Stereo-selective synthesis of amino acids for production of tumor image

FIELD: medicine.

SUBSTANCE: new pure syn-aminoacids of formulas I and II have ability of specific binding in biological system and may be used to produce image of tumor. II and I. In formulae I and II Y and Z are independently selected from group made of CH2 and (CR4R5)n, n=1, 2; R1-R3 are independently selected from group made of H and alkyl C1-C4; R4, R5 = H and R7 = 18F. Invention is related to method of synthesis of syn-aminoacids with formula II, which includes stages of ketone transformation into trans-spirit of formula I and transformation of produced trans-spirit into syn-aminoacid of formula II, and also to pharmaceutical composition for production of tumor image and method for production of tumor image.

EFFECT: improved efficiency of compounds and method of treatment.

12 cl, 1 tbl, 3 dwg, 3 ex

 

Cross-reference to related applications

This application claims priority to provisional application No. 60/693385, registered on June 23, 2005, which is incorporated here in its entirety to the extent not compatible with the present application.

Confirmation of Federal research funding bodies

This invention was made with government support under grant No. 5-R21-CA-098891 provided by the National Institute of Health (National Institute of Health). The government has certain rights in this invention.

The level of technology

This invention relates to a method of synthesis of analogues SYN-amino acids and the compounds synthesized according to this method, in particular analogs of SYN-1-amino-3-CYCLOBUTANE-1-carboxylic acid (ASWS). Similar amino acids of the invention have the ability of specific binding to a biological system and can be used in the methods of obtaining images of positron emission tomography (PET) and single photon emission computed tomography (mect).

Development labeled with radioactive isotopes of amino acids for use as metabolic indicators to produce images of tumors using positron emission tomography (PET) and single photon emission computed tomography (mect) was carried out for n is time. Although labeled with radioactive isotopes of amino acids used for various types of tumors, their application to intracranial tumors paid considerable attention due to the potential advantages relative to other modalities produce images. After surgical resection and/or radiotherapy of brain tumors common imaging procedures such as CT (computed tomography) and MRI (magnetic resonance imaging), does not reliably distinguish residual or recurrent tumor from tissue damage due to interference and are not optimal for monitoring the effectiveness of treatment or detection of tumor recurrence [Buonocore, E (1992), Clinical Positron Emission Tomography. Mosby-Yaer Book, Inc. St. Louis, MO, p. 17-22; Langleben, DD et al. (2000), J. Nucl. Med. 41: 1861-1867].

Main used in PET imaging agent for diagnosis and image acquisition tumors 2-[18F]fluorodeoxyglucose (FDG) has limitations in obtaining images of brain tumors. Normal cortical tissue of the brain shows a high uptake of [18F]FDG, and inflammatory tissue, which can occur after radiation therapy or surgical therapy; these factors can complicate the interpretation of images obtained with [18F]FDG [Griffeth, LK et al. (1993), Radiology. 186: 37-44; Conti, PS (1995)].

In several publications reported that the image acquisition method is m PET and mect labeled with radioactive isotopes of amino acids helps to better define the boundaries of the tumor to normal brain, than CT or MRI, which allows you to better plan treatment [Ogawa, T. et al. (1993), Radiology, 186: 45-53; Jager, PL et al. (2001), Nucl. Med., 42: 432-445]. In addition, some studies suggest that the degree of absorption of amino acids correlates with the stage of tumor development, which can provide important prognostic information [Jager, PL et al. (2001) J. Nucl. Med. 42: 432-445].

Amino acids are the nutrients required for proliferation of tumor cells. Were obtained by different amino acids, containing a positron emitting isotopes carbon-11 and fluorine-18. They were evaluated for potential applications in clinical Oncology for obtaining images of tumors in patients with brain tumors and systemic tumors (tumors throughout the body) and got excellent characteristics in comparison with 2-[18F]FDG for some tumors. These amino acid candidates can be divided into two main categories. The first category presents labeled with radioactive isotopes - existing in nature, amino acids such as [11C]valine, I-[11C]leucine, L-[11S]methionine (MET) and L-[1-11C]tyrosine and structurally similar analogues, such as 2-[18F]fluoro-L-tyrosine and 4-[18F]fluoro-L-phenylalanine. The movement of these amino acids across the membranes of tumour cells occurs mainly through the media, Opera which has been created by the transfer of the sodium-independent transfer system leucine, amino acids of type "L". Increased uptake and prolonged retention of these existing in nature, radiolabelled amino acids in tumors compared to normal tissue is partly the result of significant and rapid regional incorporation into proteins. Of these labeled with radioactive isotopes of amino acids [11C]MET the most widely used clinically for the detection of tumors. Although discovered that [11C]MET is suitable for the detection of brain tumors and systemic lesions tumors, it is susceptible in vivo to the metabolism through multiple paths, leading to the formation of numerous labeled with radioactive isotopes metabolites. Therefore, graphical analysis with the necessary precision for reliable measurement of metabolic activity of the tumor is not possible. Study of the kinetic analysis of the uptake by the tumor [11]MET people convincingly suggest that the transfer of amino acids may provide a more sensitive measurement of the proliferation of tumor cells than protein synthesis.

Disadvantages associated with [11]MET, can be overcome by the second category of amino acids. They are non-natural amino acids, such as 1-aminocyclopentane-1-[11With]carboxylic acid ([11C]ACBC). The advantage of the [ 11C]ACBC compared with [11C]MET is that it is not metabolized. A significant limitation in the application labeled with carbon-11 amino acids for clinical use is a short 20-minute half-life of carbon-11. The 20-Minute half-life of carbon-11 requires the presence of a particle accelerator at the site to obtain labeled with carbon-11 amino acids. In addition, only one or a relatively very small doses can be obtained from each batch of obtaining labeled with carbon-11 amino acids. Consequently, labeled with carbon-11 amino acids are the weakest candidates with regional distribution for widespread clinical application.

To overcome the limitations of using carbon-11 due to the physical half-life, the inventors have recently focused their efforts on the development of several new labeled with fluorine-18 non-natural amino acids, some of which are described in U.S. patents 5808146 and 5817776, both of which are incorporated herein by reference. These amino acids include anti-1-amino-3-[18F]forceclosure-1-carboxylic acid (anti-[18F]FACBC), SYN-1-amino-3-[18F]forceclosure-1-carboxylic acid (SYN-[18F]FACBC), SYN - and anti-1-amino-3-[18F]formalistically-1-carboxylic acid (SYN - and anti-[18F]FMACBC). This photo is-18-amino acids can be used to obtain images of the brain and systemic tumors in vivo based on the transfer of amino acids, a method of obtaining images of positron emission tomography (PET). Development authors included labeled with fluorine-18 cyclobutylamine that move through the capillaries of the tumor mediated by the carrier of the transfer, including the transfer system mainly large neutral amino acids of type "L" and to a lesser extent amino acids of type "a". A preliminary assessment by the authors of cyclobutylamine, labeled with positron emitters, which are substrates for transport system L, showed excellent potential in clinical Oncology for obtaining images of the tumor in patients with brain tumor and systemic tumors. The main reasons for proposals18F-labeled cyclobutyl/branched-chain amino acids instead of11With (t1/2=20 min) are significant logistical and economic advantages obtained by the use of18F-labeled radiopharmaceuticals funds instead of11C-labeled radiopharmaceuticals tools in clinical applications. The advantage of acquiring images of tumors using18F-labeled radiopharmaceuticals funds in the Department of medical radiology, primarily due to the longer half-life18F (t1/2=11 min). A longer half-life18F makes possible the distribution of off-site and receive many doses in one obtain party of radioactive indicator. In addition, these nematerializiranih amino acids can also be widely used as agents to obtain an image of some system of solid tumors, a good image cannot be obtained PET using 2-[18F]FDG. In WO 03/093412, which is incorporated herein by reference, further describes examples of fluorinated analogues of α-aminoadamantane acid (AIB), such as 2-amino-3-fluoro-2-methylpropanoate acid (FAMP) and 3-fluoro-2-methyl-2-(methylamino)propanoic acid (N-MeFAMP)suitable for labeling by18F and use in preparation of the PET image. AIB is nematerializiranih α,α-dialkylaminomethyl, which actively transferred into cells primarily through a system of transfer of amino acids of type A. the Transfer of amino acids by the system And increases during growth and cell division and, as was also found positively regulated in tumor cells [Palacin, M et al. (1998), Physiol. Rev. 78: 969-1054; Bussolati, O et al. (1996), FASEB J. 10: 920-926]. Studies of experimentally induced tumors in animals and spontaneously occurring tumors in humans showed increased absorption of radiolabelled AIB in tumors from siteline normal tissue [Conti, PS et al. (1986), Eur. J. Nucl. Med. 12: 353-356; Uehara, H et al. (1997), J Cereb. Blood Flow Metab. 17: 1239-1253]. N-Methylated analogue of AIB, N-MeAIB detects even greater selectivity for the system of transfer of amino acids of type a than AIB [Shotwell, MA et al. (1983), Biochim. Biophys. Acta. 737: 267-84]. N-MeAIB were labeled with radioactive isotope carbon-11 and showed that he is metabolically stable in humans [Nagren, et al. (2000), J. Labelled Cpd. Radiopharm. 43: 1013-1021].

While the benefits of amino acid analogues containing isotopes that emit positrons, to produce images of tumors in patients with brain tumors and systemic tumors are approved in this area, there is still a need for a reliable and efficient synthetic method, which can provide a large number of stereospecific isomers of these compounds. When the connection candidate makes possible the transition from research validation in models of cells and animals to use for people used synthetic methods should be adapted to the mainstream, reliable receipt of such compounds. To this end, the inventors here have developed a reliable stereoselective synthetic strategy to obtain analogues of SYN-1-amino-3-CYCLOBUTANE-1-carboxylic acid (ASWS). In the description below, it will be obvious that the stereoselective synthetic strategy are the two which is suitable for the synthesis of various analogues of amino acids, especially analogues containing radioactive indicators, to obtain an image of the tumor by means of PET and the mect.

The invention

The invention provides a synthetic strategy that allows you to get a specific stereoisomer of key precursor for the synthesis of the analogous amino acid in the SYN(syn)-isomeric form. This strategy is particularly suitable for the synthesis of analogues of SYN-1-amino-3-CYCLOBUTANE-carboxylic acid (ASWS). A key stage in the synthesis is to restore synthons predecessors in the TRANS-alcohols, which are transformed into the final product in the SYN-isomeric form. The synthetic strategy described here is a reliable, efficient and allows to obtain the grams scale key predecessor to ratiocinate analogues Shin-ASS. In addition, the synthetic strategy described here, includes the introduction of a suitable isotope as the last stage to maximize suitable half-life of the isotope.

The present invention provides TRANS-alcohols having the formula:

Y and Z independently represent a =CH2, N, O, S, Se, CR4R5)n, n = 1-4, R1-R3independently represent H, alkyl, cycloalkyl, acyl, aryl, alkenyl, quinil, halogenated, halogenated, heteroaryl, halog nail, halogenerators, halogenoalkanes, halogenoalkanes,

R4-R5independently represent H, alkyl, cycloalkyl, acyl, aryl, halogen, halogenated, halogenated, heteroaryl, halogenared, halogenmethyl, quinil, alkenyl, halogenoalkanes, halogenoalkanes, where halogen is non-radioactive F, CI, Br, I.

The invention also provides methods of synthesis of TRANS-alcohols having the General structure of formula 1. A key stage in the synthesis of TRANS-alcohols mentioned formula is a direct recovery of the metal hydride with the use of reducing agents associated with the polymer (for example, product linking borohydride-polymer Aldrich 32864-2 deposited on amberlite IRA 400; precipitated product link cyanoborohydride-polymer Aldrich 52630-4; product link borohydride-polymer Aldrich 35994-7 deposited on amberlite A-26; product link zincbased-polymer Aldrich 59603-5). Figure 3 here is an example of such a reaction with the use of triisobutylene lithium and ZnCl2.

