CN114805417B - Nuclide-labeled ornithine and preparation method and application thereof - Google Patents
Nuclide-labeled ornithine and preparation method and application thereof Download PDFInfo
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- CN114805417B CN114805417B CN202210484624.XA CN202210484624A CN114805417B CN 114805417 B CN114805417 B CN 114805417B CN 202210484624 A CN202210484624 A CN 202210484624A CN 114805417 B CN114805417 B CN 114805417B
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- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 title claims abstract description 63
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 title claims abstract description 63
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 229960003104 ornithine Drugs 0.000 title claims abstract description 63
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- 238000006243 chemical reaction Methods 0.000 claims description 58
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
- A61K51/0406—Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/06—Aluminium compounds
- C07F5/069—Aluminium compounds without C-aluminium linkages
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- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention provides ornithine marked by nuclide, a preparation method and application thereof, and belongs to the technical field of nuclear medicine radiopharmaceuticals. The invention provides a compound having a structure shown in formula I 68 Ga-marked ornithine 68 Ga-NOTA-Orn) and has a structure represented by formula II 18 Ornithine marked by F 18 F-AlF-NOTA-Orn) uses macrocyclic compound NOTA-Bn-SCN as bifunctional chelating agent, and has good stability; with nuclides 68 Ga or 18 F is used as a marker, has good targeting property, is higher in uptake in tumor tissues, has higher tumor/normal tissue ratio (i.e. target/non-target ratio), has good application prospect in the aspect of being used as a PET-CT tumor imaging agent, can meet the dosage requirement of clinical diagnosis, and is more beneficial to clinical transformation.
Description
Technical Field
The invention relates to the technical field of nuclear medicine radiopharmaceuticals, in particular to nuclide-labeled ornithine, and a preparation method and application thereof.
Background
Positron Emission Tomography (PET) technology is taken as an important representative of functional imaging, and is increasingly mature in application in tumor diagnosis, stage and subdivision, curative effect monitoring and evaluation and radiotherapy target area delineation, and the technology gradually develops and applies to predictability and specificity. [ 18 F]Fluorodeoxyglucose ([ solution ]) 18 F]FDG) is the most clinically used PET imaging agent for tumor metabolism, but due to its prevalence of metabolism, there is also a higher uptake in non-tumor tissues such as brain, inflammation, tumor-like lesions, etc., and diagnosis of some tumors such as mucous adenocarcinoma, bronchoalveolar carcinoma, prostate cancer, etc., which do not cause significant glucose metabolism abnormality is liable to cause false negative results. Thus, the research and development is more [ 18 F]FDG has higher sensitivity and higher tumor sensitivityThe tracer with good specificity has important significance.
Polyamine is a substance which is a metabolic control substance widely distributed in living bodies and is essential for maintaining vital activities such as cell growth and differentiation. Under normal physiological conditions, polyamines are regulated by a range of synthetic, catabolic and transmembrane transport mechanisms, thereby maintaining intracellular polyamine levels in a dynamic equilibrium state. Studies have shown that tumor development is associated with an imbalance in polyamine metabolism, and that rapid proliferation of tumor cells is dependent on intracellular high polyamine levels, manifested as upregulation of polyamine synthase expression and activity within the tumor cells. Ornithine is used as a main raw material for in vivo polyamine synthesis, and is decarboxylated by Ornithine Decarboxylase (ODC) to synthesize polyamine. ODC is a first-order rate-limiting enzyme that regulates intracellular polyamine biosynthesis, and has an important role in regulating intracellular polyamine levels. Studies have shown that overexpression of oncogenes induces the production of a large amount of ODC, resulting in increased intracellular polyamine levels, such as a significant increase in ODC activity detected in glioma, gastric cancer, prostate cancer, melanoma, breast cancer, colorectal cancer, and the like. Changes in the intracellular expression levels of ODC can also affect various growth factor functions, such as stimulation of oncogene expression, etc. In addition, the activity of ODC begins to increase early in the cellular stimulated phase, which is earlier than the change in DNA synthesis, and thus ODC is considered a biological factor in response to "super-early" and has become a target for anti-tumor therapy.
Ornithine is used as a main material for polyamine synthesis, and can realize tumor imaging after nuclide labeling, for example, patent WO2011133115A1 discloses a series of single photon nuclides 99m Tc-labeled ornithine and derivatives thereof as tumor imaging agents for Single Photon Emission Computed Tomography (SPECT) techniques. However, the above 99m Tc-labeled ornithine is used for Single Photon Emission Computed Tomography (SPECT) imaging, but the image resolution is not high enough when applied to PET imaging.
Disclosure of Invention
In view of the above, the present invention aims to provide a nuclide-labeled ornithine, a preparation method and an application thereof, and the nuclide-labeled ornithine provided by the present invention has high resolution of PET imaging images.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a nuclide-labeled ornithine, which comprises a structure shown in a formula I 68 Ga-labeled ornithine or ornithine having a structure represented by formula II 18 F-labelled ornithine:
the invention provides a preparation method of ornithine marked by nuclide in the technical scheme,
the said 68 The preparation method of Ga-marked ornithine comprises the following steps: NOTA-Bn-SCN-Orn, 68 Mixing Ga source and first acetate buffer solution to perform first chelation reaction to obtain 68 Ga-labeled ornithine;
the said 18 The preparation method of the F-marked ornithine comprises the following steps: NOTA-Bn-SCN-Orn, 18 F Source and second acetate buffer, alCl 3 Mixing with dimethyl sulfoxide to perform second chelation reaction to obtain 18 F-labelled ornithine;
NOTA-Bn-SCN-Orn。
preferably, the quality and the weight of the NOTA-Bn-SCN-Orn 68 The ratio of the radioactivity of the Ga source is 0.01-0.2 mg: 2.0-200 mCi; the said 68 Ga source is 68 Aqueous hydrochloric acid of Ga;
the quality and the quality of the NOTA-Bn-SCN-Orn 18 The ratio of the radioactivity of the F source is 0.01-0.2 mg: 0.001-1 Ci.
