CN114366824A - Probe for isotope targeted imaging and preparation method and application thereof - Google Patents
Probe for isotope targeted imaging and preparation method and application thereof Download PDFInfo
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- CN114366824A CN114366824A CN202011105276.8A CN202011105276A CN114366824A CN 114366824 A CN114366824 A CN 114366824A CN 202011105276 A CN202011105276 A CN 202011105276A CN 114366824 A CN114366824 A CN 114366824A
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Classifications
-
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
-
- 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
-
- 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
- A61K51/0478—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 complexes from non-cyclic ligands, e.g. EDTA, MAG3
- A61K51/048—DTPA (diethylenetriamine tetraacetic acid)
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Optics & Photonics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The application discloses an isotope targeting imaging probe and a preparation method and application thereof, wherein the isotope targeting imaging probe comprises a targeting group, a coupling group and an isotope imaging element; the targeting group, the coupling group and the isotope imaging element are connected in sequence; the targeting group is combined with the coupling group through an amido bond; the isotope imaging element is connected with the coupling group by a chemical coupling mode or a chemical coordination mode. The isotope targeting imaging probe can be used for molecular imaging probes for in vivo medical diagnosis, preparation of diagnostic drugs for preventing and/or treating cancers and preparation of imaging agents for diagnosing diseases. The isotope targeting imaging probe has the characteristics of good targeting property, low dosage and high sensitivity; meanwhile, the composition has good in vivo circulation stability and high biocompatibility, and reduces toxic and side effects on normal tissues and organs.
Description
Technical Field
The application relates to a probe for isotope targeted imaging, a preparation method and application thereof, belonging to the field of medical detection.
Background
Cancer is a serious disease that seriously harms human health. At present, many patients in clinic are not diagnosed until the middle and late stage of cancer, so that cancer patients cannot be treated in time, and the cure rate and survival rate of the patients are too low. Therefore, the diagnosis accuracy of the cancer is improved, the treatment scheme can be made in time, and more patients can be hopefully saved.
The nuclear medicine imaging method is simple, sensitive, specific, non-invasive, safe (the radiation dose of a patient is lower than that of a single X-ray film), easy to repeat, accurate and reliable in result, and capable of reflecting the functions and metabolism of organs, so that the nuclear medicine imaging method is increasingly widely applied to clinical and basic research. Importantly, it can provide information about organ function and related physiological and biochemical information. In general, the functional changes of organs and tissues are earlier than the morphological changes in the course of the disease. Radioisotope imaging is therefore of particular clinical importance. However, the radioactive isotope imaging has the defects of health risk due to the introduction of radioactive substances, generation of toxic and side effects in different degrees due to lack of specificity, damage to normal tissues and the like. When the targeting group is introduced into the radioactive isotope imaging agent, the radioactive nuclide can be specifically and durably gathered at the tumor part, the damage of normal tissues and organs is avoided, the toxic and side effects are reduced, the targeting efficiency can be further improved, and the treatment effect is enhanced. Therefore, the development of safe and efficient targeting imaging probes has become a hotspot for the targeted imaging diagnosis of tumor molecules.
Neuropeptide Y (npy), one of the most abundant neuropeptides in the mammalian brain, exerts a variety of physiological processes in humans through four different receptor subtypes Y1, Y2, Y4, and Y5. At present, the known neuropeptide Y receptor subtype is over-expressed on various tumor cells and tissues such as breast cancer and the like, becomes a new target for cancer diagnosis or treatment, and is expected to improve the specificity of the probe for isotope-targeted imaging.
Disclosure of Invention
According to one aspect of the present application, a probe for isotope-targeted imaging is provided, in which a targeting group is derived from a ligand of a neuropeptide Y receptor, and which has good targeting properties.
The isotope targeting imaging probe comprises a targeting group, a coupling group and an isotope imaging element;
the targeting group, the coupling group and the isotope imaging element are connected in sequence;
the targeting group is combined with the coupling group through an amido bond;
the isotope imaging element is connected with the coupling group by a chemical coupling mode or a chemical coordination mode.
