PSMA inhibitor derivatives for labelling with 99mTc via HYNIC, a radiopharmaceutical kit, radiopharmaceutical preparations and their use in prostate cancer diagnostics

Abstract

The subject matter of the invention is PSMA inhibitor-HYNIC derivatives of PSMA-L.sub.1-L.sub.2-HYNIC formula, aromatic and aliphatic hydrazone derivatives, a radiopharmaceutical kit for 99mTc isotope labelling, radiopharmaceutical preparation and its application for prostate cancer and its metastasis diagnostics.

Claims

1. PSMA-HYNIC inhibitor derivatives of general formula 1: ##STR00015## wherein: L.sub.1=L-Trp, L-2NaI, and L.sub.2=6Ahx, 4Amc and their pharmaceutically acceptable salts or esters.

2. Derivatives according to claim 1 being aliphatic hydrazone derivatives of general formula 2: ##STR00016## wherein: L.sub.1=L-Trp, L-2NaI; L.sub.2=6Ahx, 4Amc; RH, CH.sub.3, (CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nCH.sub.2OH, (CH.sub.2).sub.nCH.sub.2NO.sub.2, (CH.sub.2).sub.nCH.sub.2N(CH.sub.3).sub.2, (CH.sub.2).sub.nCH.sub.2X, (CH.sub.2).sub.nCHO, CHOCH.sub.3, (CH.sub.2).sub.nCHOCH.sub.3 XCl, Br, I, F and their pharmaceutically acceptable salts or esters.

3. Derivatives according to claim 1 being aromatic hydrazone derivatives of general formula 3: ##STR00017## wherein: L.sub.1=L-Trp, L-2NaI; L.sub.2=6Ahx, 4Amc RR.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5H, X, CH.sub.3, (CH.sub.2).sub.nCH.sub.3, OCH.sub.3, O(CH.sub.2).sub.nCH.sub.3, OH, NO.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, (CH.sub.2).sub.nNCH.sub.3, (CH.sub.2).sub.nN(CH.sub.3).sub.2, CF.sub.3, OCF.sub.3, SCH.sub.3, SO.sub.3Na, SO.sub.3K, SO.sub.2CH.sub.3, COO, COONa, COOK, (CH.sub.2).sub.nCOOH, (CH.sub.2).sub.nCOONa, (CH.sub.2).sub.nCOOK, CN XCl, Br, I, F and their pharmaceutically acceptable salts or esters.

4. Radiopharmaceutical preparation characterized in that it comprises one of the compounds defined in claims 1 to 3, which is linked via chemical bond to 99mTc isotope.

5. The radiopharmaceutical kit for labelling with 99mTc isotope characterized in that it comprises one of the compounds defined in claims 1 to 3, and excipients.

6. The kit according to claim 5 characterized in that it is in sterile lyophilisate form under inert gas atmosphere.

7. The kit according to any claim from 5 to 6, characterized in that the excipients are chosen from the group comprising tin(II) chloride, tricine, ethylenediaminetetraacetic acid (EDDA) and buffer agents.

8. The application of derivatives as defined in claims 1 to 3 for scintigraphy diagnostics of prostate cancer and its metastasis.

Description

FIGURES DESCRIPTION

[0023] FIG. 1 shows radiochromatograms of HPLC: A.sup.99mTc-PSMA-T4; B.sup.99mTc-4 PSMA-T4-(dimethylaminebenzen)hydrazone.

[0024] FIG. 2 shows the body scan and target SPECT-CT imaging with numerous visible metastases to the lymph nodes, bones and the abdominal cavity with intense radiopharmaceutical uptake.

EMBODIMENTS

[0025] The invention has been illustrated with the following embodiments, which are not intended to limit the scope of the invention.

[0026] New PSMA inhibitors comprising HYNIC as a chelator and tryptophane or naphtylalanine as lipophilicity modifying linkers have been synthesized on solid phase, whose preparation has been described in Example 1, while the synthesis of HYNIC-PSMA conjugates with free hydrazine group has been described in Example 2. The synthesis and purification method for the compounds according to the invention via transformation into HYNIC-PSMA hydrazone have been described in Example 3. Example 4 describes the preparation of the radiopharmaceutical kit for preparation of .sup.99mTc-HYNIC-PSMA comprising one of the PSMA inhibitors according to the invention, tin(II) chloride as a reducing agent, buffer agents and co-ligands for Technetium-99m such as tricine and EDDA. Examples 5 and 6 show the results of comparative in vitro and in vivo studies on new compounds according to the invention as compared to other preparations used in prostate cancer diagnostics, while Example 7 shows the results of preliminary SPECT studies on patients with prostate cancer using .sup.99mTc-HYNIC-PSMA according to the invention.