Described synthetic strategy can be applied to obtain the SYN-isomers of the various amino acid compounds for use in the detection and evaluation of brain tumors and tumors of the whole body and other applications. These compounds combine the favorable properties of 1-aminocyclohexane-1-carboxylic acid is, namely, its rapid uptake and prolonged retention in tumors, with the properties of halogen substituents, including some suitable isotopes of Halogens, including fluorine-18, iodine-123, iodine-125, iodine-131, bromine-75, bromine-76, bromine-77, bromine-82, astatine-210, astatine-211 and other isotopes of astatine. In addition, the compounds can be marked with isotopes of technetium and rhenium with the use of chelated complexes. A detailed description, see WO 03/093412 and U.S. patent 5817776.

Analogues SYN-amino acids can be obtained by application of the inventive synthetic strategy, which includes TRANS-alcohols, which include, but are not limited to, compounds having the following formula:

Y and Z independently represent a =CH2, N, O, S, Se, CR4R5)n, n = 1-4, R1-R3independently represent H, alkyl, cycloalkyl, acyl, aryl, alkenyl, quinil, halogenated, halogenated, heteroaryl, halogenared, halogenmethyl, halogenoalkanes, halogenoalkanes,

R4-R5independently represent H, alkyl, cycloalkyl, acyl, aryl, halogen, halogenated, halogenated, heteroaryl, halogenared, halogenmethyl, alkenyl, quinil, halogenoalkanes, halogenoalkanes, where halogen is non-radioactive F, Cl, Br, I,

R7represents halogen, halogenated, halogen is lceil, halogenoalkanes, garageglamour, halogennitroalkanes, halogennitroalkanes, halogenared, halogenmethyl, where halogen represents F, Cl, Br, I, and included labeled compounds, such as containing F-18, I-123, I-124, TC-99m and Re chelates.

Specific radiolabelled analogues of amino acids, which can be obtained using the inventive methods described herein include, but are not limited to, fluoro-, bromo - or izlesene cyclopropyl, cyclobutyl, cyclopentyl-, cyclohexyl-, cycloheptyl-, cyclooctyl, cycloneii, cyclotetrasiloxane having the structure shown above, or alicyclic compounds containing heteroatom, i.e. N, O and S and Se.

Derivatives of amino acids obtained according to the invention, have a high specificity for tumor tissue when administered to a subject in vivo. In accordance with this invention also provides pharmaceutical and diagnostic compositions comprising the analogs SYN-amino acids obtained according to the method of the invention. Preferred derivatives of amino acids, showing the relation of the target to namesti at least 2:1, are stable in vivo and essentially localized in the target within 1 hour after injection. The preferred examples of amino acid derivatives include SYN-[18F]-1-AMI is about-3-forceclosure-1-carboxylic acid (FACBC), SYN-[123I]-1-amino-3-iodcyclization-1-carboxylic acid (ASWS) and SYN-[18F]-1-amino-3-peralkylated-1-carboxylic acid, for example, SYN-[18F]-1-amino-3-formalistically-1-carboxylic acid (FMACBC).

Similar amino acids of the invention are suitable as agent for obtaining images for tumor detection and/or monitoring the development of tumors in the subject. Similar amino acids, used as an agent to obtain images of the tumors injected in vivo and used for monitoring using method appropriate to the label. Preferred methods for detecting and/or monitoring with the use of similar amino acids as agent for obtaining images include positron emission tomography (PET) and single photon emission computed tomography (mect).

Brief description of the graphical material

Figure 1 shows the absorption in vivo of the compounds in 9L tumors. The results are expressed as percentage uptake relative to the control after 60 minutes after injection. See details in example 2.

Figure 2 shows the absorption in vivo of the compounds in the contralateral normal brain after 60 minutes after injection.

Figure 3 shows the ratio of absorption in vivo of the compounds in tumor cells to absorb normal is leccami through 60 minutes after injection. The ratio was obtained from the percentages shown in figures 1 and 2.

Detailed description of the invention

This invention relates to new methods of synthesis of analogues SYN-amino acids suitable for obtaining images of the tumor, among other applications. The authors of the present invention have developed a synthetic strategy that allows stereoselective synthesis of the key precursor in the TRANS-isomeric form for the synthesis of analogues Shin-ASS.

Analogues of ASWS obtained inventive synthetic strategy, are essentially pure SYN-isomeric form. The term "essentially pure"used here means that the product in its isomeric form has a purity of at least 60%, preferably purity 70%, more preferably a purity above 90% in the SYN-isomeric form. It is assumed that it includes all intermediate values from 60% to 100% and all intermediate ranges, regardless of whether they are listed separately, or not listed.

In common terms and phrases used herein have their decision in this area is, which can be found by reference to standard books, journal references and contexts known to the person skilled in the art. The following definitions are offered to clarify their specific use in the context of the invention.

The term "pharmaceutically acceptable salt"as used here, refers to those carboxylate salts or acid additive salts of the compounds of the present invention, which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like, have a reasonable ratio of benefit/risk and are effective for their intended use, as well as to zwitterionic forms, when possible, of the compounds of the invention. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, additive salts of the compounds of the present invention and inorganic and organic acids. Also included such salts derived from nontoxic organic acids, such as aliphatic mono - and dicarboxylic acids, for example acetic acid, phenylsilane alcamovia acid, hydroxyalkanoate and arcangioli acids, aromatic acids and aliphatic and aromatic sulfonic acids. These salts can be obtained in situ during the final isolation and purification of the compounds or separately by the reaction of the purified compound in its free base form with a suitable organic or inorganic acid and allocation thus formed salt. Further representative salts include the hydrobromide, ghidrah arid, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naftilan, mesilate, glucoheptonate, lactobionate and laurylsulphate, propionate, pialat cyclamate, isetionate and the like. These may include cations based on the alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium cations, Quaternary ammonium and amine, including, but not limited to the above, the cations ammonium, Tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. See, for example, Berge S. M., et al., Pharmaceutical Salts, J. Pharm. Sci. 66; 1-19 (1977), which is incorporated herein by reference.

Similarly, the term "pharmaceutically acceptable carrier"as used herein is an organic or inorganic composition, which serves as a carrier/stabilizer/diluent for the active ingredient of the present invention in the pharmaceutical or diagnostic composition. In some cases, pharmaceutically acceptable carriers are salt. The following examples of pharmaceutically acceptable carriers include, but are not limited to, water, Sabu ereny phosphate salt solution, saline regulating pH agents (e.g., acids, bases, buffers, stabilizers such as ascorbic acid, isotonic agents (e.g. sodium chloride), aqueous solvents, surfactant (ionic and nonionic), such as Polysorbate or tween 80(TWEEN 80).

The term "alkyl", used here by itself or as part of another group refers to saturated hydrocarbon, which may be unbranched, branched or cyclic and contains up to 10 carbon atoms, preferably 6 carbon atoms, more preferably 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and isobutyl. The alkyl groups of the invention include such groups, optionally substituted where one or more carbon atoms in the main chain may be replaced by heteroatoms, one or more hydrogen atoms may be replaced by halogen or-HE. The term "aryl", used here by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing 5-12 carbon atoms in the cyclic portion, preferably 6-10 carbon atoms in the cyclic portion, such as phenyl, naphthyl or tetrahydronaphthyl. One or more rings of the aryl group may include a condensed ring. Aryl which the group may be substituted by one or more alkyl groups, which may be unbranched, branched or cyclic. Aryl groups may also be substituted in the provisions of the ring substituents that do not have a significant adverse effect on the function of the connection or parts of the connection in which it is found. Substituted aryl group include groups having a heterocyclic aromatic ring in which one or more heteroatoms (such as N, O or S, optionally with hydrogen atoms or substituents suitable for valence) replaced by one or more carbon atoms in the ring.

The term "alkoxy" is used here to denote an alkyl radical with unbranched or branched chain, as stated above, only if, in addition, the chain length is not limited, associated with the oxygen atom, such term includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and the like. Chain alkoxy length preferably contains 1-6 carbon atoms, more preferably 1-4 carbon atoms in length.

"Acyl" group is a group that includes a group - WITH-.

The term "monoalkylation"used here by itself or as part of another group, refers to the amino group, which is substituted by one alkyl group specified above.

The term "dialkylamino", use aemy here by itself or as part of another group, refers to the amino group, which is substituted by two alkyl groups specified above.

The term "halogen"used here by itself or as part of another group refers to chlorine atom, bromine, fluorine or iodine.

The term "heterocycle" or "heterocyclic ring"as used here, except when indicated otherwise, is a system of stable 5-7-membered managerialism ring which may be saturated or unsaturated, and which consists of carbon atoms and one to three heteroatoms selected from the group consisting of N, O and S, where the nitrogen atom and sulfur may be optionally oxidized. Particularly suitable are the rings that contain one nitrogen atom in combination with one oxygen atom or sulfur, or two atoms of nitrogen. Examples of such heterocyclic groups include piperidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidine, thiazolyl, diazolidinyl, isothiazolin, homopiperazine, homopiperazine, pyridazinyl, pyrazolyl and pyrazolidine, most preferably thiomorpholine, piperazinil and morpholinyl.

The term "heteroatom" is used here to denote an oxygen atom ("O"), sulfur atom ("S") or a nitrogen atom ("N"). It should be clear, tokoha the heteroatom is a nitrogen atom, it can form part NRaRbwhere Raand Rbrepresent, independently from each other, hydrogen or C1-4alkyl, C2-4aminoalkyl,1-4halogenated, halogenmethyl or Raand Rbtaken together with the formation of a 5-7-membered heterocyclic ring optionally having O, S or NRcin the specified ring, where Rcrepresents hydrogen or C1-4alkyl.

Compounds of the invention are suitable as binding with tumor agents and as ligands that bind to the NMDA receptor, and in the form of a radioactive isotope are particularly suitable as compounds of indicators for ways to obtain images of tumors, including image acquisition by means of PET and the mect. Especially suitable as agent for image acquisition are such compounds, labeled F-18, as the F-18 has a half-life of 110 minutes, which provides sufficient time for receipt of radiolabelled indicator for cleaning and introduction into the human or animal. In addition, F-18-labeled compounds can be used in installations that are distant from the cyclotron radius of more than about 200 miles.

In the apparatus for obtaining images of the mect applied isotope tracers that emit photons you the Oka energy (γ-emitters). The range of suitable isotopes greater than that for the rat, but the mect provides a lower three-dimensional resolution. However, the mect is widely used for obtaining clinically relevant information about the speed of binding, localization and excretion of analogs. A suitable isotope for imaging of the mect is a [123I], γ-emitter with a half-life of 13.3 hours. Compounds labeled with [123I], can be transported to a distance of approximately 1,000 miles from the place of production or the isotope can be transported for the synthesis of "on the spot". Eighty percent of spuskanii isotopes are photons 159 V, which are easily measured using the currently used tool mect.

Accordingly, the compounds of the invention can be quickly and effectively to tag [123I] for use in the analysis of the mect as an alternative of obtaining images of the PET. In addition, due to the fact that the same connection can be marked by any isotope, it is possible to compare the results obtained with PET and mect using the same indicator.

To obtain images of the PET or the mect or for conventional tagging isotopic indicators you can use other isotopes of Halogens. They include75Br,76VG,77VG and82VG, as having an acceptable half-life and features : the tick issue. In General, there is a chemical method for replacing described isotopes part of any halogen. Therefore, biochemical or physiological activity of any halogenated homologs of the compounds of the invention are now available for use by specialists in this field, including homologues with a stable isotope of a halogen. Other isotopes of halogen can be replaced by astatine, [210At] emits alpha particles with a half-life of 8.3 hours. Therefore, At-substituted compounds are suitable for treatment of tumors, when the binding is quite tumor-specific.

The invention provides methods for obtaining images using PET and the mect. These methods include the introduction of the subject (which may be a human or an animal for experimental and/or diagnostic purposes) that creates the image of a number of compounds of the invention labeled with a suitable isotope, and then measuring the distribution of the PET connection, if you use a [18F] or the other emitter positrons, or mect if you use a [123I] or other gamma emitter. Creating the image number is the number that, at least, able to create the image in the scanner PET or mect, when taking into account the sensitivity of detection and the noise level of the scanner, cf the services of an isotope, the body size of the subject and the route of administration, and all such parameters are the model parameters are known and explained by calculations and measurements known to the person skilled in the art without applying undue experimentation.