Preferably, the pH of the first acetate buffer and the second acetate buffer are independently 3 to 5.
Preferably, the temperature of the first chelation reaction and the second chelation reaction are independently 35-110 ℃ and the time is independently 5-25 min.
Preferably, the first chelation reaction and the second chelation reaction further comprise performing Sep Pak C18 column purification on the obtained chelation reaction solution to obtain the ornithine marked by nuclide.
Preferably, the Sep Pak C18 column purification comprises washing with water and ethanol sequentially.
The invention also provides application of the nuclide-labeled ornithine according to the technical scheme or the nuclide-labeled ornithine obtained by the preparation method according to the technical scheme in serving as a PET-CT tumor imaging agent.
Preferably, the tumor comprises an epithelial-derived tumor.
The invention provides a nuclide-labeled ornithine, which comprises a structure shown in a formula I 68 Ga-marked ornithine 68 Ga-NOTA-Orn) or having a structure represented by formula II 18 Ornithine marked by F 18 F-AlF-NOTA-Orn). The ornithine marked by the nuclide provided by the invention takes the macrocyclic compound NOTA-Bn-SCN as the bifunctional chelating agent, has good stability, and can realize nuclide 68 Ga or 18 F, marking; has good targeting property, higher uptake in tumor tissues, higher tumor/normal tissue ratio (i.e. target/non-target ratio), good application prospect in the aspect of being used as PET-CT tumor imaging agent, can meet the application requirement of tumor diagnosis, and is more beneficial to clinical transformation.
The invention provides a preparation method of ornithine marked by nuclide. The invention utilizes nuclides 68 Ga or 18 F labeling NOTA-Bn-SCN-Orn (precursor), and synthesizing in one step 68 Ga or 18 F marked ornithine, the raw materials are easy to obtain, the process is simple, the operation is easy, and the automatic preparation can be realized; furthermore, the radiochemical yield of the nuclide-labeled ornithine is 45-50%, and the yield is high.
As shown in the test results of the examples, 68 the radiochemical purity of the Ga-NOTA-Orn injection is more than 97%. An activity concentration of 25MBq/mL 68 The Ga-NOTA-Orn injection has radiochemical purity of 97%, 97% in 30min, 60min, 90min and 120min97% and 96% are all above 95%, indicating 68 Ga-NOTA-Orn has excellent in vitro stability. Description of aberrant toxicity experiments 68 Ga-NOTA-Orn injection has no toxicity to organism. In injection 68 After Ga-NOTA-Orn injection, obvious imaging agent concentration is formed at the tumor part, the contrast agent is well reserved, the relative uptake ratio of tumor/muscle is about 8.82 at 90min, and the distinction from surrounding tissues is obvious. In addition to kidneys and pancreas, contrast to tumor tissue uptake, contrast agent uptake by other normal tissues or organs is low.
Drawings
FIG. 1 is an HPLC ultraviolet chromatogram of NOTA-Bn-SCN-Orn;
FIG. 2 is a mass spectrum of NOTA-Bn-SCN-Orn;
FIG. 3 is a schematic view of 68 HPLC radiogram of Ga-NOTA-Orn;
FIG. 4 is a diagram of 68 TLC spectra of Ga-NOTA-Orn;
FIG. 5 is a schematic view of a display 68 PET-CT image of Ga-NOTA-Orn in tumor animal model.
Detailed Description
The invention provides a nuclide-labeled ornithine, which comprises a structure shown in a formula I 68 Ga-labeled ornithine or ornithine having a structure represented by formula II 18 F-labelled ornithine:
the invention provides a preparation method of ornithine marked by nuclide,
68 the preparation method of Ga-marked ornithine comprises the following steps: NOTA-Bn-SCN-Orn, 68 Mixing Ga source and first acetate buffer solution to perform first chelation reaction to obtain 68 Ga-labeled ornithine;
the said 18 The preparation method of the F-marked ornithine comprises the following steps: NOTA-Bn-SCN-Orn, 18 F Source and second acetate buffer, alCl 3 Mixing with dimethyl sulfoxide for second chelationThe synthesis reaction is carried out to obtain 18 F-labelled ornithine;
NOTA-Bn-SCN-Orn。
in the present invention, all raw material components are commercially available products well known to those skilled in the art unless specified otherwise.
In the present invention, 68 the preparation method of Ga-marked ornithine comprises the following steps: NOTA-Bn-SCN-Orn, 68 Mixing Ga source and first acetate buffer solution to perform first chelation reaction to obtain 68 Ga-labeled ornithine.
In the present invention, the NOTA-Bn-SCN-Orn is preferably purchased or self-made. In the invention, the preparation method of the NOTA-Bn-SCN-Orn preferably comprises the following steps:
activating Wang resin to obtain activated resin;
mixing the activated resin, boc-Orn (Fmoc) -OH, 4-dimethylaminopyridine and 1, 3-diisopropylcarbodiimide, performing a coupling reaction in a protective atmosphere, mixing the obtained Boc-Orn (Fmoc) -resin, pyridine and acetic anhydride for a capping reaction, and then performing Fmoc-removal reaction to obtain Boc-Orn-resin;
Boc-Orn(Fmoc)-OH。
mixing the Boc-Orn-resin, NOTA-Bn-SCN, DIEA and an organic solvent for addition reaction to obtain NOTA-Bn-SCN-Boc-Orn-resin;
and cutting the NOTA-Bn-SCN-Boc-Orn-resin in a cutting fluid and purifying to obtain the NOTA-Bn-SCN-Orn.