Example 1. Preparation of Glu(tBu)-Urea-Lys-NH.SUB.2 .Resin Support

[0027] The synthesis of the substance was carried out on solid phase being Wang polystyrene support, which is used in peptide synthesis.

[0028] Fmoc-L-Lys(Alloc) was attached to hydroxyl groups in the support in the manner described previously [7].

##STR00004## ##STR00005##

After the reaction had been completed, the support was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane, dichloromethane and dried in vacuum.

##STR00006## ##STR00007##

[0029] Double molar excess of triphosgene in dry dichloromethane was cooled in dry-ice bath to 50 C. The solution of L-Glu(tBu)OtBu*HCl 0.75% N,N-diisopropylethylamine in dry dichloromethane was prepared separately using sixfold molar excess. The solution was slowly added dropwise into triphosgene solution with stirring so that the temperature would not exceed 50 C. After dropping had been completed, the bath was removed and the solution was stirred until it reached room temperature. To the so obtained isocyanate solution, the dried resin with L-Lys(Alloc) was added and the mixture was stirred for 3 days. The resin was filtered, washed with dichloromethane and dried in vacuum.

##STR00008##

[0030] The Alloc detachment reaction was carried out in darkness. In the vessel made of dark glass, Pd[P(Ph).sub.3].sub.4 (tetrakis(triphenylphosphine)palladium(0)) catalyst was dissolved in 10% morpholine solution in dry dichloromethane in molar ratio of 0.1. The swollen resin was stirred for 3 hours in the previously prepared solution. The resin was filtered and washed with: N,N-dimethylformamide, 2% N,N-diisopropylethylamine solution in N,N-dimethylformamide, 20 mg/ml sodium diethylthiocarbamate in N,N-dimethylformamide, N,N-dimethylformamide and dichloromethane and then dried in vacuum.

Example 2. Synthesis of PSMA-T4 (PSMA-LTrp-4Amc-HYNIC

[0031] ##STR00009##

[0032] Polystyrene Wang resin with Glu(tBu)-urea-Lys-NH2 was used in the reaction. To the free amine group of Lysine, the Fmoc-L-Trp(Boc) was attached using 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminemorpholino)]uronium hexafluorophosphate (COMU) in the manner described previously [8,9]. The resin was placed in a vessel for peptide synthesis and swollen by stirring with dichloromethane. In a separate vessel, threefold molar excess of Fmoc-L-Trp(Boc), threefold molar excess of COMU and N,N-dimethylformamide were placed and stirred until dissolved. Then N,N-diisopropylethylamine was added and stirred for 5 minutes. Dichloromethane was added and stirred. The activated amino acid solution prepared in such a manner was transferred to the vessel with swollen resin and stirred for 1 hour. The resin was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane and dichloromethane.

[0033] The Fmoc protection group was removed in the manner usually used in peptide synthesis [10]. To the vessel with swollen resin, 20% piperidine solution in N,N-dimethylformamide was poured and stirred for 30 minutes After that time, pyridine solution was changed for the fresh one and the mixture was stirred for another 30 minutes. The resin was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane and at the end with dichloromethane.

##STR00010##

[0034] Fmoc-4Amc attachment and detachment of the Fmoc protection group were carried out in the manner analogous to the one used in the previous synthetic step. The resin was swollen by stirring in dichloromethane for at least 20 minutes. Threefold molar excess of Fmoc-4Amc, threefold molar excess of COMU and N,N-dimethylformamide were placed in a separate vessel and stirred until dissolved. Then N,N-diisopropylethylamine was added and stirred for 5 minutes. Dichloromethane was added and stirred. The activated amino acid solution prepared in such a way was transferred into the vessel with the swollen resin and stirred for 1 hour. The support was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane and, finally, with dichloromethane.