It will be understood that the compounds of the invention can be marked by isotope of any atom or combination of atoms in the structure. Although [18F], [123I] and [125] highlighted here as being particularly suitable for PET, mect and analysis of labeled atoms, discusses other applications, including applications that arise from physiological and pharmacological properties of homologues with stable isotopes and should be obvious to specialists in this field.

Compounds of the invention can also be marked with technetium (TC) using the adducts of the Vehicle. Isotopes of TC, namely Tc99mwas used to obtain images of the tumors. The present invention provides an integrated adducts of Cu and compounds of the invention, which are suitable for receiving images of the tumor. Such adducts are coordination complexes of TC associated with a cyclic amino acid chain of 4-6 carbon atoms which may be saturated or has a double or triple bond. When there is a double bond, can be synthesized either E (TRANS)or Z (CIS)-isomers and possible p is any change any isomer. The inventive compounds, labeled TC, synthesize the inclusion of isotope99mTC as the last stage for maximizing the usable life of the isotope.

In U.S. patent 5817776 described desyatiletiya sequence of reactions for the synthesis of (anti[18F]-1-amino-3-forceclosure-1-carboxylic acid (FACBC), which includes the division of labour-intensive prepreparation liquid chromatography under high pressure after stage 4 a mixture of 75:25 key intermediate compounds, CIS-1-amino-3-benzyloxycarbonyl-1-carboxylic acid and TRANS-1-amino-3-benzyloxycarbonyl-1-carboxylic acid, respectively. Cleared main isomer, CIS-1-amino-3-benzyloxycarbonyl-1-carboxylic acid, and then turn in triflates predecessor in rectitudinous sequence of reactions.

When trying to improve synthetic methods, the inventors have developed a stereoselective synthesis of TRANS(anti)-1-amino-3-[18F]forceclosure-1-carboxylic acid (anti-[18F]FACBC) for synthesis on a large scale as a precursor to radiolabelling, methyl ester CIS-1-tert-BUTYLCARBAMATE-3-triftormetilfullerenov-1-CYCLOBUTANE-carboxylic acid (8)and TRANS-1-amino-3-forceclosure-1-carboxylic acid (anti-[18F]FACBC) (10). In schemes 1 and 2 illustrate the synthesis of anti-FACBC. Using the provided synthetic steps, the authors were able to obtain triflates predecessor (8) simistatin sequence of reactions. A key step in the synthesis is getting Sinton, 3-benzyloxyacetophenone (2). Getting cyclobutanone 3 includes cyclization by treatment of 1-bromo-2-benzyloxy-3-bromopropane (1) methylethylketoxime and n-butyllithium. Ketone 2 was converted directly to the hydantoins 3 and 4 under the reaction conditions Bucherer-Strecker. A mixture of 80:20 CIS:TRANS isomers as easily purified flash chromatography, thus obtaining the desired CIS-as 4. Turning 4 in triflates predecessor, methyl ester CIS-1-tert-BUTYLCARBAMATE-3-triftormetilfullerenov-1-CYCLOBUTANE-carboxylic acid (8) was performed by the sequence of reactions described in U.S. patent 5817776. Using this method, the inventors were able to obtain gram quantities of compounds 9 [McConathy et al. (2003) Jour. Of Applied Radiation and Isotopes, 58: 657-666].

a) benzylbromide, Hg2Cl2, 150°C; (b) nBuLi, CH3S(O)CH2SCH3, THF then 35% HClO4/Et2O; c) NH4(CO3)2, NH4Cl, KCN,1:1 EtOH: H2O, 60°C; (d) 3N NaOH, 180°C then Boc2O 9:1 CH3OH:Et3N; e) (CH3)3SiCHN2that 1:1 CH3OH:THF; f) 10% Pd/C, H2CH3OH.

(g) (CF3SO2)2O, pyridine, CH2Cl2; h) K18F, K222, K2CO3, 90°C; (i) 4N HCl, 120°C.

To obtain sufficient quantities of analogues is of minislot in the SYN-isomeric form to obtain images of the tumors, in particular CIS(SYN)-1-amino-3-forceclosure-1-carboxylic acid (SYN-FACBC), has developed a new General synthetic approach, as shown in schemes 3-5, to obtain on a large scale methyl ester of TRANS-1-tert-BUTYLCARBAMATE-3-triftormetilfullerenov-1-CYCLOBUTANE-1-carboxylic acid. A key stage in the synthesis involves the restoration of synthons, methyl ester 1-cryptorchidectomy-3-one-1-carboxylic acid (11a), methyl ester 1-phthalimidobutyl-3-one-1-carboxylic acid (11b), methyl ester 1-tert-butylcarbamoyl-3-one-1-carboxylic acid (11C) and methyl ester 1-benzimidazolone-3-one-1-carboxylic acid (11d). Ketones 11a-d were converted directly into TRANS(anti)-alcohols with access 63-80% processing of maitressemadeline and ZnCl2. This method gave a mixture of 95:5, 97:3, 70:30 and 90:10 TRANS:CIS-alcohols 12A, 12b, 12C and 12d, respectively. Alcohols 12a-12d easily purified flash chromatography to obtain the desired TRANS-alcohols 12a-d. Turning 12a-d in triflate predecessors can be performed by the sequence of reactions described in U.S. patent 5817776. The development of these synthetic approaches is essential to ensure a readily available supply of precursor to the distribution centers PET for future clinical studies in many centers to confirm the suitability of SYN and ant is-FACBC as a valuable agent to produce images for diagnosis and treatment of cancer.

The above reaction is carried out as follows. To a solution of ketone (11a, b, C or d) in THF (betwedn.) add 2 equivalent ZnCl2(betwedn., in THF) at room temperature (K.T.) in argon atmosphere. The solution was stirred at room temperature for 30 min followed by the addition of 1.5 equivalents of LiBR'3H at -78°C. the Mixture was stirred at -78°C for 2 hours, then when K.T. during the night. Add NH4Cl (1 N. aqueous solution, 3 EQ.) and the mixture was stirred at K.T. within 30 minutes the Reaction mixture is washed with saturated salt solution and the aqueous phase is again extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated to dryness. The product was then purified on silica gel using as eluent a mixture of 1:1 hexane and ethyl acetate. Outputs approximately 63-80%.

However, the stage of the reaction, shown in scheme 3 specifically illustrates the recovery of four synthons (11a-11d) in four TRANS-alcohol 12a-12d, this stereoselective synthetic stage can be used for synthesis of various TRANS-alcohols for the synthesis of analogues of SYN-amino acids suitable for imaging tumors. Scheme 4 below illustrates this aspect of the invention.

Scheme 5 illustrates the synthesis of SYN-FACBC.

a) benzylbromide, Hg2Cl2, 150°C; (b) nBuLi, CH3S(O)CH2SCH3, THF then 35% HClO4/Et2O; C) NH4CO3)2, NH4Cl, KCN, 1:1 EtOH:H2O,60°C d) 3N NaOH, 180°C then Boc2O 9:1 CH3OH:Et3N; e) (CH3)3SiCHN2that 1:1 CH3OH:THF; f) 10% Pd/C, H2CH3O; g) oxalicacid, DMSO; (h) L-selectride, Znl2); (i)(CF3SO2)2O pyridine, CH2CL2;

(j) (K18F, K222, K2CO3, 90°C; (k) 4N HCl, 120°C.

Scheme 6 illustrates the synthesis of similar amino acids, [18F]-1-amino-4-forcelogix-1-carboxylic acid (FACHC), which can be synthesized with the use described here stereoselective synthetic method.

a) MN4(CO3)2, NH4Cl KCN. 1:1 EtOH:H2O,60°C b) 3N NaOH, 180°C then Boc2O,

9:1 CH3HE:E3N; C), (CH3)3SiCHN2that 1:1 CH3OH:THF; d) 10% Pd/C. H2CH3About; (e)oxalyl-chloride, DMSO; 1)L-selectride. ZnCl2); (g) (CF3SO2)2Oh, pyridine, CH2CL2; h) K18F222To2CO3, 90°C, i) 4N Hcl, 120°C.

Scheme 7 shows the synthesis of SYN/anti-1-amino-3-benzyloxycarbonyl-1-carboxylic acid 20, which is a key synthon used in described here stereoselective method.

Figure 8 show the s-step synthesis of methyl ester 1-[N-(tert-butoxycarbonyl)amino]-4-cyclohexanone-1-carboxylic acid (24), methyl ester of 1-amino-4-cyclohexanone-1-carboxylic acid (25), which are key cyclohexanone intermediate compounds used are described here stereoselective synthetic method.

Scheme 9 illustrates the synthesis of methyl ether SYN/anti-1-[N-substituted amine]-4-hydroxycyclohexane-1-carboxylic acid 27a-d, obtained as described here stereospecific synthetic method.

EXAMPLES

The following description provides exemplary syntheses of preferred embodiments of the present invention. However, the average person skilled in the art should be understood that in practice of the invention can be applied to the original substances, reagents, solvents, temperature, solid substrates, synthetic methods, purification methods, analytical methods, and other reaction conditions different from the conditions specified in the examples, without undue experimentation. It is assumed that all known in the field of functional equivalents of any of such substances and methods included in this invention. The terms and expressions which have been used are used as terms of description and not of limitation, without intent in the application of such terms and expressions drop is to be any equivalents shown and described signs or parts thereof, but it is recognized that within the scope of the invention described in the claims, various modifications are possible. Thus, it should be understood that although the present invention specifically described the preferred option implementation and optional features, the experts in this field can resort to modifications and variant described herein entity of the invention and it is believed that such modifications and variations are within the scope of the invention defined by the attached claims.

Example 1: synthesis of SYN - and anti-[18F]-1-amino-3-forceclosure-1-carboxylic acid (FACBC) (schemes 1, 2 and 5)

The following methods are used in the techniques described here. [18F]-Fluoride was obtained from a cyclotron Seimens using18O(p,n)18F-reactions with proton 11 MeV at 95% enriched [18Of] water. All solvents and chemicals were of analytical grade and were used without additional purification. The melting point of the compounds was determined in capillary tubes using equipment Buchi SP. Analysis by thin-layer chromatography (TLC) was performed using a 250-mm thick layers of silica gel G PF-254 printed on aluminum (obtained from Analtech, Inc. Newark, DE). Column chromatography was performed using silica gel 60-200 mesh (Sigma-Aldrich, St. Louis, MO). Infrared spectra (is) were recorded on a spectrophotometer Beckman 18A with NaCl plates. Spectra of proton nuclear magnetic resonance (1H NMR) were obtained at 300 MHz on the device Nicolet high resolution.

Synthesis of 1-bromo-2-benzyloxy-3-bromopropane 1

In a flask equipped with a fridge, a mixture consisting of benzylbromide (83 ml, 0.70 mol), epibromohydrin (60 ml, 0.70 mol) and mercury chloride (I) (120 mg, 0.25 mmol) is heated with stirring at 150°C during the night. The product distinguish by vacuum distillation with the aid of the fridge 30 cm Vigreux (110-115°C, 0.5 mm Od), while receiving 1 (152 g, 70%) as a colorless liquid:1H NMR (Dl3) δ of 3.45 (4H, d, J=5,2), 3,66-3,71 (1H, m), 4,55 (2H, s), 7,19-7,27 (5H, m).

Synthesis of 3-benzyloxyacetophenone 2

Getting cyclobutanone 2 based on the method described by Ogura et al. (1984) Bull, Chem. Soc. Jpn. 57; 1637-42. A portion of the 2.4 equiv. n-utility (1.6 M in hexane, 243 ml) was added dropwise to a solution containing 2.4 equiv. methyltetrahydrofolate (41 ml, 0,39 mmol) in 400 ml of tetrahydrofuran at -10°C. the Reaction mixture was then stirred at -10°C for 2 hours and then cooled to -70°C. the Yellow reaction mixture was kept at -70°C and added dropwise 1 equivalent of dibromoethane 1 (50 g, 0.16 mmol) in 85 ml of tetrahydrofuran. The reaction mixture allow to warm to room temperature over night. The reaction mixture was added to saturated salt solution and extracted twice what dilatatum. The combined organic layers are subjected to normal processing, while receiving ~60 ml dark red-brown liquid. The mixture of intermediate compounds, S-oxide SYN - and anti-dithioketal, clear into three portions by column chromatography on silica gel (90 g silica). Less polar impurities elute first with a mixture of 3:7 ethyl acetate-hexane, followed by elution of the product pure ethyl acetate. This way we obtain 23.8 g of intermediate compounds. In the second synthesis gain of 24.6 grams 2 using identical conditions.