The Wang resin is activated to obtain the activated resin. In the present invention, the activation is preferably performed using an activating reagent, preferably N, N-Dimethylformamide (DMF); the activation temperature is preferably 10 to 30 ℃, more preferably 20 to 25 ℃, and in particular embodiments of the present invention, activation is preferably performed at room temperature; the activation time is preferably 10 to 60 minutes, more preferably 20 to 50 minutes, and still more preferably 30 to 40 minutes; the amount of the activating agent is not particularly limited, and the Wang resin can be immersed; the purpose of the activation is to activate the Wang resin surface groups to facilitate subsequent reactions. After the activation is completed, the invention preferably further comprises the step of carrying out solid-liquid separation on the obtained activation system, wherein the obtained solid product is activated resin. The solid-liquid separation is not particularly limited, and a solid-liquid separation method well known to those skilled in the art may be employed, and specifically, filtration is preferably performed by using a sand core funnel.
After the activated resin is obtained, the activated resin, boc-Orn (Fmoc) -OH, 4-dimethylaminopyridine and 1, 3-diisopropylcarbodiimide are mixed, a coupling reaction is carried out under a protective atmosphere, the obtained Boc-Orn (Fmoc) -resin, pyridine and acetic anhydride are mixed for end-capping reaction, and Fmoc-removal reaction is carried out to obtain the Boc-Orn-resin.
In the present invention, the ratio of the amounts of Wang resin, boc-Orn (Fmoc) -OH, 4-Dimethylaminopyridine (DMAP) and 1, 3-Diisopropylcarbodiimide (DIC) is preferably 1g: 1-4 mmol: 3-12 mmol:3 to 12mmol, more preferably 1g:1.5 to 3.5mmol: 4-10 mmol:4 to 10mmol, more preferably 1g: 2-3 mmol: 5-8 mmol: 5-8 mmol.
The present invention is not particularly limited to the above-mentioned mixing, and the raw materials may be uniformly mixed, specifically, stirring and mixing.
The protective atmosphere is not particularly limited, and protective atmospheres well known to those skilled in the art, such as nitrogen, argon or helium, are used. In the present invention, the temperature of the coupling reaction is preferably 10 to 30 ℃, more preferably 20 to 25 ℃, and in the specific embodiment of the present invention, the coupling reaction is preferably performed under room temperature conditions; the coupling reaction time is preferably 1 to 5 hours, more preferably 2 to 4 hours, and still more preferably 3 hours. After the coupling reaction is completed, the present invention preferably further comprises subjecting the obtained coupling reaction solution to solid-liquid separation, and washing the obtained solid product to obtain Boc-Orn (Fmoc) -resin. The solid-liquid separation is not particularly limited, and a solid-liquid separation method well known to those skilled in the art may be employed, and specifically, filtration is preferably performed by using a sand core funnel. In the present invention, the washing solvent for washing preferably includes DMF, and the number of times of washing is preferably 4 to 6, more preferably 5; the ratio of the amount of Boc-Orn (Fmoc) -resin to the amount of single-wash solvent is preferably 1mmol:4 to 6mL, more preferably 1mmol:5mL.
In the present invention, the volume ratio of pyridine to acetic anhydride is preferably 1:0.5 to 1.1, more preferably 1:0.8 to 1. The present invention is not particularly limited to the above-mentioned mixing, and the raw materials may be uniformly mixed, specifically, stirring and mixing. In the present invention, the temperature of the capping reaction is preferably 10 to 30 ℃, more preferably 20 to 25 ℃, and in the specific embodiment of the present invention, the capping reaction is preferably performed under room temperature conditions; the capping reaction time is preferably 10 to 60 minutes, more preferably 20 to 50 minutes, and still more preferably 30 to 40 minutes.
After the end capping reaction is completed, the method preferably further comprises the steps of carrying out solid-liquid separation on the obtained end capping reaction liquid, and washing the obtained solid product to obtain the end capped Boc-Orn (Fmoc) -resin. The solid-liquid separation is not particularly limited, and a solid-liquid separation method well known to those skilled in the art may be employed, and specifically, filtration is preferably performed by using a sand core funnel. In the present invention, the washing solvent for washing preferably includes DMF, and the number of times of washing is preferably 4 to 6, more preferably 5; the ratio of the amount of Boc-Orn (Fmoc) -OH to the amount of single-use washing solvent is preferably 1mmol:4 to 6mL, more preferably 1mmol:5mL.
In the present invention, the Fmoc removing reagent for Fmoc group removal reaction preferably comprises a piperidine solution; the solvent in the piperidine solution preferably comprises DMF; the volume concentration of the piperidine solution is preferably 15 to 25%, more preferably 20%. The Fmoc group removing reaction preferably includes sequentially performing a first Fmoc group removing reaction and a second Fmoc group removing reaction; the Fmoc group removal reaction is preferably carried out under stirring. In the present invention, the temperature of the first Fmoc-removing reaction and the second Fmoc-removing reaction is independently preferably 10 to 30 ℃, more preferably 20 to 25 ℃, and in the specific embodiment of the present invention, is preferably performed under room temperature conditions; the time of the first Fmoc group removal reaction and the second Fmoc group removal reaction is independently preferably 5 to 15 minutes, more preferably 8 to 12 minutes, and even more preferably 10 minutes. In a specific embodiment of the present invention, the blocked Boc-Orn (Fmoc) -resin is preferably mixed with an Fmoc removing reagent for the first Fmoc group removing reaction, solid-liquid separated, and the Fmoc removing reagent is added to the obtained solid product to mix for the second Fmoc group removing reaction. In the present invention, the solid-liquid separation method is not particularly limited, and may be any solid-liquid separation method known to those skilled in the art, such as filtration, and the filtration is preferably performed using a sand core funnel. The ratio of the amount of Boc-Orn (Fmoc) -OH to the amount of Fmoc-removing reagent for the first Fmoc-removing reaction is preferably 1mmol:5 to 15mL, more preferably 1mmol:10mL; the ratio of the amount of the Fmoc-removing reagent used for the reaction of Boc-Orn (Fmoc) -OH to the second Fmoc-removing reagent is preferably 1mmol:5 to 15mL, more preferably 1mmol:10mL. After the Fmoc group removal reaction is completed, the method preferably further comprises the steps of carrying out solid-liquid separation on the obtained Fmoc group removal reaction liquid, and washing the obtained solid product to obtain the Boc-Orn-resin. The solid-liquid separation is not particularly limited, and a solid-liquid separation method well known to those skilled in the art may be employed, and specifically, filtration is preferably performed by using a sand core funnel. In the present invention, the washing preferably includes a DMF washing and a methanol washing in sequence; the number of times of DMF washing is preferably 4 to 6, more preferably 5; the ratio of the amount of Boc-Orn (Fmoc) -OH to DMF for a single DMF wash is preferably 1mmol:4 to 6mL, more preferably 1mmol:5mL; the number of times of the methanol washing is preferably 2 to 4 times, more preferably 2 to 3 times; the ratio of Boc-Orn (Fmoc) -OH to methanol for a single methanol wash is preferably 1mmol:4 to 6mL, more preferably 1mmol:5mL. In a specific embodiment of the present invention, it is preferred to use ninhydrin to detect the blue color of the Boc-Orn-resin before proceeding with the subsequent reaction.
