MANDUCA GEBRAUCHSANLEITUNG PDF

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This invention relates to the field of radioimaging probes, and more particularly radioimaging samples analogues of esters and ethers of polyiodiertem diacylglyceryl IDGand their use as diagnostic radiolabeled samples for clinical radioimaging.

Radio imaging samples are useful tools in the diagnosis of a number of clinically relevant diseases. Nuclear medicine techniques, such as computed tomography CT and Radionukleotidszintigraphie to use these samples for non-invasive means to obtain important functional and biochemical information about a particular organ or area to be examined.

The success of nuclear imaging methods depends largely on the selective uptake of the sample molecule from the target tissue, which in turn depends on the performance of samples with a high degree of specificity for the target tissue. Sample molecules are for radioimaging have been developed that possess certain inherent physical properties that allow them to take specific cell types as a target group.

Um zum Beispiel die hohen Konzentration von Phospholipidethern in den Zellmembranen von Tumorzellen, verglichen mit normalen Zellen, auszunutzen, sind radioiodierte mittel- und langkettige Phospholipidether entwickelt worden.

The high concentration of Phospholipidethern in the cell membranes of tumor cells compared to normal cells, for example, exploit, radioiodinated medium- and long-chain Phospholipidether have been developed.

Administration of these ethers solubilized in Tween to rats that were subsequently inoculated with a carcinosarcoma cell line resulted in selective accumulation of the radiolabel in the tumor cells Canadian Patent application no.

An alternative method for the alignment of radioimaging probes to specific target areas or tissues is to incorporate them in a targeted delivery vehicle.

Examples of such vehicles include liposomes, chemically modified low-density lipoproteins LDLand synthetic emulsions. The benefits of such carrier vehicles based on lipids is because they mimic natural occurring compounds in the body. In particular, chemically modified LDL due to the presence of specific receptors for both native LDL and for modified LDL in a variety of human tissues including hepatocytes, peripheral blood lymphocytes, smooth muscle cells, macrophages and neurons of the central nervous system CNSa significant effect as a targeted delivery vehicle.

Receptors for modified LDL, the AcLDL- or “scavenger” receptors, are responsible internalization and the subsequent elimination of by oxidation, glycation, alkylation or nitration modified lipoproteins for the binding. As such, scavenger receptors are mainly found in activated macrophages, dendritic cells and Kupffer cells of the liver.

However, the scavenger receptor expression also occurs in other cells, including endothelial cells, aortic smooth muscle cells, nerve cells, and keratinocytes. Diseases that are accompanied by a lipoprotein oxidation, such as atherosclerosis, Alzheimer’s disease, glomerulosclerosis and ataxia with vitamin E deficiency, therefore, the common feature of unregulated expression of scavenger receptors may have [Zingg et al.

Chen und Hughes-Fulford, Int. Chen and Hughes-Fulford, Int. However, with the use of LDL as a carrier vehicle two major limitations are associated. This competition requires high levels of built in the support sample to ensure that sufficient amounts are delivered to the target cells. Secondly, there are radioimaging probes developed to be supplied by means of LDL particles, usually of either surface components ie, apolipoprotein B apo Bor short, based on the apo B sequence peptidesor core components ie cholesterol ether CE labeled with a suitable radioisotope.

Sowohl apo-B als auch CE reagieren extrem empfindlich auf die Hydrolyse durch Lysosomalenzyme in vivo. Both apo B and CE are extremely sensitive to hydrolysis by lysosomal enzymes in vivo. The subsequent transport of the hydrolyzed Fragmen te from the target cells out leads to the loss of the radio signal and a weak image quality. Since apo B is critical for the interaction of LDL with its cellular receptor, radiolabeling this surface element may interfere with the interaction between native LDL receptor and beyond.

Auf apo-B-Protein basierende Proben erzielten jedoch einen gewissen Erfolg. However, based on apo B protein samples achieved some success. For example, a system based on the sequence of apo B radiolabeled short peptide currently delivering promising results in a clinical multi-center US study [Lees and Lees, Atherosclerosis X, ppElsevier Scientific ]. A further potential advantage of labeling core components that include specific cells, particularly the liver, adrenals and ovary, are able to provide a disproportionately greater amount of core lipid than surface protein [Glass et al.

Given the slight hydrolysis of native CE, the attempts to develop based on core LDL components samples, however, directed to analogs that have a higher resistance to hydrolysis. The investigation of radiolabeled CI as a means of orientation in imaging samples to specific target tissues has confirmed the effectiveness of lipoproteins as delivery vehicles. Preliminary studies showed that I-labeled CI preferably instead of the atheroma in normal arterial tissue enriched [DeGalen et al.