[0035] To the vessel with swollen support, 20% piperidine solution in N,N-dimethylformamide was poured and stirred for 30 minutes After that time, piperidine solution was changed for the fresh one and the mixture was stirred for another 30 minutes. The resin was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane and dichloromethane.

##STR00011##

[0036] HYNIC-Boc attachment was carried out in the manner analogous to the one used in the previous synthetic step, but with longer reaction time. The resin was swollen by stirring in dichloromethane for at least 20 minutes. Threefold molar excess of HYNIC-Boc, threefold molar excess of COMU and N,N-dimethylformamide were placed in a separate vessel and stirred until dissolved. Then N,N-diisopropylethylamine was added and stirred for 5 minutes. Dichloromethane was added and stirred. The solution of activated amino acid prepared in such a way was transferred into the vessel with swollen resin and stirred for 2 hours. The resin was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane and with dichloromethane and dried in vacuum.

##STR00012##

[0037] In a separate vessel, the solution of trifluoroacetic acid with addition of triisopropylsilane, phenol, thioanisole, water and 1,2-ethanedithiole was prepared in order to detach the product from the resin and to remove the protection groups. The ready solution was transferred to the vessel comprising the resin and stirred for 3 hours. The product was precipitated with diethyl ether. The precipitate was centrifuged and washed with diethyl ether. After it had been dissolved in 0.1% trifluoroacetic acid solution, it was heated on a vacuum evaporator up to 60 C. at 800 mbar for 1 hour. The obtained solution was lyophilized.

[0038] The lyophilized product was dissolved in acetonitrile/water solvent mixture with addition of 0.1% trifluoroacetic acid and then purified on a preparative polymeric HPLC reversed phase column. Collected fractions containing the compound (PSMA-T4) fulfilling the purity requirements were combined and lyophilized.

In the way analogous to PSMA-T4, the following combinations were obtained:
PSMA-NaI-Amc-HYNIC (PSMA T1) using Fmoc-L2NaI instead of Fmoc-LTrp.
PSMA-NaI-6Ahx-HYNIC (PSMA-T2) using Fmoc-L2NaI instead of Fmoc-LTrp.
PSMA-LTrp-6Ahx-HYNIC (PSMA-T3) using Fmoc-6Ahx instead of Fmoc4Amc.

TABLE-US-00001 TABLE 1 Physicochemical data of PSMA-T1, PSMA-T2, PSMA-T3, PSMA-T4 compounds. Molecular formula; Solubility according HPLC Compound MW; MS: m/z to Ph. Eur. Form purity PSMA-T1 C.sub.39H.sub.50N.sub.8O.sub.10; water: slightly soluble White 97.0% 790.86 g/mol; pH 7.4 phosphte buffer: lyophilisate m/z = 791.37[M + H].sup.+ very slightly soluble ethanol: soluble PSMA-T2 C.sub.35H.sub.47N.sub.9O.sub.10; water: practicaly insoluble White 95.0% 764.34 g/mol; pH 7.4 phosphte buffer: lyophilisate m/z = 755.35[M + H].sup.+ very slightly ethanol: soluble PSMA-T3 C.sub.35H.sub.47N.sub.9O.sub.10; water: insoluble White 97.0% 753.34 g/mol; pH 7.4 phosphte buffer: lyophilisate m/z = 754.35[M + H].sup.+ very slightly soluble ethanol: soluble PSMA-T4 C.sub.37H.sub.49N.sub.9O.sub.10; water: practicaly insoluble White 97.0% 779.36 g/mol; pH 7.4 phosphte buffer: lyophilisate m/z = 780.31[M + H].sup.+ very slightly soluble ethanol: soluble

Example 3. PSMA-T4 (PSMA-LTrp-4Amc-HYNIC) Hydrazone Synthesis

[0039] ##STR00013##

wherein:
RR.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5H, X, CH.sub.3, (CH.sub.2).sub.nCH.sub.3, OCH.sub.3, O(CH.sub.2).sub.nCH.sub.3, OH, NO.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, (CH.sub.2).sub.nNCH.sub.3, (CH.sub.2).sub.nN(CH.sub.3).sub.2, CF.sub.3, OCF.sub.3, SCH.sub.3, SO.sub.3Na, SO.sub.3K, SO.sub.2CH.sub.3, COOH, COONa, COOK, (CH.sub.2).sub.nCOOH, (CH.sub.2).sub.nCOONa, (CH.sub.2).sub.nCOOK, CN