After Boc-Orn-resin is obtained, the Boc-Orn-resin, NOTA-Bn-SCN, DIEA and an organic solvent are mixed for addition reaction, so that the NOTA-Bn-SCN-Boc-Orn-resin is obtained. In the present invention, the molar ratio of Boc-Orn (Fmoc) -OH, NOTA-Bn-SCN and DIEA is preferably 1:1.1 to 2.1:3.3 to 10.6, more preferably 1:1.2 to 1.8:3.5 to 10, more preferably 1:1.4 to 1.6:4 to 6. In the present invention, the organic solvent preferably includes DMF; the amount of the organic solvent used in the present invention is not particularly limited, and it is sufficient to dissolve NOTA-Bn-SCN. The present invention is not particularly limited to the above-mentioned mixing, and the raw materials may be uniformly mixed, specifically, stirring and mixing. In the present invention, the temperature of the addition reaction is preferably 10 to 30 ℃, more preferably 20 to 25 ℃, and in the specific embodiment of the present invention, it is preferably performed under room temperature conditions; the time of the addition reaction is independently preferably 10 to 60 minutes, more preferably 20 to 50 minutes, and further preferably 30 to 40 minutes. After the addition reaction is completed, the invention preferably further comprises the steps of carrying out solid-liquid separation on the obtained addition reaction liquid, and washing the obtained solid product to obtain the NOTA-Bn-SCN-Boc-Orn resin. The solid-liquid separation is not particularly limited, and a solid-liquid separation method well known to those skilled in the art may be employed, and specifically, filtration is preferably performed by using a sand core funnel. In the present invention, the washing is preferably DMF washing; the number of times of DMF washing is preferably 4 to 6, more preferably 5; the ratio of the amount of Boc-Orn (Fmoc) -OH to DMF for a single DMF wash is preferably 1mmol:4 to 6mL, more preferably 1mmol:5mL. In a specific embodiment of the present invention, it is preferable to use ninhydrin to detect that the NOTA-Bn-SCN-Boc-Orn resin is colorless, then drying the resin until the weight is constant by suction filtration, and then carrying out the subsequent reaction.
After obtaining NOTA-Bn-SCN-Boc-Orn (Boc) -resin, the invention cuts the NOTA-Bn-SCN-Orn (Boc) -resin in cutting fluid and purifies the cut resin to obtain NOTA-Bn-SCN-Orn. In the invention, the cutting fluid is preferably a TFA cutting fluid, and the TFA cutting fluid preferably comprises the following components in percentage by mass: 95% trifluoroacetic acid (TFA), 2% TIS, 2% EDT and 1%H 2 O. The amount of the cutting fluid is not particularly limited, and NOTA-Bn-SCN-Boc-Orn (Boc) -resin can be immersed. In the present invention, the temperature of the cutting is preferably 10 to 30 ℃, more preferably 20 to 25 ℃, in the present inventionPreferably at room temperature; the time of the cutting is independently preferably 0.5 to 3 hours, more preferably 1 to 2.5 hours, and further preferably 1.5 to 2 hours. In the present invention, the purification comprises: and (3) carrying out solid-liquid separation on the reaction liquid obtained by cutting, and sequentially carrying out precipitation, HPLC purification and drying on the obtained liquid product to obtain NOTA-Bn-SCN-Orn. The solid-liquid separation is not particularly limited, and a solid-liquid separation method well known to those skilled in the art may be adopted, such as suction filtration. In the present invention, the precipitating agent preferably includes diethyl ether. In the present invention, the conditions for the HPLC purification preferably include: the chromatographic column is preferably a C18 column; the mobile phase system is preferably a mobile phase A and a mobile phase B, the mobile phase A is a trifluoroacetic acid-acetonitrile mixed solution, and the volume fraction of trifluoroacetic acid in the trifluoroacetic acid-acetonitrile mixed solution is preferably 0.05-0.2%, more preferably 0.1-0.15%; the mobile phase B is a trifluoroacetic acid-water mixed solution, and the volume fraction of the trifluoroacetic acid in the trifluoroacetic acid-water mixed solution is preferably 0.05-0.2%, more preferably 0.1-0.15%; the flow rate of the mobile phase is preferably 3-10 mL/min, more preferably 4-8 mL/min, and even more preferably 5-6 mL/min; the elution mode is preferably gradient elution, and the gradient elution program is preferably: 0-0.01 min, wherein the volume fraction of the mobile phase A is 85%, 0.01-25 min, the volume fraction of the mobile phase A is reduced from 85% to 45% at average speed, and the volume fraction of the mobile phase A is reduced from 45% to 0% at average speed for 25-30 min; the detection wavelength is preferably 220nm. In the invention, the drying mode is preferably freeze-drying, and the temperature of the freeze-drying is preferably-60 to-80 ℃, more preferably-70 ℃; the drying time is not particularly limited, and the drying may be carried out until no solvent is present.