Intermediate compounds, S-oxide SYN - and anti-dithioketal (48,4 g, 0.18 mol), dissolved in 1200 ml of diethyl simple ether and the solution treated with 68 ml of 35% perchloro acid. After stirring over night the reaction mixture was neutralized with sodium bicarbonate, followed conventional treatment. Purification by column chromatography on silica gel (mixture of 15:85 ethyl acetate:hexane) gives the ketone 2 (23,6 g, yield 41% from 1) in the form of an orange-yellow liquid:1H NMR □ 3,11-3,29 (4H, m), 4,35 was 4.42 (1H, m), a 4.53 (2H, s), 7,30-7,40 (5H, m).

Synthesis of CIS/TRANS-3-(3-benzyloxyresorufin)as 3

To a solution of 10 EQ. ammonium carbonate (125 g, 1.3 mol) and 4 EQ. ammonium chloride (27.8 g, 0.52 mol) in 900 ml of water was added 1 EQ. cyclobutanone 2 (23,6 g, 0.13 mol) in 900 ml of ethanol. After paramasivan what I at room temperature for 30 minutes add 4,5 EQ. a portion of the potassium cyanide (38 grams of 0.58 mol) and the reaction mixture is heated at 60°C over night. The solvent is removed under reduced pressure and the crude yellow solid is thoroughly washed with approximately 1 liter of water to remove salts. Get a white crystalline product (16.4 g, 51%) as a mixture of 5:1 SYN:anti isomers. Main isomer allocate by column chromatography on silica gel (mixture of 2:98 methanol:dichloromethane). Using this technique, cleaning and 1.0 g of a mixture of 95 g of silica gel gives 500-600 mg of pure 3 in one transmission, SYN-5-(3-benzyloxyresorufin)as (3):1H NMR CDCl3) δ is 2.30 to 2.35 (2H, m), 2,87 of 2.92 (2H, m), 4,18-of 4.25 (1H, m), to 4.46 (2H, s), to 5.66 (1H, user. C), 7,28-7,38 (5H, m), 7,55 (1H, user. C), anti-5-(3-benzyloxyresorufin)as (4):1H NMR (CDCl3) δ of 2.44-2.50 (2H, m), 2.77-to and 2.83 (2H, m), 4,21-4,27 (1H, m), to 4.46 (2H, s), of 5.82 (1H, user. C), 7,29-7,38 (6N, m).

Synthesis of SYN/anti-1-(N-(tert-butoxycarbonyl)amino)-3-benzyloxycarbonyl-1-carboxylic acid 5

A suspension of compound 3 (1.35 g, 5.5 mmol) in 30 ml of 3 n sodium hydroxide is heated at 180°C overnight in a sealed vessel made of stainless steel. After cooling, the reaction mixture is neutralized to pH 6-7 with concentrated hydrochloric acid. After evaporation of the water under reduced pressure, the resulting solid is extracted with 4×30 ml of hot ethanol. Unite the military ethanol extracts are concentrated and the residue is dissolved in 50 ml of a mixture of 9:1 methanol:triethylamine. To the solution was added portion 1.3 EQ. di-tert-BUTYLCARBAMATE (1.56 g) and the solution stirred at room temperature over night. The solvent is removed under reduced pressure and the crude product is stirred in a mixture of ice 80 ml of ethyl acetate and ice 80 ml of 0.2 N. hydrochloric acid for five minutes. The organic layer is preserved and the aqueous phase extracted with 2×80 ml ice ethyl acetate. The combined organic layers are washed with 3×60 ml of water with subsequent normal processing. N-BOC-acid 5 (1.27 g, 72%) was obtained as a white solid suitable for use in the next stage without additional purification.1H NMR (CDCl3) δ 1,44 (N, s), 2.21 are of 2.26 (2H, m), 3,02-is 3.08 (2H, user. m), 4,12-4,19 (1H, m), of 4.44 (2H, s), is 5.18 (1H, user. C), 7,27-7,37 (5H, m).

Synthesis of methyl ester of SYN/anti-1-(N-(tert-butoxycarbonyl)amino)-3-benzyloxycarbonyl-1-carboxylic acid 6

1.5 EQ. part 2.0 M trimethylsilyldiazomethane in hexane (1.4 ml) is added dropwise to a solution of N-BOC-acid 5 (600 mg, of 1.87 mmol) in 10 ml of a mixture of 1:1 methanol-tetrahydrofuran. During the exothermic add is a significant evolution of gas. After 20 minutes of stirring, the reaction mixture was concentrated under reduced pressure and the crude product purified by column chromatography on silica gel (mix 2:8 ethyl acetate:Huck is EN). N-BOC-methyl ester 6 (0.45 g, 72%) was obtained as a white crystalline solid.1H NMR (CDCl3) 61,42 (N, C), 2,24-of 2.36 (2H, user. m), 2,88-2,96 (2H, m in), 3.75 (3H, s), 4,16-to 4.23 (1H, m), of 4.44 (2H, s)to 5.13 (1H, s), 7,27 and 7.36 (5H, m).

Synthesis of methyl ester of SYN/anti-1-(N-(tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-carboxylic acid 7

To a solution of 6 (450 mg, of 1.34 mmol) in 10 ml of CH3In the atmosphere of argon is added 200 mg of 10% Pd/C. the Reaction mixture was stirred over night at room temperature in a hydrogen atmosphere. The suspension is then filtered through celiteRand concentrate under reduced pressure. Purification by column chromatography on silica gel (mix 6:4 ethyl acetate:hexane) to give alcohol 7 (200 mg, 61%) as a white crystalline solid: 134-135°C (128-130°C according to Shoup and Goodman, J. Labelled Compd Radiopharm, 1999; 42: 215-225.1H NMR (CDCl3) δ of 1.45 (9H, s), 2,54-2,61 (2H, user. m), 2,98 totaling 3.04 (2H, m), with 3.79 (3H, s), 4.26 deaths-4,34 (1H, user. m), 5,63 (1H, user. C). Analysis (C11H19NO5calculated With: 53,87; N: 7,81; N: 5,71 found: 53,93; N: 8,00; N: 5,71.

Synthesis of methyl ester 1-[N-(tert-butoxycarbonyl)amino]CYCLOBUTANE-3-one-1-carboxylic acid 11

To 1,1 EQ. part of oxalicacid (1,05 ml of 2 M solution in dichloromethane) in 4 ml of dichloromethane at a temperature from -50 to -60°C in argon atmosphere is added dropwise 2,2 EQ. dimethyl sulfoxide (290 μl) in 1 ml dichloromethane. Yes the hydrated solution is stirred for 3 minutes, followed by adding dropwise isomere pure 7 (458 mg, 1.9 mmol)dissolved in 2 ml of dichloromethane and 0.8 ml of dimethylsulfoxide. The reaction mixture is stirred at a temperature of -50 to -60°C for 20 minutes and then add 5 EQ. triethylamine (1.3 ml). The reaction mixture is stirred for 5 minutes, the cooling bath removed and the solution stirred for an additional 15 minutes. The crude product is purified by column chromatography on silica gel (mixture 1:4 ethyl acetate-hexane), while receiving 11S (456 mg, yield 100%) as a white solid: 118-119°C (mixture of ethyl acetate/hexane):1H NMR (CDCl3) δ1,46 (9H, s), 3,49-3,66 (4H, m), 3,83 (3H, s), vs. 5.47 (1H, user. C). Analysis (C11H17NO5calculated With: 54,31; N:? 7.04 baby mortality; N: 5,76 found: 54,50; N: Of 6.96; N: 5,61.

Synthesis of methyl ester of anti-1-(N-(tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-carboxylic acid 12s

To a solution of ketone (11S, and 16.4 mg, 0,067 mmol) in 1 ml THF (betw.) add ZnCl2(18 mg, 0,134 mmol, in THF) at K.T. in the atmosphere of AG. The solution was stirred at K.T. for 30 min followed by the addition of L-selectride (19 mg, 0.10 mmol, in THF) at -78°C. the Mixture was stirred at -78°C for 2 hours, then when K.T. during the night. Add NH4Cl (1 N. water, 3 equivalents) and the mixture was stirred at K.T. within 30 minutes the Reaction mixture is washed with saturated salt solution and the aqueous phase extravert with ethyl acetate. Merged the content of inorganic fillers phase is dried over sodium sulfate and concentrated to dryness. The product was then purified on silica gel using 1:1-mixture of hexane and ethyl acetate as eluent. Product (12C, 16 mg, 100%) is a white solid:1H NMR (CDCl3) δ 1,44 (N, C), 2,53-2,63 (4H, user. m), of 3.77 (3H, s), 4,43-4,50 (1H, user. m), 5,02 (1H, user. C).

Synthesis of methyl ester of anti-1-(N-(tert-butoxycarbonyl)amino)-3-triftormetilfullerenov-1-carboxylic acid 13

A solution of 9 (10 mg, 0.04 mmol) dissolved in 2 ml of dichloromethane in an argon atmosphere. Upon cooling bath with ice add 100 ál portion of pyridine followed by the addition of 4.5 EQ. part triftormetilfullerenov anhydride (30 μl). After stirring for 15 minutes the solvent is removed under reduced pressure and at room temperature. The crude product is purified by column chromatography on silica gel (mixture of 3:7 ethyl acetate:hexane), while receiving the precursor for labelling 13.

Synthesis of SYN-[18F]-1-amino-3-forceclosure-1-carboxylic acid (FACBC) 15

[18F}-Fluoride receive using18O(p,n)18F-reactions with protons 11 MeV at 95% enriched [18Of] water. After evaporation of water and drying of fluoride by evaporation of acetonitrile, triplet protected acid 13 (20 mg) injected into a solution of acetonitrile (1 ml). Without adding media (NCA), the fluorination reaction is carried out at 85°C for 5 min in a sealed vessel in Pris the accordance of potassium carbonate and kryptofix (trademark Aldrich Chemical Co., Milwaukee, WI). Unreacted18F is removed by diluting the reaction mixture with methylene chloride, followed by passing through a silica gel Seppak that gives18F-labeled product 14. The removal of protection from 14 to reach using 1 ml of 6 N. HCl at 115°C for 15 min and then the aqueous solution containing SYN-[18F]FACBC 15, passed through insideria resin (AG 11A8, 50-100 mesh).

Synthesis of anti-[18F]FACBC 10

[18F]-Fluoride receive using18O(R,n]18F-reactions with protons 11 MeV at 95% enriched [18Of] water. After evaporation of water and drying of fluoride by evaporation of acetonitrile, triplet protected amino acid, methyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-triftoratsetilatsetonom-1-carboxylic acid (20 mg) injected into a solution of acetonitrile (1 ml). Without adding media (NCA), the fluorination reaction is carried out at 85°C for 5 min in a sealed vessel in the presence of potassium carbonate and kryptofix (trademark Aldrich Chemical Co., Milwaukee, WI). Unreacted18F is removed by diluting the reaction mixture with methylene chloride, followed by passing through a silica gel Seppak that gives18F-labeled product, methyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-[18F]forceclosure-1-carboxylic acid with the release of EOF 42%. Removing protection from methyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-[8 F]forceclosure-1-carboxylic acid is carried out with the use of 1 ml of 4 n HCl at 115°C for 15 min and then the aqueous solution, containing18FACBC 13, passed through insideria resin (AG 11A8, 50-100 mesh). The complete synthesis for 60 min EOW with the overall radiochemical yield of 12% (17,5% EOU). For details see above McConathy et al. (2003).