XCl, Br, I, F

[0040] or

##STR00014##

wherein:
R.sup.1H, CH.sub.3, (CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nCH.sub.2OH, (CH.sub.2).sub.nCH.sub.2NO.sub.2, (CH.sub.2).sub.nCH.sub.2N(CH.sub.3).sub.2, (CH.sub.2).sub.nCH.sub.2X, (CH.sub.2).sub.nCHO, CHOCH.sub.3, (CH.sub.2).sub.nCHOCH.sub.3

XCl, Br, I, F

[0041] Crude, unpurified PSMA-T4 inhibitor is used for hydrazone synthesis. The compound is dissolved in water/ethanol solution and alcohol solution of suitable aldehyde is added in tenfold molar excess in relation to the inhibitor. The reaction is carried out for 10 to 20 minutes in room temperature depending on the aldehyde used. The reaction mixture comprising 4-(dimethylaminebenzo)hydrazone of PSMA-T4 is purified on a preparative polymeric HPLC reversed phase column. Collected PSMA-T4 hydrazone fractions fulfilling the purity requirements are combined and lyophilized. The applied modification according to the invention allows to obtain the compound whose retention time differs significantly from the one for PSMA-T4 and the majority of the impurities difficult to separate in the case of unmodified peptide. This simplifies the purification process of hydrazone derivatives and enhances its yield. Obtained compounds exhibit high purity, i.e. above 99%, and higher stability in solutions. For example, 4-(dimethylaminebenzeno)hydrazone of PSMA-T4 was stable in the pH=7 phosphate buffer solution at least for a day.

Examples of PSMA-T4 hydrazones and their physicochemical characteristics are presented in Table 2.

TABLE-US-00002 TABLE 2 Physicochemical data of chosen hydrazones of PSMA-T4 compound Molecular formula; Solubility according HPLC Compound M.sub.cz; MS: m/z to Ph. Eur. Form purity Benzenesulfonic acid C.sub.44H.sub.53N.sub.9O.sub.13S; water: soluble White or 97.0% hydrazone of PSMA-T4 948,00 g/mol; pH 7.4 phosphte buffer: slightly m/z = 948.35 soluble yellow [M + H].sup.+ ethanol: soluble lyophilizate 4- C.sub.46H.sub.58N.sub.10O.sub.10; water: practicaly insoluble yellow .sup.99% (dimethylaminebenzene) 911.01 g/mol; pH 7.4 phosphte buffer: lyophilizate hydrazone of PSMA-T4 m/z = 911.44 soluble [M + H].sup.+ ethanol: soluble Vanilin hydrazine C.sub.45H.sub.55N.sub.9O.sub.12; water: practicaly insoluble White 97.0% of PSMA-T4 M = 913.97 g/mol; pH 7.4 phosphte buffer: lyophilizate m/z = 914.40 slightly soluble [M + H].sup.+ ethanol: soluble

Example 4. Preparation of Radiopharmaceutical Kit for Preparing .SUP.99m.Tc-HYNIC-PSMA

[0042] The pharmaceutical kit according to the invention comprises a dry composition of ingredients necessary for labelling with Technetium-99m, sealed under nitrogen atmosphere.

[0043] The dry composition comprises PSMA inhibitor according to the invention, for instance PSMA-T4 compound or its hydrazone derivative, reducing agent SnCl.sub.22 H.sub.2O, coligands for obtaining a stable complex with radiometal: tricine and ethylenediamine-(N,N)-diacetic acid (EDDA) as well as phosphate buffer for pH adjusting.