In the present invention, the 68 The Ga source is preferably 68 Ga-GaCl 3 Is an aqueous solution of hydrochloric acid of (2) 68 Ga-GaCl 3 The concentration of hydrochloric acid in the aqueous hydrochloric acid solution is preferably 0.04 to 0.06mol/L, more preferably 0.05mol/L; the said 68 The activity of the Ga source is preferably 2.0-200 mCi, more preferably 4.0-50 mCi. In the present invention, the 68 Preparation of aqueous Ga hydrochloric acid solutionThe method preferably comprises the steps of: eluting with aqueous hydrochloric acid 68 Ge- 68 Ga generator, get 68 Ga-GaCl 3 Is an aqueous solution of hydrochloric acid. In a specific embodiment of the present invention, it is preferable to use 4mL of hydrochloric acid aqueous solution having a concentration of 0.05mol/L for rinsing 68 Ge- 68 Ga generator, each 0.5mL of eluent is respectively collected in an independent 10mL sterile vacuum bottle and the activity is measured, and 1.0mL of eluent of two vacuum bottles with larger radioactivity is taken as the eluent 68 Ga, or, eluting with 4mL of hydrochloric acid aqueous solution having a concentration of 0.05mol/L 68 Ge- 68 Ga generator, obtained leacheate as 68 Ga-GaCl 3 Is an aqueous solution of hydrochloric acid. In the invention, the quality and the quality of the NOTA-Bn-SCN-Orn 68 The ratio of the radioactivity of the Ga source is preferably 0.01-0.2 mg:2.0 to 200mCi, more preferably 0.05 to 0.1mg:4.0 to 50.0mCi. In the present invention, ornithine is used for marking 68 Ga is a positron nuclide for PET imaging, is obtained after leaching by a germanium gallium generator, has convenient availability, and is more suitable for clinical use.
In the present invention, the pH of the first acetate buffer is preferably 3 to 5, more preferably 3.5 to 4.5, still more preferably 3.96 to 4.01, and most preferably 4. In the present invention, the acetate buffer is mixed with 68 The volume ratio of the Ga source is preferably 0.38:1 to 1.5, more preferably 0.38:1.2 to 1.5, more preferably 0.38:1.4 to 1.5
In the present invention, the mixing is preferably carried out by dissolving NOTA-Bn-SCN-Orn in acetate buffer and then mixing with 68 The Ga sources are mixed.
In the present invention, the temperature of the first chelation reaction is preferably 35 to 110 ℃, more preferably 50 to 105 ℃, still more preferably 90 to 100 ℃; the time of the chelation reaction is preferably 5 to 25 minutes, more preferably 10 to 20 minutes, and still more preferably 15 minutes; the chelation reaction is preferably carried out under sealed conditions.
The present invention preferably further comprises subjecting the resulting chelation reaction solution to Sep Pak C18 column purification to obtain 68 Ga-labeled ornithine. In the present invention,the Sep Pak C18 column is preferably activated before purification, wherein the activation comprises washing with absolute ethanol and water in sequence, and then purifying the chelating reaction liquid by the obtained activated Sep Pak C18 column. In the present invention, the Sep Pak C18 column purification preferably comprises sequentially performing water rinsing and ethanol rinsing, and subjecting the obtained 68 Evaporating the Ga-NOTA-Orn ethanol eluent to dryness to obtain a solvent-free extract 68 Ga-labeled ornithine. In the invention, the ratio of the mass of the NOTA-Bn-SCN-Orn to the volume of water for rinsing is preferably 0.05mg:3 to 5mL, more preferably 0.05mg:3.5 to 4.5mL, more preferably 0.05mg:4mL. In the present invention, unreacted components can be removed by rinsing with water 68 Ga ions and acetate. In the invention, the Sep Pak C18 column is preferably washed with water, dried by using air extracted by a syringe and washed with ethanol. In the present invention, the ratio of the mass of the NOTA-Bn-SCN-Orn to the volume of ethanol for ethanol leaching is preferably 0.05mg:0.5 to 2mL, more preferably 0.05mg:1 to 1.5mL.
In the present invention, the 68 Ga-labeled ornithine is preferably used 68 Ga-marked ornithine 68 Ga-NOTA-Orn) injection. In the present invention, the 68 The preparation method of the Ga-NOTA-Orn injection preferably comprises the following steps: at the said 68 Adding physiological saline into Ga-marked ornithine for dilution to obtain 68 Ga-NOTA-Orn injection; or, at the said 68 Adding normal saline into Ga-NOTA-Orn ethanol leaching solution to dilute until the volume fraction of ethanol is lower than 10%, thereby obtaining 68 Ga-NOTA-Orn injection. The concentration is not particularly limited, and the concentration may be carried out by a concentration method well known to those skilled in the art to a constant weight, specifically, distillation under reduced pressure until no solvent remains. The invention also preferably comprises the steps of filtering the obtained diluted solution by a sterile filter membrane to obtain 68 Ga-NOTA-Orn injection. In the present invention, the 68 The concentration of Ga-NOTA-Orn injection is preferably adjusted according to actual needs. In a specific embodiment of the invention, the 68 The concentration of Ga-NOTA-Orn injection is preferably 10-100 MBq/mL, more preferably 20-50 MBq/mL, and furtherThe preferred step is 25MBq/mL.
In the present invention, the 18 The preparation method of the F-marked ornithine comprises the following steps: NOTA-Bn-SCN-Orn, 18 F Source and second acetate buffer, alCl 3 Mixing with dimethyl sulfoxide to perform second chelation reaction to obtain 18 F-labelled ornithine.