Example 2: synthesis of esters of SYN - and anti-1-amino-4-hydroxycyclohexane-1-carboxylic acid (scheme 7-9)

4-Ethylenethiourea (16)

To a solution of monoethyleneglycol 1,4-cyclohexandione (3,41 g and 21.8 mmol) in 50 ml of methanol, cooled to 0°C, add portions of borohydride sodium (0,826 g and 21.8 mmol). The reaction mixture is stirred for an additional 1.5 hours before establishing pH 7 by adding 1 N. HCl. The mixture is distributed between ethyl acetate and a saturated solution of salt. The water layer is concentrated to a point at which begins the formation of sludge, and this layer is extracted twice with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. This crude alcohol (3.28 g, 95.2 percent) used without further purification.1H NMR (CDCl3) δ: 1,54-to 1.87 (8H, 4×CH2-), of 3.77 (1H, m, -CH-), 3,91 (4H, 2×O-CH2-).

1-Ethylenically-4-benzyloxyacetophenone (17)

To a suspension of sodium hydride (410 mg, 17,1 mmol) in 15 ml THF at O°C type 4-ethylenethiourea (1) (1,36 g, 8,61 mmol) is 5 ml THF. The reaction mixture was stirred at 0°C for 1.5 h and add benzylbromide (1.75 g, 10.2 mmol). The reaction mixture was stirred at K.T. during the night. The reaction is quenched with ammonium chloride (feast upon.). The product is extracted with ethyl acetate and the organic phase is washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified by chromatography on silica gel (20% ethyl acetate in hexane), while receiving 2.17 g (100%) benzyl simple ether.1H NMR (CDCl3) δ: 1,51-of 1.88 (8H, m, 4×CH2-), 3,51 (1H, m, -CH-), 3,91 (4H, t, 2×O-CH2-), to 4.52 (2H, s, Ph-CH2-), 7,25-7,34 (5H, m, PH-H).

4-Benzyloxyacetophenone (18)

To a solution of 1-ethylenically-4-benzyloxyacetophenone (17) (3.13 g, 12.6 mmol) in 50 ml THF at K.T. added aqueous hydrochloric acid (1 N., 30 ml). The reaction mixture was stirred overnight and neutralized with sodium bicarbonate (feast upon.). The product is extracted with ethyl acetate and the organic phase is washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated. Purification by chromatography on silica gel (20% ethyl acetate in hexane) gives of 2.45 g (95.2 per cent) indicated in the title ketone.1H NMR (CDCl3) δ: 1,95-2,62 (8H, m, 4×CH2-), 3,82 (1H, m, -CH-), 4,59 (2H, s, Ph-CH2-), 7,28 and 7.36 (5H, m, Ph-H).

SYN/anti-6-(4-Benzyloxycarbonyloxy)hydantoins (19)

To a solution of 4-benzyloxy is yclohexanol (18) (2,45 g, 12 mmol) in 100 ml of ethanol is added a solution of ammonium carbonate (4.6 g, 48 mmol) and ammonium chloride (1.28 g, 24 mmol) in 100 ml of water. The mixture was stirred at K.T. for 15 min and then add potassium cyanide (940 mg, 14.4 mmol). The reaction mixture was stirred at K.T. during the night. The solvent is removed under reduced pressure. The resulting solid is washed repeatedly with water and collected by filtration. This crude SYN/anti mixture hydantoins (3,02 g, 91,8%) used without further purification.1H NMR (CD2OD)□: 1,58-of 2.15 (8H, m, 4×CH2-), 3,48, 3,66 (1H, m, -CH-), to 4.52, 4,56 (2H, s, Ph-CH2-), 7,25-7,33 (5H, m, Ph-H).

SYN/anti-1-Amino-4-benzyloxycarbonyloxy-1-carboxylic acid (20)

SYN/anti Hydantoins (19) (2,72 g to 9.93 mmol) are suspended in 30 ml of 3 N. NaOH and sealed in a steel cylinder, which is heated at 120°C for 1 day. After cooling to K.T. pH of the reaction mixture set to 7 by adding concentrated hydrochloric acid. The crude product SYN/anti-amino acids obtained by concentration to dryness under reduced pressure. The product is used without further purification.

SYN/anti-1-[N]-(tert-Butoxycarbonyl)amino-4-benzyloxycarbonyloxy-1-carboxylic acid (21)

To a suspension of SYN/anti-1-amino-4-benzyloxycarbonyloxy-1-carboxylic acid (20) from the above obtain 50 ml of a mixture of 9:1 Meon/three is tillin add di-tert-BUTYLCARBAMATE (3.25 g, 14.9 mmol). The reaction mixture was stirred at K.T. within 24 hours. The solvent is removed under reduced pressure. The resulting residue is dissolved in 50 ml ice mix 1:1 water/ethyl acetate. the pH of the solution set to 2-3 by adding 3 N. HCl. The organic layer is preserved, while the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3×25 ml). The combined organic layers are dried over magnesium sulfate and the solvent is removed under reduced pressure. This product (of 3.46 g, 100%) used without further purification.1H NMR (CD3OD) δ: 1,41 [N,- C(CH3)3], 1,57 was 2.25 (8H, m, 4×CH2-), 3,40, to 3.58 (1H, m, -CH-), 4,49, of 4.54 (2H, s, Ph-CH2-), 4,84 (1H, user., NH), 7,25-7,33 (5H, m, Ph-H).

Methyl esters of SYN/anti-1-[N]-(tert-butoxycarbonyl)amino]-4-benzyloxycarbonyloxy-1-carboxylic acid (22)

SYN/anti-1-[N-(tert-Butoxycarbonyl)amino]-4-benzyloxycarbonyloxy-1-carboxylic acid (21) (1,14 g, 3,26 mmol) dissolved in 40 ml of benzene and 10 ml of methanol and K.T. add trimethylsilyldiazomethane (558 mg, 4,88 mmol, 2.5 ml of 2 M solution in hexane). The reaction mixture was stirred at K.T. for 30 min, then the solvent is removed under reduced pressure. Purification with flash chromatography with 20% ethyl acetate in hexane gives of 1.03 g (87,2%) of pure product in the form of butter.1H NMR (CD3D) δ: 1,408, 1,413 [N,- C(CH3)3]of 1.5 to 2.3 (8H, m, 4×-With the 2-), 3,40, to 3.58 (1H, m, -CH-), 3,69, 3,71 (3H, s, PINES3), 4,49, of 4.54 (2H, s, Ph-CH2-), 4,77, 4,79 (1H, user., NH), 7,25-7,33 (5H, m, Ph-H).

Methyl esters of SYN/anti-1-[M-(tert-butoxycarbonyl)amino-4-hydroxycyclohexane-1-carboxylic acid (23)

A suspension of benzyl ethers (22) (947 mg, 2.6 mmol) and 10% palladium on coal (142 mg) in 50 ml of ethanol is stirred in an atmosphere of hydrogen overnight. The reaction mixture was filtered through celiteRand the filtrate concentrated under reduced pressure. Purification by column chromatography on silica gel (50% ethyl acetate in hexane) gives (23) (701 mg, 98.4 per cent), the ratio of anti/SYN is 34:66.1H NMR (CD3OD) δ: 1,411, 1,416 [N,- C(CH3)3], 1,53 was 2.25 (8H, m, 4×CH2-), 3,65, 3,91 (1H, m, -CH-), 3,70, 3,71 (3H, s, PINES3), of 4.77 (1H, user., NH).

Methyl ether of 1-[N-tert-butoxycarbonyl)amino-4-cyclohexanone-1-carboxylic acid (24)

Perruthenate of tetrapropylammonium (26 mg, of 0.075 mmol) added in one portion to a stirred mixture of alcohols (23) (410 mg, 1.5 mmol), N-oxide N-methylmorpholine (264 mg, 2.25 mmol) and 750 mg of molecular sieves 4 And 15 ml of 10% acetonitrile in dichloromethane in an argon atmosphere. The reaction mixture was stirred at K.T. for 1 hour, then the solvent is removed under reduced pressure. The resulting residue is transferred in dichloromethane and purified column chromatography on silica gel (30% utilized the t in hexane). Obtain 372 mg (of 91.6%) of the ketone (24) in the form of a white solid.1H NMR (CD3OD) δ: 1,43 [N,- C(CH3)3], 1.32 to 2,42 (8H, m, 4×CH2-), 3,74 (3H, s, PINES3), 5,04 (1H, user., NH).

Methyl ester of 1-amino-4-cyclohexanone-1-carboxylic acid (25)

To a solution of ketone (24) (325 mg, 1.2 mmol) in 5 ml of dichloromethane add triperoxonane acid (1,37 g, 12 mmol). The reaction mixture was stirred at K.T. during the night. The solvent and the reagent is removed under reduced pressure. The resulting white solid used without further purification.

Methyl ether of 1-[N-(phthaloyl)amino-4-cyclohexanone-1-carboxylic acid (26b)

To a suspension of amine (25) (80 mg, 0.47 mmol) and triethylamine (476 mg, 4.7 mmol) in 10 ml of toluene added phthalic anhydride (77 mg, 0.52 mmol). The mixture is refluxed at 120°C for 5 hours. The reaction mixture is washed with saturated salt solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The crude product was purified flash chromatography using a mixture of 1:4 ethyl acetate and hexane, thus obtaining the ketone (26b) (37.6 mg, 26.6 per cent, stage 2) in the form of a white solid.1H NMR (CD3OD) δ: 2,54-3,14 (8H, m, 4×CH2-), of 3.77 (3H, s, PINES3), 7,73-a 7.85 (4H, m, Ph-H).

Methyl ether of 1-[N-(TRIFLUOROACETYL)amino-4-cyclohex the non-1-carboxylic acid (26C)

To a suspension of amine (25) (14 mg, 0,082 mmol) and triethylamine (166 mg, of 1.64 mmol) in 1 ml dichloromethane, cooled to -10°C, add triperoxonane anhydride (86 mg, 0.41 mmol). The mixture is heated to K.T. and stirred over night. Add a few drops of 1 n ammonium chloride and the mixture is stirred for 30 minutes, the Reaction mixture was washed with saturated salt solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The crude product was purified flash chromatography using a mixture of 1:2 ethyl acetate and hexane, thus obtaining the ketone (26C) (17.5 mg, 79,9%) as a clear oil.1H NMR (CD3D) δ: 2,44-of 2.56 (8H, m, 4×CH2-), with 3.79 (3H, s, PINES3), 6,86 (1H, user., NH).

Methyl ether of 1-[N-(benzoyl)amino-4-cyclohexanone-1-carboxylic acid (26d)

To a suspension of amine (25) (50 mg, 0.29 mmol) and pyridine (934 mg, of 11.8 mmol) in 3 ml of dichloromethane, cooled to 0°C, add benzoyl chloride (62 mg, 0.44 mmol). The mixture is heated to K.T. and stirred over night. The reaction mixture is washed with saturated salt solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The crude product was purified flash chromatography using a mixture of 1:2 ethyl acetate and hexane, thus obtaining the ketone (26d) (22 m is, 27,6%) as a white solid.1H NMR (CD2OD) δ: 2,46-2,58 (8H, m, 4×CH2-), 3,81 (3H, s, PINES3), PC 6.82 (1H, user, NH), of 7.48-8,13 (5H, m, PH-H).

Methyl esters of SYN/anti-1-[N-(tert-butoxycarbonyl)amino-4-hydroxycyclohexane-1-carboxylic acid (27A)

To a solution of ketone (26a) (18 mg, of 0.066 mmol) in 1 ml THF added zinc chloride (18 mg, 0.13 mmol, 264 μl of 0.5 M solution in THF) at K.T. and the mixture is stirred for 30 minutes, the Reaction mixture was cooled to -78°C and add L-selectride (19 mg, 0.10 mmol, 100 μl of 1 M solution in THF). The mixture was stirred at -78°C for 2 h and at room temperature over night. Add a few drops of 1 n ammonium chloride and the mixture is stirred for 30 minutes, the Reaction mixture was washed with saturated salt solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The crude product was purified flash chromatography using 1:1-mixture of ethyl acetate and hexane, thus obtaining the alcohols (27A) (12,7 mg, 70,5%) as a clear oil, the ratio of the anti-isomer to the SYN-isomer of 67:33.1H NMR (CD3OD) δ: 1,411, 1,415 [N,- C(CH3)3], 1,55-of 2.26 (8H, m, 4×CH2-), 3,65, to 3.92 (1H, m, -CH-), 3,70, 3,71 (3H, s, PINES3), 4,70 (1H, user., NH).