[0044] As part of the pharmaceutical method for preparation of the kit, in order to obtain the dry composition, 0.1 M pH 7.4 phosphate buffer solution is prepared, in which the solution of PSMA-T4 or its hydrazone derivative at the concentration of 0.01 M to 0.05 M, tricine at the concentration of 0.06 mM to 0.56 mM, EDDA at the concentration of 0.03 mM to 0.09 mM is prepared. The solution prepared in such a way is purged with gaseous nitrogen and then the solution of 0.1 M to 0.4 M SnCl.sub.22H.sub.2O in the 0.1 M to 0.5 M hydrochloric acid is added. The solution is then filtered through the 0.22 m antimicrobial filter and dispensed into 1 mL portions in glass vials and freezed. Next, the freeze-drying process is carried out. After the freeze-drying is finished, the lyophilizer chamber containing the vials is filled with nitrogen and inside the chamber, the vials are sealed with stoppers and after their removal from the chamber they are also sealed with metal caps to prevent them from unsealing. In such a way, a sterile and free of bacterial endotoxins radiopharmaceutical kit of the following exemplary composition is prepared:

PSMA-T4 or its hydrazone derivative 20 g

Tricine 50 mg

EDDA 5 mg

[0045] SnCl.sub.22H.sub.2O 40 g
Na.sub.2HPO.sub.412H.sub.2O 29 mg
NaH.sub.2PO.sub.42H.sub.2O 3.0 mg.

[0046] As part of the method for obtaining radiopharmaceutical preparation with the use of the kit containing the above-mentioned composition, 0.5-2.5 mL of sodium pertechnetate Na.sup.99mTcO.sub.4 solution of required radioactivity (300-1500 MBq) is introduced to the vial containing the dry composition. After dissolving, the solution is heated at 100 C. for 15-30 minutes and then cooled down in room temperature for 20 minutes. Radiochemical purity of the preparation obtained in such a way and assessed with thin layer chromatography is above 90%. The radiopharmaceutical preparations obtained as a result of Technetium-99m labelling of PSMA-T4 and its hydrazone derivatives are identical as it has been confirmed by HPLC and LC/MS methods (see FIG. 1).

Example 5. Biological Activity In Vitro

[0047] An important advantage of the compounds described herein is their high affinity to the PSMA receptor present on prostate cancer cells. Competition ligand binding in vitro studies carried out on LNCaP carcinoma cell membranes allowed for determination of IC50 values, namely the concentrations at which the dissociation equilibrium is maintained. The studies were carried out using 96-well plates equipped with filters, to which the identical amount of membranes was applied. Next, increasing concentrations of inactive formulations and active competitive .sup.131I-MIP1095 of high receptor affinity were added. After 2-hour incubation, the filters were washed and radioactivity was measured. IC50 values were determined using GraphPad Prism 7.0 statistics software.

[0048] In the course of the studies, IC50 values for the compounds according to the invention were from 75 nM to 97 nM respectively, which means that the compounds according to the invention have over 7 times higher affinity as compared to the commonly available tracer for prostate cancer diagnosticsPSMA 11 (Table 3).

TABLE-US-00003 TABLE 3 In vitro comparison of PSMA-T1, PSMA-T2, PSMA-T3, PSMA-T4 and PSMA 11 affinity to PSMA receptor. PSMA-T1 PSMA-T2 PSMA-T3 PSMA-T4 (PSMA- (PSMA- (PSMA- (PSMA- Nal-Amc- Nal-AHX- Trp-AHX- Trp-Amc- PSMA 11 HYNIC) HYNIC) HYNIC) HYNIC) IC50 [nM] 719 97 143 75 80 R.sup.2 0.956 0.963 0.926 0.984 0.972

Example 6. Biodistribution of PSMA Preparations Labelled with Technetium-99m

[0049] In comparative biodistribution studies on three PSMA preparations labelled with 99mTc, healthy BALB/c mice (males with body weight of 18-27 g) were used. 0.1 mL preparations with the activity of around 6 MBq were administered to the tail vein. After 4 hours of p.i.v. administration, animals were subjected to inhalation euthanasia and then required organs were collected and weighted, and the radioactivity accumulated therein was measured. Preparation accumulation in selected organs or tissues is given as % ID (percentage of injected dose) and % ID/g (percentage of injected dose per gram of the organ or tissue). Biodistribution data in Table 4 indicate that the critical organ for Technetium PSMA preparations is kidneys, wherein the retention levels of radioactivity in kidneys after administration of preparations based on PSMA-T3 and PSMA-T4 analogues were significantly lower than in the case of 99mTc-iPSMA reference preparation.