In the present invention, the 18 The F source is preferably [ [ 18 F]F-source. The invention is directed to the [ 18 F]The method for producing the F-source is not particularly limited, and is conventional in the art 18 F]The preparation method of F-source is sufficient, in the embodiment of the invention, the 18 F]The preparation method of the F-source preferably comprises the following steps: capturing with Sep Pak QMA column 18 F]F-, and then eluting with an eluent to obtain [ 18 F]F-source. In the present invention, said [) 18 F]F-is preferably produced from the cyclotron after nuclear reaction 18 F]HF. The invention adopts Sep Pak QMA column to capture [ 18 F]The method of F-is not particularly limited, and methods well known to those skilled in the art may be employed. In the present invention, the eluent is preferably normal saline, and the amount of the eluent is preferably 0.1 to 3mL, more preferably 0.5mL.
In the invention, the quality and the quality of the NOTA-Bn-SCN-Orn 18 The ratio of the radioactivity of the F source is preferably 0.01-0.2 mg:0.001 to 1Ci, more preferably 0.02 to 0.1mg: 0.005-0.2 Ci.
In the invention, the ratio of the mass of NOTA-Bn-SCN-Orn to the volume of water is preferably 0.01-0.2 mg:0.01 to 1.0mL, more preferably 0.02 to 0.1mg: 0.05-0.5 mL.
In the invention, the ratio of the mass of NOTA-Bn-SCN-Orn to the volume of dimethyl sulfoxide is preferably 0.01-0.2 mg:0.01 to 1.0mL, more preferably 0.02 to 0.1mg: 0.05-0.5 mL.
In the present invention, the NOTA-Bn-SCN-Orn and AlCl 3 Preferably 0.01 to 0.2mg:1 to 50. Mu.g, more preferably 0.02 to 0.1mg: 4.6-23 mug.
In the present invention, the mixing is preferably carried out by dissolving NOTA-Bn-SCN-OrnIn water, then with dimethyl sulfoxide (DMSO) and AlCl 3 And a second acetate buffer, mixing the obtained mixture with 18 And F, mixing the sources.
In the present invention, the pH of the second acetate buffer is preferably 3 to 5, more preferably 3.5 to 4.5, still more preferably 3.96 to 4.01, and most preferably 4.
In the present invention, the temperature of the second chelation reaction is preferably 35 to 110 ℃, more preferably 50 to 105 ℃, still more preferably 90 to 100 ℃; the time of the second chelation reaction is preferably 5 to 25 minutes, more preferably 10 to 20 minutes, and even more preferably 15 minutes; the second chelation reaction is preferably carried out under sealed conditions.
After the second chelation reaction, the present invention preferably further comprises subjecting the resulting chelation reaction solution to Sep Pak C18 column purification to obtain 18 F-labelled ornithine. In the invention, the Sep Pak C18 column is preferably activated before purification, wherein the activation comprises washing by adopting absolute ethanol and water in sequence, and then purifying the chelating reaction liquid by using the obtained activated Sep Pak C18 column. In the present invention, the Sep Pak C18 column purification preferably comprises sequentially performing water rinsing and ethanol rinsing, and subjecting the obtained 18 Concentrating F-NOTA-Orn ethanol eluate to obtain 18 F-labelled ornithine. In the invention, the ratio of the mass of the NOTA-Bn-SCN-Orn to the volume of water for rinsing is preferably 0.05mg:3 to 10mL, more preferably 0.05mg:3.5 to 4.5mL, more preferably 0.05mg:4mL. The invention can remove unreacted by rinsing with water 18 F ions and acetate. In the invention, the Sep Pak C18 column is preferably washed with water, dried by using air extracted by a syringe and washed with ethanol. In the present invention, the ratio of the mass of the NOTA-Bn-SCN-Orn to the volume of ethanol for ethanol leaching is preferably 0.05mg:0.5 to 2mL, more preferably 0.05mg:1 to 1.5mL. The concentration is not particularly limited, and the concentration may be carried out by a concentration method well known to those skilled in the art to a constant weight, specifically, distillation under reduced pressure until no solvent remains.
In the present invention, the 18 F-labelled ornithine is preferably used 18 Ornithine marked by F 18 F-NOTA-Orn) in the form of an injectable solution. In the present invention, the 18 The preparation method of the F-NOTA-Orn injection preferably comprises the following steps: at the said 18 F-marked ornithine is diluted by adding normal saline to obtain 18 F-NOTA-Orn injection (25 MBq/mL); or, at the said 18 Adding normal saline into F-NOTA-Orn ethanol leaching solution, diluting until the volume fraction of ethanol is less than 10%, and obtaining 18 F-NOTA-Orn injection. The concentration is not particularly limited, and the concentration may be carried out by a concentration method well known to those skilled in the art to a constant weight, specifically, distillation under reduced pressure until no solvent remains. The invention also preferably comprises the steps of filtering the obtained diluted solution by a sterile filter membrane to obtain 18 F-NOTA-Orn injection.
The invention provides the technical proposal 68 Ga-labeled ornithine or obtained by the preparation method according to the technical scheme 68 Use of Ga-labeled ornithine as PET-CT tumor imaging agent. In the present invention, the tumor preferably includes an epithelial-derived tumor, more preferably includes pancreatic exocrine tumor, liver cancer, lung cancer, stomach cancer, glioma, colon cancer, osteofibrosarcoma, melanoma, or breast cancer. In the present invention, the 68 Ga-NOTA-Orn injection can be directly used as PET-CT tumor imaging agent.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
(1) Preparation of NOTA-Bn-SCN-Orn
0.5g Wang resin placed in a dry reaction tube was immersed in DMF at room temperature and activated for 30min and filtered using a sand funnel to give the solid product as an activated resin.