Methyl esters of SYN/anti-1-[N-(tert-butoxycarbonyl)amino]-4-hydroxycyclohexane-1-carboxylic acid (27A) (recip is tion in the absence of zinc chloride)

To a solution of ketone (24) (21,7 mg, 0.08 mmol) in 1 ml THF, cooled to -78°C, add L-selectride (of 22.8 mg, 0.12 mmol, 120 μl of 1 M solution in THF). The mixture was stirred at -78°C for 2 h and at room temperature over night. Add a few drops of 1 n ammonium chloride and the mixture is stirred for 30 minutes, the Reaction mixture was washed with saturated salt solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The crude product was purified flash chromatography using 1:1-mixture of ethyl acetate and hexane, thus obtaining the alcohols (27A) (3 mg, 13,7%) as a clear oil, the ratio of the anti-isomer to the SYN-isomer 11:89.1H NMR (CD3CD) δ: 1,415, 1,420 [N,- C(CH3)3], 1,53 was 2.25 (8H, m, 4×CH2-), the 3.65 (1H, m, -CH-), 3,70, 3,71 (3H, s, PINES3), 4,70 (1H, user., NH).

Methyl esters of SYN/anti-1-[N-(phthaloyl)amino-4-hydroxycyclohexane-1-carboxylic acid (27b)

To a solution of ketone (26b) (20 mg, of 0.066 mmol) in 1 ml THF added zinc chloride (18 mg, 0.13 mmol, 260 μl of 0.5 M solution in THF) at K.T. and the mixture is stirred for 30 minutes, the Reaction mixture was cooled to -78°C and add L-selectride (19 mg, 0.10 mmol, 100 μl of 1 M solution in THF). The mixture was stirred at -78°C for 2 h and at room temperature over night. Add a few drops of 1 n chloride, shumilkin) and the mixture is stirred for 30 minutes The reaction mixture is washed with saturated salt solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The crude product was purified flash chromatography using 1:1-mixture of ethyl acetate and hexane, thus obtaining the alcohols (27b) (13.2 mg, 66%) as a clear oil, the ratio of the anti-isomer to the SYN-isomer 52:48.1H NMR (CD3OD) δ: 1.60-to a 2.01 (8H, m, 4×CH2-), 3,70, of 3.75 (3H, s, PINES3), 3,86 (1H, m, -CH-), 7,69-of 7.82 (4H, m, Ph-H).

Methyl esters of SYN/anti-1-[N-(phthaloyl)amino-4-hydroxycyclohexane-1-carboxylic acid (27b) (getting in the absence of zinc chloride)

To a solution of ketone (26b) (18 mg, 0,059 mmol) in 1 ml THF, cooled to -78°C, add L-selectride (17 mg, 0.09 mmol, 90 μl of 1 M solution in THF). The mixture was stirred at -78°C for 2 h and at room temperature over night. Add a few drops of 1 n ammonium chloride and the mixture is stirred for 30 minutes, the Reaction mixture was washed with saturated salt solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The crude product was purified flash chromatography using 1:1-mixture of ethyl acetate and hexane, thus obtaining the alcohols (27b) (13.2 mg, 66%) as a clear oil, the ratio of the anti-isomer to the SYN-isomer 52:48.

Methyl is Fira SYN/anti-1-[N-(TRIFLUOROACETYL)amino-4-hydroxycyclohexane-1-carboxylic acid (27)

To a solution of ketone (26C) (17 mg, 0,064 mmol) in 1 ml THF added zinc chloride (17 mg, 0.13 mmol, 256 μl of 0.5 M solution in THF) at K.T. and the mixture is stirred for 30 minutes, the Reaction mixture was cooled to -78°C and add L-selectride (18 mg, 0,096 mmol, 96 μl of 1 M solution in THF). The mixture was stirred at -78°C for 2 h and at room temperature over night. Add a few drops of 1 n ammonium chloride and the mixture is stirred for 30 minutes, the Reaction mixture was washed with saturated salt solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The crude product was purified flash chromatography using 1:1-mixture of ethyl acetate and hexane, thus obtaining the alcohols (27C) (13.5 mg, 78,4%) as a clear oil, the ratio of the anti-isomer to the SYN-isomer of 66:34.1H NMR (CD3OD) δ: 1,67-is 2.37 (8H, m, 4×CH2-), 3.72 points, to 3.75 (3H, s, PINES3), of 3.97 (1H, m, -CH-), to 6.43 (1H, user., NH).

Methyl esters of SYN/anti-1-[N-(benzoyl)amino-4-hydroxycyclohexane-1-carboxylic acid (27d)

To a solution of ketone (26d) (22 mg, 0.08 mmol) in 1 ml THF added zinc chloride (22 mg, 0.16 mmol, 320 μl of 0.5 M solution in THF) at K.T. and the mixture is stirred for 30 minutes, the Reaction mixture was cooled to -78°C and add L-selectride (23 mg, 0.12 mmol, 120 μl of 1 M solution in THF). The mixture was stirred at -78°C for 2 hours and when anatoy temperature throughout the night. Add a few drops of 1 n ammonium chloride and the mixture is stirred for 30 minutes, the Reaction mixture was washed with saturated salt solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. (The product could not be detected).

Example 3: analysis of the absorption of amino acids in vitro and in vivo

Tumor cells were first grown as monolayers in T-flasks containing modified by way of Dulbecco Wednesday Needle (DMEM) in the humid conditions of the incubator (37°C, 5% CO2/95% air). Environment for the cultivation was supplemented with 10% fetal bovine serum and antibiotics (10,000 units/ml penicillin and 10 mg/ml streptomycin). Environment for the cultivation was replaced three times per week and cells were passivatable, so that the cells could reach a state of confluently for a week long time.

When monolayers became confluent, the cells are prepared for experiments as follows. Environment for the cultivation was removed from T-flasks and cell monolayers were subjected to the action of a mixture of 1 X trypsin EDTA for ~1 minute to loosen the attachment protein of the cells to the flask. The flask was then patted to cause the release of cells. Added an augmented environment for the inhibition of the proteolytic action of trypsin and cells are aspirated through the needle 18 Ga until the eye they were not monodispersion. The sample cells were counted under the microscope using hemocytometer and the fraction of live/dead cells was evaluated by staining Trianon blue (>98% viability). The remaining cells were placed in centrifuge tubes, centrifuged at 75×g for 5 minutes and supernatant was removed. The cells are then suspended in the system of amino acid/serum-free salt DMEM.

In this study, approximately 4,55×105cells were exposed to either [18F]10 (anti-FACBC)or [18F]15 (SYN-FACBC, 5 µci) in 3 ml of medium without amino acids ± inhibitors conveyor (10 mm) for 30 minutes under the conditions of the incubator in glass vessels 12×75 mm Analysis in each condition was performed in duplicate. After incubation, the cells centrifuged twice (75×g for 5 minutes) and washed with ice-system amino acid/serum-free salt DMEM to remove residual activity in the supernatant. The vessels were placed in the counter Packard Cobra II Auto-Gamma, the source count rate was corrected for decomposition labels and activities were determined by the number of cells. The data from these studies (expressed as percentage uptake relative to control) were applied to graph using Excel with static comparisons between groups was analyzed using one-factor ANOVA analysis (software package is a lot of software GraphPad Prism).

To test the hypothesis that [18F]10 and [18F]15 enter cells mainly through a system of transfer of amino acids L-type, tested the absorption of amino acids with the use of cultured cells gliosarcoma 9L and various cancer cell lines human in the presence and in the absence of two well-described inhibitor of transfer of amino acids. N-MeAlB is a selective competitive inhibitor system of transfer of amino acids A-type, whereas 2-aminobutyl[2.2.1]heptane-2-carboxylic acid (VSN) is usually used as an inhibitor for the sodium-independent transfer system L-type, although this compound is also competitively inhibits the uptake of amino acids by sodium-dependent transfer systems In the0,+and0. The system of transfer of amino acids A - and L-type participated in the acquisition of in vivo labeled with radioactive isotopes of amino acids used to produce images of the tumor.

In the absence of inhibitors of [18F]10 and [18F]15 showed similar levels of absorption in the cells of gliosarcoma 9L and various cancerous human cell lines with intracellular accumulation of 0.43% and 0.50% of the initial dose per million cells after 30 minutes of incubation, respectively. To facilitate comparison of the action of inhibitors data were expressed as percentage uptake relative to the control is inogo conditions (without inhibitor), as shown in the table. In the case of [18F]10 and [18F]15 VSN blocked >50% activity uptake relative to controls. Decrease absorption of [18F]10 and [18F]15 because VSN compared to controls was statistically significant (p<0.05 to p<0.01 respectively by one-factor ANOVA analysis). These inhibition studies show that [18F]10 and [18F]15 are substrates for a system of transfer of amino acids in the L-type investigated cancer cells on the basis of inhibiting the absorption of both compounds in the presence of VSN.

The absorption of SYN - and anti-[18F]FACBC in tumor cells, expressed as percentage uptake relative to the control
DU145SKOV3Glioma2549MB 468
prostateovarianU87lungbreast cancer
No
SYN-[18F]FACBCinhibitor20,2711,6724,7711,9133,53
BCH9,11by 5.875,003,85of 10.93
MeAlB17,168,4814,80being 9.6128,25
anti-[18F]FACBCWithout inhibitor16,06to 4.683,4112,1715,51
BCH4,16the 1.441,512,694,43
MeAlB13,906,393,451,02 14,80

The induction of tumor and preparation of animals

All animal experiments were conducted under humane conditions and approved by the Institutional Animal Use and Care Committee (IUCAC) at Emory University Committee on use and care of animals Emory University). Cell gliosarcoma 9L rat implanted in the brain of male Fischer rats. In short, shot mice, placed in a stereotaxic head camera, were injected with a suspension of 4×104cells gliosarcoma 9L rat (1×107per ml) in place of 3 mm to the right of the midline and 1 mm ahead from bregma to a depth of 5 mm outer plates of the cranial bone. The injection was carried out for 2 minutes and the needle was removed for 1 minute to minimize backflow of tumor cells. Trepanation hole and the scalp incision was closed and the animals were returned to their original colony after recovery from the procedure. In rats with tumor developed intracranial tumors that caused the weight loss, apathy and acceptance of the bent position of the body, animals used for the study after 17-19 days after implantation. Of the 30 animals that were implanted tumor cells in 25 developed tumors that are visible to the naked eye upon dissection, it was used in the study. Figure 1-3 shows the results of these studies.

Research is moreprecisely radioactivity in rodents

The distribution of radioactivity in tissues were determined in 16 normal male rats of the Fischer 344 (200-250 g) after intravenous injection of ~85 µci of [18F]10 or [18F]15 in 0.3 ml of sterile water. Before the experiment the animals were given feed and water ad libitum. Injection in the tail vein injected awake animals using devices to secure the rodent RTV-190 (Braintree Scientific)to avoid mortality that accompanies anesthesia in the presence of an intracranial mass. Groups of four rats were killed after 5 minutes, 30 minutes, 60 minutes and 120 minutes after injection of the dose. Animals were opened and selected tissues were weighed and counted together with the standards of the dose counter Packard Cobra II Auto-Gamma. The source count rate was corrected for the decay of the label and number of pulses were normalized as a percentage of the total injected dose per gram tissue (% ID/g). For comparison, the absorption activity in tumor tissue the appropriate area of the cerebral cortex, contralateral to the tumor, cut out and used for comparison in each moment of time the analysis was performed using one-factor ANOVA analysis (software package GraphPad Prism). Figure 1-3 below shows the results of these studies.