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It has been demonstrated that the radiolabeled CI conjugate selectively accumulates in the areas of the atherosclerotic lesions of the arteries, demonstrating the suitability of both CI as a sample molecule and of chemically modified lipoproteins, such as AcLDL, as targeted delivery vehicles.

LDL particles contain both CE and triglycerides in the inner core. In another study a hydrolysis sample was developed, based on the triglyceride structure. In microemulsions dispersed radioimaging samples were developed for targeted delivery to the liver. It is believed that the specific targeting properties of microemulsions are due to their close resemblance to chylomicron remnants. Chylomicrons occurring lipoproteins, triglycerides and cholesterol are naturally transported away from the intestinal tract.

Endogene Lipasen hydrolysieren die Triglyceridkomponente der Chylomikronen, und die resultierenden cholesterinreichen Reste sind als Chylomikron-Reste bekannt. Endogenous lipases hydrolyse the triglyceride component of the chylomicrons and the resulting cholesterol-rich residues are known as chylomicron remnants.

Wie andere Lipoproteine, sind Chylomikron-Reste mit bestimmten Apoproteinen assoziiert; Like other lipoproteins, chylomicron remnants are associated with certain apoproteins; in diesem Fall apo B und apo E. Chylomikron-Reste werden durch die Leber mittels eines rezeptorvermittelten Verfahrens, das apo B und apo E erkennt, rasch aus dem Kreislauf entfernt.

One of the more promising emulsion-based radio samples, an emulsion of iodinated poppyseed oil in saline known as EOE was tested in the US extensively in animals and humans. Although this sample gave a good targeted delivery to the liver cells and acceptable diagnostic efficiency, has been reported a high incidence of harmful side effects [Miller et al.

Andere auf Mikroemulsion basierende Radioimaging-Proben sind ua iodierte Triglyceride in synthetischen Lipidemulsionen, die auf Leberzellen als Ziel ausgerichtet sind. Other based microemulsion radioimaging probes include iodinated triglycerides in synthetic lipid emulsions that are targeted to liver cells as target.

Weichert et al, J. Recently, a new method of using microemulsions to enhance the incorporation of a radiopharmaceutical into LDL has been developed. Several core lipids were tested in the donor microemulsions including triolein, canola oil, squalene and seal oil, with seal oil proved to be most effective. LDL und Mikroemulsionen bewiesen somit einen guten praktischen Nutzen zur zielgerichteten Zufuhr diagnostischer und therapeutischer Verbindungen.

LDL and microemulsions thus proved a good practical use for targeted delivery of diagnostic and therapeutic compounds. However, in order to increase the effectiveness of these delivery vehicles in the field of clinical Radio Imaging, the installation amounts of radiolabeled probe must be maximized in the carrier vehicle. This background information is for the purpose of disclosure of information from the applicants believe that it is for the present invention may be of interest, provided.

It is not an admission necessarily intended, nor should it be interpreted as such that any one of the preceding information constitutes prior art against the present invention. An object of this invention is to provide novel radioimaging samples.

According to one aspect of the present invention there is provided a compound of formula I: According to a further aspect of the present invention, a composition is provided which comprises one or more compounds of formula I and a suitable carrier vehicle. Examples of suitable carrier vehicles include, but are not limited to, liposomes, low-density lipoprotein LDLmodified LDL and synthetic microemulsions. The present invention also provides the use of compounds of formula I and compositions comprising these compounds for diagnostic radioimaging available.

The compounds and compositions of the present invention can be used to include tissues and organs in a mammal, high concentrations of LDL receptors, such as atherosclerotic lesions, liver cells, neural cells and tumor cells, to make them visible.

According to a further aspect of the present invention, a diagnostic kit is provided comprising the compound of formula Ia suitable delivery vehicle, reagents necessary for the radiolabeling of the compound with an appropriate radioisotope of iodine and instructions for use.

The present invention also provides kits for preparing a radiolabeled diagnostic compound for use in radioimaging available, comprising the compound of formula I and the radiolabelling of the compound with an appropriate radioisotope of iodine suitable reagents.

The kits may further contain emulsifying agents and core lipids necessary to prepare a microemulsion. The high quality radioimaging depends on maximum accumulation of a radiolabeled probe with a high specific radioactivity in the imaged tissue. This invention provides hydrolysis-resistant analogues of esters of polyiodiertem diacylglyceryl IDG for use as radiolabeled samples for the diagnostic radioimaging available.