The activated resin was placed in a reaction flask, 1mmol of Boc-Orn (Fmoc) -OH, 3mmol of DMAP and 3mmol of DIC were added and mixed uniformly, and the mixture was subjected to coupling reaction under nitrogen protection at room temperature for 3 hours, then filtered with a sand core funnel, the obtained solid product was subjected to DMF washing 5 times (each time the DMF usage was 5 mL), the obtained Boc-Orn (Fmoc) -resin was placed in the reaction flask, pyridine and acetic anhydride were added in a volume ratio of 1:1 were added, the end-capped reaction was performed for 30 minutes at room temperature, the mixture was filtered with a sand core funnel, and the obtained solid product was subjected to DMF washing 5 times (each time the DMF usage was 5 mL), thus obtaining the end-capped Boc-Orn (Fmoc) -resin.
The blocked Boc-Orn (Fmoc) -resin was placed in a reaction flask, 10mL of piperidine dimethylformamide solution (piperidine concentration: 20%) was added, fmoc-removed reaction was performed at room temperature under stirring for 5min, filtration was performed, 10mL of piperidine dimethylformamide solution (piperidine concentration: 20%) was further added to the obtained solid product, fmoc-removed reaction was performed at room temperature under stirring for 5min, filtration was performed, the obtained solid product was subjected to DMF washing 5 times (DMF usage: 5mL each time), methanol washing 2 times (methanol usage: 5mL each time), and ninhydrin as a resin residue was detected as blue, to obtain Boc-Orn-resin.
Placing Boc-Orn-resin in a reaction tube, adding 1.5mmol of NOTA-Bn-SCN, adding DMF until the NOTA-Bn-SCN is completely dissolved, adding 4mmol of DIEA, mixing uniformly, adding the mixture under the room temperature reaction condition for 40min, filtering by a sand core funnel, washing the obtained solid product DMF for 5 times (each time the DMF consumption is 5 mL), carrying out ninhydrin detection on resin filter residues until the color is colorless, and carrying out suction filtration until the weight is constant to obtain the NOTA-Bn-SCN-Boc-Orn-resin.
Under room temperature conditions, TFA cleavage solution (95% TFA, 2% TIS, 2% EDT and 1%H) 2 O) cutting NOTA-Bn-SCN-Boc-Orn-resin for 2h, suction filtering, drying the lysate with nitrogen as much as possible, precipitating with diethyl ether, centrifuging, washing with diethyl ether for 3-5 times to obtain white solid, dissolving with pure water, purifying with HPLC for desalting, and lyophilizing at-70deg.C to obtain the final productTo NOTA-Bn-SCN-Orn of the structure shown in formula I. Wherein the conditions for HPLC purification include: the chromatographic column is a C18 column; the mobile phase system is a mobile phase A and a mobile phase B, wherein the mobile phase A is a 0.1% trifluoroacetic acid-acetonitrile mixed solution, and the 0.1% trifluoroacetic acid-acetonitrile mixed solution; the mobile phase B is 0.1% trifluoroacetic acid-water mixed solution, and the flow rate of the mobile phase is 5mL/min; the elution mode is gradient elution, and the gradient elution program is as follows: 0-0.01 min, wherein the volume fraction of the mobile phase A is 85%, 0.01-25 min, the volume fraction of the mobile phase A is reduced from 85% to 45% at average speed, and the volume fraction of the mobile phase A is reduced from 45% to 0% at average speed for 25-30 min; the detection wavelength was uv=220 nm.
(2) Preparation 68 Ga source
Eluting with 4mL of aqueous hydrochloric acid solution with concentration of 0.04983mol/L 68 Ge- 68 Ga generator, in turn, will 68 Ga hydrochloric acid leacheate is respectively collected in 8 10mL sterile vacuum bottles for measuring activity every 0.5mL, and 1mL of the two vacuum bottles with larger radioactivity is taken as 68 Ga source [ (Ga source) 68 Ga-GaCl 3 Has a radioactivity of 5.5 mCi).
(3) Preparation 68 Ga-NOTA-Orn
50 μg of NOTA-Bn-SCN-Orn was dissolved in 380 μ LpH =4 acetate buffer and added 68 Ga source (1.5 mL,5.5 mCi) is evenly mixed, sealed and heated to 100 ℃, the chelating reaction is kept for 15min, the mixture is cooled to room temperature, the Sep Pak C18 column is leached and activated by absolute ethyl alcohol and water in sequence, then the chelating reaction liquid is purified by using the obtained activated Sep Pak C18 (the chelating reaction liquid is leached by 5mL deionized water, then is blown dry by using a syringe to extract air, and then is leached by 1mL ethanol), the obtained chelating reaction liquid is purified 68 Evaporating ethanol from Ga-NOTA-Orn ethanol eluent to obtain 68 Ga-NOTA-Orn, then adding 4mL of physiological saline to redissolve and adjusting the concentration according to the actual activity by using the physiological saline to obtain the concentration of 25MBq/mL 68 Ga-NOTA-Orn injection.
The attenuation formula will be used to calculate the corrected 68 The activity of Ga-NOTA-Orn injection divided by the use 68 Activity of Ga source to obtain the productThe radiochemical yield after calibration in the examples was about 45%.
FIG. 1 shows the HPLC ultraviolet chromatogram of NOTA-Bn-SCN-Orn, and the chemical purity of NOTA-Bn-SCN-Orn is > 95% as shown in FIG. 1.
FIG. 2 is a mass spectrum of NOTA-Bn-SCN-Orn. As can be seen from FIG. 2, the molecular weight of NOTA-Bn-SCN-Orn is 583.50[ M+1 ]] + 。
Test example 1
Chemical purity, radiochemical purity and in vitro stability
Determination by HPLC 68 Chemical purity and radiochemical purity of Ga-NOTA-Orn injection. FIG. 3 is a schematic view of 68 HPLC radioactive chromatogram of Ga-NOTA-Orn injection, and retention time corresponding to radioactive peak is 9min. The radiochemical purity was further determined by Thin Layer Chromatography (TLC) under the following conditions: a silica gel plate (1 cm. Times.10 cm) was used, the developing agent was an aqueous acetonitrile solution having a volume concentration of 85%, the measurement results were as shown in FIG. 4, and the results were measured by TLC, 68 r of Ga-NOTA-Orn injection f A value of 0.47 (under the TLC conditions 68 Ga- 68 GaCl 3 ( 68 Ga 3+ ) R of (2) f Values less than 0.2), see 68 The radiochemical purity of the Ga-NOTA-Orn injection is more than 97%.