TABLE-US-00004 TABLE 4 Biodistribution data .sup.99mTc-iPSMA 4 h p.i.v. .sup.99mTc-PSMA-T1 4 h p.i.v. .sup.99mTc-PSMA-T2 4 h p.i.v. mice n = 3 mice n = 3 mice n = 3 (mass 22.6 g 4.2 g) (mass 26.1 g 6.6 g) (mass 26.6 g 2.5 g) Organ % ID SD % ID/g SD % ID SD % ID/g SD % ID SD % ID/g SD blood 0.35 0.11 0.30 0.06 0.43 0.12 thyroid 0.10 0.04 0.73 0.38 0.10 0.04 0.64 0.22 0.17 0.03 0.94 0.24 heart 0.04 0.01 0.35 0.15 0.02 0.00 0.15 0.07 0.04 0.01 0.27 0.08 lungs 0.10 0.03 0.55 0.17 0.10 0.06 0.53 0.21 0.11 0.02 0.72 0.26 liver 0.57 0.06 0.50 0.18 0.63 0.48 0.43 0.24 0.77 0.22 0.53 0.11 spleen 0.23 0.05 1.33 0.45 0.61 0.60 1.62 1.83 0.37 0.19 1.72 0.50 pancreas 0.06 0.03 0.44 0.21 0.07 0.02 0.54 0.23 0.12 0.06 0.63 0.28 kidneys 65.75 23.44 190.64 113.13 57.60 12.57 159.27 71.09 67.72 4.66 156.05 28.41 small 0.49 0.24 0.27 0.14 1.75 2.61 0.83 1.25 0.32 0.06 0.17 0.03 intestine large 1.20 0.94 1.23 0.98 0.50 0.20 0.39 0.07 1.39 0.27 0.97 0.05 intestine stomach 0.06 0.02 0.34 0.10 0.12 0.13 0.62 0.70 0.09 0.02 0.38 0.10 bone 0.63 0.60 0.42 0.24 0.31 0.13 muscle 0.19 0.08 0.12 0.11 0.50 0.54 urine 26.83 24.37 33.77 12.71 20.68 5.54 rest of 4.18 0.18 4.47 0.69 7.73 1.45 body .sup.99mTc-PSMA-T3 4 h .sup.99mTc-PSMA-T4 4 h p.i.v. p.i.v. mice n = 3 (mass 24.2 g 3.9 g) mice n = 5 (mass 19 g 1.1 g) Organ % ID SD % ID/g SD % ID SD % ID/g SD blood 0.35 0.06 0.14 0.04 thyroid 0.36 0.23 2.04 1.26 0.00 0.00 0.14 0.15 heart 0.02 0.01 0.12 0.10 0.01 0.00 0.08 0.04 lungs 0.06 0.04 0.32 0.19 0.03 0.01 0.23 0.06 liver 0.98 0.30 0.68 0.18 0.12 0.04 0.12 0.04 spleen 0.18 0.18 0.58 0.42 0.04 0.02 0.27 0.11 pancreas 0.04 0.02 0.31 0.23 0.02 0.01 0.30 0.08 kidneys 23.05 9.05 60.37 29.88 9.92 2.36 37.54 9.40 small 0.91 0.92 0.59 0.58 0.19 0.06 0.12 0.05 intestine large 0.99 0.31 0.78 0.20 0.86 1.00 0.84 0.95 intestine stomach 0.18 0.14 1.04 0.95 0.01 0.01 0.12 0.03 bone 0.27 0.01 0.00 0.00 0.15 0.12 muscle 0.05 0.03 0.07 0.05 urine 67.90 11.46 86.64 2.86 rest of 5.04 1.64 2.05 0.70 body

Example 7. Clinical Application of PSMA-T4 Labelled with Technetium-99m

[0050] SPECT-CT study was carried out 1-3 hours after intravenous administration of 99mTc-PSMA-T4 preparation according to the invention to 9 patients with prostate cancer. Imaging was performed using gamma camera SPECT-CT Symbia T2, Siemens. 9 patients post prostate cancer radical therapy (total prostatectomy or final radiotherapy) were enrolled in the studies. Patients with biochemical progress and clinical data concerning the disease relapse were examined for disease recurrence. Proper biodistribution of radiopharmaceuticals with high activity was observed in the liver, spleen, kidneys, salivary glands, intestine and bladder. In 7 patients, a local relapse was observed, metastases to lymph nodes and/or bones with intense tracer uptake. In 2 patients with a negative MRI result, a local relapse was suspected.

REFERENCES

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