As can be seen in figure 1-3 in rats that were implanted intracranially cell gliosarcoma 9L, retention of radioactivity in tumor tissue was high che is ez 60 minutes after intravenous injection of [ 18F]10 and [18F]15, whereas the uptake of radioactivity into brain tissue contralateral to the tumor remained low (<0.3% of dose/g). Relations absorption by the tumor to absorb normal brain [18F]10 was 6.5:1 in 60 and 120 minutes, whereas for [18F]15 ratio was 5.3:1 in the same time. These results show that like the anti-[18F]F, [18F]10, SYN-[18F]FACBC, [18F]15 is an excellent candidate for imaging of brain tumors.

Compounds obtained by the method of the invention may be solvated, especially hydrated. Hydrating may occur during retrieval of the compounds or compositions comprising compounds or hydration may occur over time due to the hygroscopic nature of the compounds. In addition, the compounds of the present invention may exist in resolutiony forms, as well as in forms, solvated pharmaceutically acceptable solvents such as water, ethanol and the like. In General, the solvated forms are considered equivalent nonsolvated forms for the purposes of the present invention.

When the compounds of the invention should be used as agents to produce images, they need to mark the appropriate radio is active isotopes of halogen, such as123I131I18F,76Br and77Br. Radiohalogenated the compounds of this invention can easily provide the sets of materials required to produce images of the tumor. For example, the kit can contain the final product, labeled with a suitable radioisotope (for example,18F), ready for use to obtain the image, or the intermediate connection and the label (for example, K[18F]F) with reagents (e.g., solvent, agent for removing protection), so that the final product you could get on the spot or during the application.

In the first stage of the method of obtaining images of tumors labeled compound of the invention is introduced into a tissue or into the patient in detektiruya number. The connection is usually part of a pharmaceutical composition and administered to the tissue or patient by methods well known to the person skilled in the art. For example, the connection can be entered either orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracavitary, endovaginal, intraperitoneal, intravesical, local (powders, ointments or drops) or by spray to transbukkalno or nasal administration.

In the method of obtaining images of the invention labeled compound is administered to the patient in detektiruya number and after lying is neither, elapsed after the introduction and sufficient to ensure that the connection has been associated with tumor tissues or cells, labeled connection detects non-invasive inside of the patient. In another embodiment of the invention labeled compound is administered to the patient, and the time after injection should be sufficient so that the connection became associated with tumor tissues, and then take a tissue sample of the patient and labeled compound in the tissue detects outside of the patient. In the alternative case, the patient takes a tissue sample and a labeled compound of the invention is introduced into the tissue sample. After a time sufficient for the connection became associated with the tissue sample, the connection is detected. The term "tissue" means a portion of a patient's body. Examples of tissues include brain, heart, liver, blood vessels and arteries. Detektivami number is the number of labeled compounds necessary for detection of the chosen method of detection. The amount of labeled compound that is administered to the patient to ensure its detection can easily identify the person skilled in the art. For example, increasing the number of labeled compounds can be given to the patient until then, until a connection is detected by the selected method of detection. Label enter the connection to ensure the detection of compounds.

The introduction of the labelled compound to the patient can be performed by General or local injection. For example, labeled connection, you can enter the patient so that it is transported throughout the body. In the alternative case, the labeled compound can be entered into certain interest organ or tissue.

Specialists in this field are familiar with the definition of the length of time for the connection, sufficient for it to become an associate with the tumor. The length of time needed can be identified easily by the introduction of the detected amount of labelled compound to a patient and then detecting the labeled compound at different time points after injection.

Specialists in this field are familiar with the various ways to detect the labeled compounds. For detection radiometric compounds can be applied, for example, magnetic resonance imaging (MR), positron emission tomography (PET) or single photon emission computed tomography (mect). PAT and mect are preferred when the compounds of the invention are used as agents for obtaining images of the tumors. The label, which is injected into the connection will depend on the desired method of detection. For example, if your PET is chosen as the method of detection, the connection needs them the te positron emitting atom, such as11With or18F.

Radioactive diagnostic agent must have sufficient radioactivity and concentration of radioactivity, which can guarantee a reliable diagnosis. For example, in the case where the radioactive metal is technetium-99m, it is usually included in an amount of 0.1 to 50 MCI of approximately 0.5 to 5.0 ml at the time of introduction. The amount of the compounds of formula may be the same, which is sufficient for the formation of a stable chelate compound with the radioactive metal.

The compound of the invention as a radioactive diagnostic agent is sufficiently stable so it can be entered directly as such, or to save the application. When you need to, radioactive diagnostic agent may contain any additive such as regulating the pH of agents (e.g., acids, bases, buffers), stabilizers (for example, ascorbic acid) or isotonic agents (e.g. sodium chloride). Obtaining images of the tumor can also be quantified with the use of compounds here so that therapeutic agent to the tumor can be evaluated on its effectiveness.

The preferred connection for receiving image include a radioisotope, such as123I124I125I131I18F,76VG,77 11C.

Synthetic schemes described herein are exemplary syntheses of preferred embodiments of the present invention. However, the average person skilled in the art will understand that in practice of the invention can be applied to the original substances, reagents, solvents, temperature, solid substrates, synthetic methods, purification methods, analytical methods, and other reaction conditions, other than conditions specifically described in the examples, without undue experimentation. It is assumed that all known in the field of functional equivalents of any of such substances and methods included in this invention. The terms and expressions which have been used are used as terms of description and not of limitation, and without intention in the use of such terms and expressions to exclude any equivalents shown or described signs or portions thereof, but it is recognized that within the scope of the invention described in the claims, various modifications are possible. Thus, it should be understood that although the present invention specifically described the preferred option implementation and optional features, the experts in this field can resort to modifications and variant described herein entity of the invention and is, h is of such modifications and variations are within the scope of the present invention, defined by the attached claims.

When there is described a group of substituents, it is understood that all individual members of this group and all subgroups, including any isomers and enantiomers of the members of the group, described separately. It is assumed that when they use the Markush group or other group, all individual members of the group and all possible combinations and subcombinations group included in the description separately. It is assumed that, when they describe the connection so that a particular isomer or enantiomer of the compound is not specified, for example, in the formula or chemical name, the description includes each isomer and enantiomer compounds described individually or in any combination. In addition, it is assumed, unless otherwise stated, all isotopic variants of the compounds described herein are included in this description. For example, it should be understood that any one or more of the hydrogen atoms in this molecule can be replaced by deuterium or tritium. Isotopic variants of a molecule are usually suitable as standards in assays of molecules in chemical and biological research related to the molecule or its application. It is assumed that the specific names of compounds are approximate, because you know that the average person in this is blasti can say the same connection otherwise.

Many of the molecules described herein contain one or more inisheer groups [groups you can remove a proton (e.g.,- COOH) or add a proton (e.g., amines) or which can be quaternization (e.g., amines)]. It is assumed that all possible ionic forms of these molecules and their salts are included separately in this description. As for the salts of the described compounds, the average person skilled in the art can choose among the wide variety available counterions counterions, which are suitable for obtaining salts of the present invention for this application.

Each drug or combination of components described or shown as examples here can be used in practice of the invention unless otherwise stated.

It is assumed that whenever the description indicates the range of, for example, a temperature range, a time range, the range of purity or range of composition or concentration, all intermediate ranges and subranges, as well as all individual values included in these ranges are included in the description.

All patents and publications referred to in the description of the invention, are an indication of the levels of qualification of specialists in the field to which the invention relates. References cited here, is included here as the links in their entirety to describe the state of this field to the date of their filing, and the this information can be applied here, if necessary, to the exclusion of certain embodiments, which are known in the prior art. For example, when the connection is declared, it should be understood that compounds known and available in the prior art before the invention of applicants, including compounds for which includes their description is presented in the references cited here are not intended for inclusion here claims related to chemical compounds.

Used here, the term "comprising" is synonymous with the term "comprising", "containing" or "characterized by", included in any value and does not exclude additional unspecified elements or stages of the method. In this context, the term "consisting of" excludes any element, any stage or any ingredient not specified in items related to the item. In this context, the term "consisting essentially of" does not exclude substances or stage, which does not actually affect the basic and novel characteristics of this item. In each case here, any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with any of the other two terms. The invention illustratively described herein suitably may be put into practice in Otsu is the absence of any element or elements, limitations or restrictions that specifically is not described here.

All references cited here, so included by reference to the extent which is not compatible with this description. In particular, the U.S. patent 5808146, 5817776 and WO 03/093412 quote here and include as a reference here to provide examples of analogues of amino acids, which can be obtained with the use of the invention and detailed synthetic methods. Some of the links provided here, are included as a reference to provide details concerning sources of starting compounds, additional source connections, additional reagents, additional methods of synthesis, additional methods of analysis and additional applications of the invention.

1. The method of synthesis is essentially pure SYN-amino acids of formula II
,
where Y and Z are independently selected from the group consisting of CH2and (CR4R5)n=1, 2; R1-R3independently selected from the group consisting of H and alkyl With1-C4; R4, R5=N and R7=18F; or its pharmaceutically acceptable salt, comprising the stage of transformation of the ketone in the TRANS-alcohol formula I and converting the obtained TRANS-alcohol SYN-amino acid of formula II, where formula I is a

where Y, Z, R1-R3have the above values.

2. The method according to claim 1, where Y and Z represent the amino acid CH2.

3. The method according to claim 1, where the amino acid is SYN-[18F]-1-amino-3-forceclosure-1-carboxylic acid (SYN-3-[18F]FACBC).

4. Essentially pure compound of the formula I

where Y and Z are independently selected from the group consisting of CH2and (CR4R5)n; n=1, 2; R1-R3independently selected from the group consisting of H and alkyl, C1-C4; R4, R5=N.

5. The compound according to claim 4, where R1, R2and R3are hydrogen and Y and Z represent CH2.

6. The compound according to claim 4, where R1, R2and R3are hydrogen and Y and Z represent2H4.

7. Essentially pure SYN-amino acid of formula II indicated in claim 1.

8. The amino acid according to claim 7, representing SYN-3-[18F]F.

9. Pharmaceutical composition for obtaining images of the tumor, including SYN-amino acid according to claim 7 in an effective amount and a pharmaceutically acceptable carrier.

10. The composition according to claim 9, where the amino acid is SYN-3-[18F]FACBC.

11. The method of obtaining images of the tumor positron emission tomography or single photon emission computed tomography, enabling the th in itself an introduction to a subject suspected appearance of tumors forming an image of the tumor, the amount of labelled compound according to claim 7; b) providing sufficient time for the labeled compound was associated with a tumor, and (C) measuring the distribution of the labeled compounds in the body of the subject of the PET and the mect.

12. The method according to claim 11, where the labeled compound is SYN-3-[18F]FACBC.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: method of synthesis of manganese (II) fumarate through direct reaction of metal with acid is presented. The process is carried out in a vertical type bead mill with mass ratio of beads to the reaction mixture equal to 1:1, and the liquid phase is a solution of fumaric acid in an organic solvent with content of acid of 0.70-1.80 mol/kg. Manganese is taken in stoichiometric amount with acid or in deficiency of up to 5%. The process is started by loading the liquid phase solvent and acid and preparation of the acid solution in a bead mill, after which metal is loaded and the process is carried out at temperature ranging from 25 to 35°C while preventing spontaneous increase of temperature through forced cooling and controlling through sample taking and determination of manganese salt in the samples and residual amount of acid until attaining values close to calculated values during quantitative conversion of the reagent in deficiency. After that stirring and cooling are stopped. The suspension of the reaction mixture is separated from the glass beads, cooled to temperature between 5.2 and 6.2°C and filtered. The filtering residue is washed with the liquid phase solvent, cooled to approximately the same temperature, and taken for purification by recrystallisation. The filtrate and the washing solvent are returned to the repeated process.

EFFECT: method is easy to implement, the end product can be easily separated and there are no auxiliary materials which contaminate the obtained product.