Will be 68 The Ga-NOTA-Orn injection is left to stand at room temperature, and is diluted with physiological saline according to the actual activity 68 The activity concentration of Ga-NOTA-Orn injection is adjusted to 25MBq/mL, and after the completion of the activity concentration adjustment, the radiochemical purity is measured by HPLC for 0min, 30min, 60min and 120min, and the result shows that the radiochemical purity at 30min, 60min, 90min and 120min is 97%, 97% and 96%, respectively, and is higher than 95%, which indicates that 68 Ga-NOTA-Orn has excellent in vitro stability.
Test example 2
Experiment of abnormal toxicity
Healthy ICR mice 4 groups of 10 mice each, each mouse tail was intravenously injected with the preparation of example 1 after 5 half-lives 68 Ga-NOTA-Orn injection (0.2 mL) is fed for 48h, and the growth condition of the mice is observed.
Mouse tail intravenous injectionAfter decay into 68 After 48 hours and one week of observation after Ga-NOTA-Orn injection, no adverse reaction and death phenomenon occur, and after dissection, no organ damage is observed.
The above results illustrate 68 Ga-NOTA-Orn injection has no toxicity to organism, and can be further used for in vivo research.
Test example 3
PET-CT imaging test
3 nude mice with AR42J rat pancreas exocrine tumor are subjected to induction anesthesia by isoflurane gas with volume fraction of 2%, and fixed in a Minerve mouse animal cabin (Minerve)Venetinaire, esternay, france) to keep animal body temperature constant, and administering 2L/min air and 2% isoflurane mixture to the animal for inhalation anesthesia, and then injecting imaging agent via tail vein (prepared in example 1) 68 Ga-NOTA-Orn injection, 0.2mL,5 MBq), simultaneously carrying out PET static scanning and CT scanning for 10min respectively after imaging agent injection for 10min, 30min, 60min, 90min and 120min, carrying out image reconstruction and quantitative analysis on each tissue of interest, determining the percent injection dose rate (% ID/g) of each gram of tissue, and calculating the uptake ratio (T/NT) of tumor to normal tissue; the resulting PET-CT image is shown in FIG. 5.
As can be seen from FIG. 5, the contrast agent is injected 68 Ga-NOTA-Orn injection) has obvious imaging agent uptake and good retention at tumor sites, and at 90min, the relative uptake ratio of tumor/muscle is about 8.82, and the distinction from surrounding tissues is obvious. In addition to kidneys and pancreas, contrast to tumor tissue uptake, contrast agent uptake by other normal tissues or organs is low.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (9)
1. Ornithine marked by nuclide is of formula I or structure shown in formula I 68 Ga-labeled ornithine;
2. process for the preparation of nuclide-labeled ornithine according to claim 1, comprising the steps of: NOTA-Bn-SCN-Orn, 68 Mixing Ga source and first acetate buffer solution to perform first chelation reaction to obtain 68 Ga-labeled ornithine;
3. the preparation method according to claim 2, wherein the NOTA-Bn-SCN-Orn has a mass/mass ratio of 68 The ratio of the radioactivity of the Ga source is 0.01-0.2 mg:2.0 to 200.0mCi; the said 68 Ga source is 68 Ga-GaCl 3 Is an aqueous solution of hydrochloric acid.
4. The method of claim 2, wherein the first acetate buffer has a pH of 3 to 5.
5. The method according to claim 2, wherein the first chelation reaction is carried out at a temperature of 35 to 110 ℃ for a time of 5 to 25 minutes.
6. The method according to claim 2 or 5, wherein the first chelation reaction is followed by subjecting the resulting chelation reaction solution to Sep Pak C18 column purification.
7. The method of claim 6, wherein the Sep Pak C18 column purification comprises sequentially eluting with water and ethanol.
8. Use of the nuclide-labeled ornithine of claim 1 or the nuclide-labeled ornithine obtained by the preparation method of any one of claims 2 to 7 in the preparation of a PET-CT tumor imaging agent.
9. The use of claim 8, wherein the tumor comprises an epithelial-derived tumor.
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| WO2011133115A1 (en) * | 2010-04-22 | 2011-10-27 | Singapore Health Services Pte. Ltd. | Tumour radiolabelling imaging agents comprising ornithine and derivatives thereof |
| CN103435684A (en) * | 2013-09-23 | 2013-12-11 | 武汉工程大学 | 18F-fluorine labeling pentapeptide complex and synthetic method thereof |
| CN108290924A (en) * | 2015-11-09 | 2018-07-17 | 生碧昂 | Peptide thiourea derivative, the radioisotope labeled compound for containing it and contain the compound as active constituent for treating or the pharmaceutical composition of diagnosis of prostate cancer |
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| WO2011133115A1 (en) * | 2010-04-22 | 2011-10-27 | Singapore Health Services Pte. Ltd. | Tumour radiolabelling imaging agents comprising ornithine and derivatives thereof |
| CN103435684A (en) * | 2013-09-23 | 2013-12-11 | 武汉工程大学 | 18F-fluorine labeling pentapeptide complex and synthetic method thereof |
| CN108290924A (en) * | 2015-11-09 | 2018-07-17 | 生碧昂 | Peptide thiourea derivative, the radioisotope labeled compound for containing it and contain the compound as active constituent for treating or the pharmaceutical composition of diagnosis of prostate cancer |
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