Similar to Cholesteriniopanoat CIthese IDG analogues are based on the structure of native Cholesterinester CEwhich is found in LDL particles, but are either completely resistant to the Lysosomalenzymhydrolyse or are hydrolyzed slowly. Als solche werden diese Verbindungen im Inneren der Zielzellen eingeschlossen, und die Strahlung, die sie aussenden, mandduca daher im Zielgewebe lokalisiert.

As such, these compounds are included in the interior of the target cells and the radiation they emit is thus localized in the gbrauchsanleitung tissue. A further advantage of the IDG analogues of the present invention is the incorporation of between two and six iodine atoms into each molecule, wherein the specific radioactivity is increased, and images with higher quality can be produced when this sample molecules are used.

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In addition, the high specific activity of the compounds is thereby help to minimize the impact of inevitable dilution of the radioisotope in the circulation. The term “carrier vehicle” as used herein means a biocompatible carrier that is capable of a synthetic compound, such as to transport the radiolabeled probes of the present invention, in the bloodstream of a mammal.

Examples include, but are not limited to, liposomes, antibody-bound conjugates, hydrocarbon derivatives of targeted microemulsions of the compound, LDL or chemically modified LDL such as acetylated LDL or gebrauchsanlektung LDL.

Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as gebraucgsanleitung by an expert, for this invention, are commonly understood. The sample molecules of the present invention are analogues of IDG esters and have the following formula I: Herstellung von Verbindungen der Formel I I.

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Preparation of compounds of formula I. The compounds of formula I as shown in Scheme I by using a combination of conventional preparative steps and recovery methods known to those skilled in the art of organic synthesis, can be produced. The starting compound 1 is coupled with dihydroxyacetone gebrauchsanleituung its alkali metal salt in the presence of a suitable solvent to obtain compound 2.

Compound 2 is then removed by using an alkali metal borohydride such as sodium borohydride, to obtain a compound of structural formula 3. Compound 3 is further provided with a Halogensterylderivat 5 coupled in the presence of a suitable base such as sodium hydride, and a suitable solvent to give the compound I.

Halogensterylderivate the structural formula 5 can be easily prepared from commercially available cholesterol and sterol derivatives of structural formula 4 using standard reactions gebrauchssnleitung to one skilled in the art, be prepared using a hydroxy group is converted into a halo group, for example by reaction with either thionyl chloride or thionyl bromide. A sterol derivative can be one of the sterols commercially available, or it may be a derivative of one of those sterols that can be easily prepared by standard synthetic methods, which are well known to the skilled person.

The starting compounds of formula 1 maduca for the preparation of gebrauchsanlwitung molecules of structural formula I are either commercially gebrauchsqnleitung or can be prepared from other commercially available starting materials using standard reactions known to one skilled in the art are prepared.

Examples of some of the general methods for preparing a compound of formula 1 are given mnaduca the following schemes II-V Method AD. Herstellung von Verbindungen der Formel 1 II. Preparation of compounds of formula 1. Verfahren A method A. Bromoethyl ester 6 is reacted with triphenylphosphine, to form a triphenylphosphonium salt 7 which results in the mxnduca of m-nitrobenzaldehyde in the presence of a suitable base to form compound 8.

Manducw 8 is reduced under catalytic hydrogenation conditions to give compound 9which is then treated with iodine monochloride in the presence of acid to obtain compound The bromoethyl esters of structural formula 6 are either manduva available or can be prepared by standard reactions known to one skilled in the art are prepared.

Verbindung 9 oder Verbindung 12 kann alternativ Teiliodierungsbedingungen unterworfen werden, um Verbindungen der Formel 1 zu erhalten, die mono- oder diiodsubstituiert sind.

Compound 9 or compound 12 can alternatively be subjected Teiliodierungsbedingungen to obtain compounds of formula 1 that are mono- or diiodsubstituiert. Verfahren B method B.

Instructions – manduca EN

Alternativ kann Verbindung 14 katalytischen Hydrierungsbedingungen unterworfen werden, um Verbindung 15 zu ergeben, die dann in Verbindung 1 umgewandelt werden kann, wobei R1 anders als H ist und Z OH ist, wie es in Schema II beschrieben ist.

Alternatively, compound 14 catalytic hydrogenation conditions are subjected to give compound 15which can be then converted to compound 1 wherein R1 is other than H and Z is OH, as described in Scheme II.

Iodoethyl ester of the structural formula 13 are either commercially available or can be prepared from other commercially gebruchsanleitung starting materials by standard procedures which are known in the art, are prepared. Verfahren C method C.

Compound 18 can then be subjected to catalytic hydrogenation, iodination and hydrolysis as outlined in Scheme II, to give compound 1in which R1 is H, Z is OH and n is Aldehyde 17 is either commercially available or can be prepared by standard reactions known to one skilled in the art are prepared.