lysine analogues patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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