2 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing manganese (II) fumarate from manganese metal and its oxide (III) through direct reaction of the metal and its oxide Mn2O3 with an acid in the presence of a liquid phase and a stimulating iodine additive in a vertical type bead mill with glass beads as grinding agent. The metal and its oxide are loaded in molar ratio (2±0.1):1 in total amount of 7.87 to 10.93% of the mass of the load. Acid is added with 15 to 25% excess of the calculated value, equal to the number of moles of metal and twice the number of moles of metal oxide in the load. The base of the liquid phase is isoamyl alcohol, in which the iodine stimulating additive is dissolved in amount of 0.02 to 0.05 mol/kg. Glass beads are loaded first, in mass ratio to the reaction mixture of 1.35:1, and then later the liquid phase solvent, acid and stimulating additive, and after brief stirring, metal oxide and metal, stirring all the while. Taking this moment as the beginning of the process, forced cooling is introduced right away. Operating temperature is stabilised in the range 33 to 45°C and in this mode, the process is carried out until virtually quantitative conversion of metal and its oxide to the target salt, after which stirring and forced cooling are stopped. The reaction mixture is separated from the glass beads, cooled to temperature 5 to 6°C and kept at that temperature for 1 to 2 hours. The solid phase of the target salt is filtered off and washed with isoamyl on a filter cooled to approximately the same temperature, after which it is taken for purification by recrystallisation. The filtrate and the cleaning solvent, containing excess acid, the bulk of the stimulating additive and a certain amount of dissolved target salt, are returned for loading in the repeated process. The process is carried out in light temperature conditions. The target substance can be easily separated.

EFFECT: design of a low-waste method, which allows for obtaining target product from available manganese oxide with an easy to implement process.

9 ex

FIELD: medicine.

SUBSTANCE: invention refers to chelating agents and their technetium complexes to be used as radiopharmaceuticals and characterised by formula I where X is -NR-, -CO2-, -CO-, -NR(C=S)-, -NR(C=O)-, -CONR- or Q; Y represents amino acid, -CH2-, -CH2OCH2-, -OCH2CH2O- or X; Z is an aggregation from peptides, their analogues, substrata, antagonists or enzyme inhibitors, receptor-bonding compounds, oligonucleotides, oligo-DNA- or oligo-RNA-fragments; n is a number 1 to 8; m is a number 0 to 30; R represents H, C1-4alkyl, C2-4alkoxyalkyl, C1-4hydroxyalkyl or C1-4fluoroalkyl; Q represents remains of succinimide , A is a pharmaceutically acceptable anion.

EFFECT: production of new chelating agents applicable for making the technetium complexes.

22 cl, 12 ex, 3 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to improved method for preparation of manganese oxalate (II) by means of direct interaction of metal with acid in bead mill in presence of liquid phase, in which manganese and oxalic acid are loaded into bead mill in stoichiometric ratio in amount of 0.75-2.4 mole/kg of load at mass ratio of load and glass beads of 1:1.2, liquid phase dissolvent used is water or organic substance, or mixture of organic substances; loading is carried out in the following sequence: liquid phase dissolvent, acid, then metal; process is started at room temperature and is carried out under conditions of forced cooling in the temperature range of 18-39°C with control over procedure by sampling method to practically complete spend of loaded reagents for product making, afterwards mixing and cooling are terminated, suspension of reaction mixture is separated from glass beads and filtered, salt deposit is sent for product cleaning from traces of non-reacted metal, and filtrate is returned into repeated process.

EFFECT: method makes it possible to produce target product in absence of manganese dioxide and stimulating additive at temperatures close to room temperature.

2 cl, 13 ex, 2 tbl

FIELD: chemical industry; methods of production of the manganese salts with the organic acids.

SUBSTANCE: the invention is pertaining to production of the manganese salts with the organic acids in particular, to the salt of the divalent manganese and formic acid. The method is exercised by interaction of manganese, its oxides in the state of the highest valence with the formic acid solution in the organic solvent in the presence of iodine as the stimulating additive. The production process is conducted in the bead grinder of the vertical type having the revertive cooler-condenser, the high-speed paddle stirrer and the glass beads of in the capacity of the grinding agent loaded in the mass ratio to the loading of the liquid phase as (1÷2): 1. The liquid phase consists of the formic acid solution in the organic solvent. The concentration of the acid is taken within the range of 3.5÷10.8 mole/kg. In the loaded liquid phase they dissolve the stimulating additive of iodine in the amount of 0.025-0.100 mole/kg of the liquid phase. The ratio of the masses of the liquid phase and the total of the metallic manganese and the manganese oxide are as(4.9÷11):1. The molar ratio of the metal and the oxide in the loading is as (1.8÷2.,2):1. The metal and the oxide are loaded the last. It is preferable in the capacity of the dissolvent to use the butyl alcohol, ethyl acetate, ethylene glycol, 1.4-dioxane, dimethyl formamide. The production process is started and conducted at the indoor temperature up to practically complete(consumption of the whole loaded manganese oxide. Then the stirring is stopped, the suspension of the salt is separated from the beads and the nonreacted manganese and after that conduct filtration. The filtrate and the nonreacted manganese are returned into the repeated production process, and the filtered out settling of the manganese salt is exposed to purification by recrystallization. The technical result of the invention is - simplification of the method at usage of accessible reactants.

EFFECT: the invention ensures simplification of the method at usage of accessible reactants.

16 ex, 2 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved solid-phase method for synthesis of radioisotope indicators, in particular, for synthesis of compounds labeled with 18F that can be used as radioactive indicators for positron- emission tomography (PET). In particular, invention relates to a method for synthesis of indicator labeled with 18F that involves treatment of a precursor fixed on resin if the formula (I): SOLID CARRIER-LINKER-X-INDICATOR wherein X means a group promoting to nucleophilic substitution by a definite center of a fixed INDICATOR with 18F- ion for preparing a labeled indicator of the formula (II): 18F-INDICATOR; to compound of the formula (Ib):

and compound of the formula (Ih): ;

to radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in PET; to a cartridge for radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in positron-emission tomography.

EFFECT: improved method of synthesis.

13 cl, 1 sch, 3 ex

FIELD: chemical industry; methods of production of the bromine derivatives of fullerene С60.

SUBSTANCE: the invention is pertaining to the method of production of the bromine derivatives of fullerene С60. The process consists in the interaction of the bromoform and the tetra bromomethane with fullerene С60 at presence of the rhodium-containing catalyst - Wilkinson's complex [RhCl(PPh3)3] at the temperature of 100°С within 10-20 hours, at the molar ratio of [Rh]:[C60]:[CHBr3 or CBr4]= 1:100:100-500. The technical result of the invention is the increased output of the product, the reduced amount of the wastes, the insignificant consumption of the catalyst.

EFFECT: the invention ensures the increased output of the product, the reduced amount of the wastes, the insignificant consumption of the catalyst.

3 ex, 1 tbl

FIELD: chemical technology.

SUBSTANCE: invention relates to technology for synthesis of acetic acid inorganic salts. Method involves interaction of metallic manganese or its dioxide with acetic acid in the presence of oxidizing agent. Process is carried out in beaded mill of vertical type fitted with reflux cooling-condenser, high-speed blade mixer and glass beads as grinding agent loaded in the mass ratio to liquid phase = 1.5:1. Liquid phase represents glacial acid solution in ethylcellosolve, ethylene glycol, 1,4-dioxane, isoamyl alcohol and n-butyl alcohol as a solvent. The concentration of acid in liquid phase is 3.4-4 mole/kg. Then method involves loading iodine in the amount 0.025-0.070 mole/kg of liquid phase, metallic manganese and manganese dioxide in the mole ratio = 2:1 and taken in the amount 11.8% of liquid phase mass. The process starts at room temperature and carries out under self-heating condition to 30-38°C to practically complete consumption of manganese dioxide. Prepared salt suspension is separated from beads and unreacted manganese and filtered off. Filtrate is recovered to the repeated process and prepared precipitate is purified by recrystallization. Invention provides simplifying method using available raw and in low waste of the process.

EFFECT: improved method of synthesis.

3 cl, 9 ex

FIELD: catalyst preparation methods.

SUBSTANCE: invention relates to preparation of manganese (III) acetylacetonate, which can be used as catalyst as well as vinyl monomer polymerization initiator. Method is implemented in aqueous medium with ammonium acetylacetonate freshly prepared by mixing acetylacetone with aqueous ammonia solution. Hydrogen peroxide is used as oxidant and sodium bicarbonate is additionally introduced into reaction mixture. Following consecutive operations are carried out: reaction of manganese (II) chloride tetrahydraye with sodium bicarbonate; separating thus formed manganese (II) bicarbonate in the form of paste; adding ammonia acetylacetonate and then hydrogen peroxide aqueous solution to the paste; and recovering manganese (III) acetylacetonate with yield 95%.

EFFECT: improved economical and environmental characteristics of process.

FIELD: organic chemistry, medicine, physiology.

SUBSTANCE: invention relates to agents for regulation (maintaining or suppression) of physical working ability and/or adaptation to different variants represented by solvated complex compounds of the general formula (I): Katm+[L1qEL2]Ann- x p.Solv (I) wherein L1 means aminothiols of the formula: R1NHCH(R2)(CH2)1-2SR3 wherein R1 means hydrogen atom (H), (C1-C20)-alkyl or RCO; R means (C1-C19)-alkyl; R2 means H or carboxyl; R3 means H, (C1-C20)-alkyl, (C2-C20)-alkenyl or benzyl; q = 1, 2 or 3; L2 means halogen atom, water and/or organic ligand. For example, bis-(N-acetyl-L-cysteinato)aquozinc (II) diheptahydrate suppresses physical working ability and in the dose 50 mg/kg increases reviving time of mice by 6 times and cats - by 2.8fold under conditions of acute hypoxia with hypercapnia, and increases reviving time of mice by 4 times under conditions of acute hypobaric hypoxia. Under the same conditions the known antihypoxic agents amtizol, acizol or mexidol are inactive or less active significantly by their activity. Bis-(N-acetyl-L-cysteinato)-ferrous (II) pentahydrate is more active as compared with the known antihypoxic agents and protects experimental animals in 4 variants of hypoxia. Bis-(N-acetyl-L-cysteinato)zinc (II) sulfate octahydrate is similar to enumerated compounds by its antihypoxic activity.

EFFECT: valuable medicinal properties of compounds.

4 cl, 1 dwg, 11 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the conjugates of formula (V)

or (VI) : wherein X is -CO-NH- or -O-; their use as radiopharmaceuticals, processes for their preparation, and synthetic intermediates used in such processes.

EFFECT: use as radiopharmaceuticals.

25 cl, 15 ex

FIELD: chemistry; medicine.

SUBSTANCE: inventions relate to novel marked with tritium analogue of physiologically active compound- uniformly marked with tritium tylosin of formula: . Said compound is drastic antibiotic.

EFFECT: extension of assortment of marked analogues of physically active compound, which are applied in organic chemistry, in biology and in medicine.

1 cl, 1 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

FIELD: biology.

SUBSTANCE: present invention relates to biotechnology, more specifically to obtaining nucleoside-5'-triphosphates, labelled with phosphorous-32 (phosphorous-33) in the alpha-position, and can be used for analysis in molecular biology, genetics and medical biochemistry. The method is realised through treatment of labelled nucleosidephosphate in a buffer solution with a mixture of deoxyribonucleoside monophosphate kinase of bacteriophage T5 and pyruvate kinase with subsequent chromatographic purification of the target product.

EFFECT: simple method of obtaining nucleoside-5'-triphosphates and stable output of the target product.

4 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula (Ia) and their application in radiological pharmaceutical compositions for linking to receptors associated with angiogenesis.

EFFECT: possible application in diagnostics or therapy, eg for malignant or cardiac diseases, endometriosis, inflammatory diseases, rheumatoid arthritis and sarcoma Kaposi.

FIELD: chemistry.

SUBSTANCE: claimed invention relates to highly labelled by tritium [methyl-3H]methyltosylate of formula: . Compound can be used in synthesis of labelled by tritium compounds, which are used in biological research.

EFFECT: obtaining of highly labelled tritium.

5 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to production of new tritiated analogues of physiologically active compounds - triterpene glycosides of holothurians Cucumaria of formula: .

EFFECT: there are produced new tritiated analogues of physiologically active compounds.

2 cl, 2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new described α-hederin of formula: uniformly marked with tritium is actually analog of α-hederin - biologically active saponin.

EFFECT: new effective biological properties.

1 cl, 1 ex

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