Optionally, the isotope-targeted imaging probe is formed by connecting a targeting group, a coupling group and an isotope imaging group in sequence.
Alternatively, the targeting group is derived from a ligand for the neuropeptide Y receptor;
the ligand for the neuropeptide Y receptor is a targeting ligand polypeptide.
Optionally, the targeting ligand polypeptide comprises a peptide chain selected from at least one of the following: NPY (28-36), [ Arg6, Pro34] pNPY, [ Phe6, Pro34] pNPY, [ Asn6, Pro34] pNPY, [ Cys 34, Pro34] pNPY, [ D-His 34, Pro34] NPY, [ Phe 34, Pro34] pNPY, [ Pro34, Nle 34, Bpa 34, Leu34] NPY (28-36), [ Pro34, Nal 34, Leu34] NPY (28-36), [ Pro34, Nle 34, Nal 34, Leu34] NPY (28-36), [ D-Arg 34] -NPY, [ D-His 34] -Pro 34, [ Arg 34, Pro 36Leu 34] NPY, [ Pro34] pNPY, [ Pro34], pNPY, [ Pro34] pNPY, [ Pro34, Pro34] pNPY, [ Pro34], pNPY, [ Pro 34-P34 ], pNPY, [ Pro34] Pro34, Pro34] NPY, [ P34, pNPY (28-34, pNPY, pP 34, pNPY-34, pNPY-34, pP 34, pNPY (28-34, pNPY-34, Pro34, pNPY-34, pNPY (28-34, pNPY-34, pNPY-34, pNPY (28-34, pNPY-34, pP 34, pNPY-34, pP 34, pNPY-34, pNPY 34, pNPY 34, pNPY-34, pNPY 34, pNPY (28-34, pP 34, pNPY 34, pNPY 36, [ Asn28, Pro30, Trp32] NPY (25-36), [ Pro30, Tyr31, Trp32] NPY (25-36), NPY (3-36) and NPY (22-36).
Optionally, the coupling group is derived from a coupling agent selected from at least one of choline, HSA, FDG, benzoic acid, DOPA, acyclovir, AV45, DOTA, citric acid, dotate, DTPA, dotacoc.
Optionally, the isotopic imaging element is selected from the group consisting of radioisotopes11C、64Cu、67Cu、124I、125I、131I、111In、213Bi、68Ga、18F、99mAt least one of Tc.
Optionally, the isotopic imaging element is selected from the group consisting of radioisotopes11C、124I、125I、131I、18At least one of F;
the coupling agent is selected from at least one of choline, HSA, FDG, benzoic acid, DOPA, acyclovir and AV 45;
the isotope imaging element is linked to the coupling agent by chemical coupling.
Optionally, the isotope is selected from radioisotopes11C、124I、125I、131I、18At least one of F, an isotope is linked to the compound by chemical coupling;
the compound is at least one selected from choline, HSA, FDG, benzoic acid, DOPA, acyclovir and AV 45.
Optionally, the isotopic imaging element is selected from the group consisting of radioisotopes67Cu、64Cu、111In、68Ga、213Bi、99mAt least one of Tc;
the coupling agent is at least one of citric acid, DTPA, DOTA and derivatives thereof;
the isotope imaging element is connected with a coupling agent through chemical coordination;
preferably, the DOTA derivative is selected from at least one of dotate, dotacoc.
According to still another aspect of the present application, there is provided a method for preparing the above isotope targeting imaging probe, comprising at least the following steps:
s100, reacting a mixture containing a coupling agent and a targeting ligand polypeptide with a reaction I to obtain an intermediate product;
s200, adding an isotope imaging element source into the intermediate product, reacting II, washing and drying to obtain the isotope targeted imaging probe;
the isotope imaging element source is an isotope salt substance.
Optionally, the isotope salt substance is selected from at least one of isotope sodium salt, isotope hydrochloride, isotope nitrate, isotope carbonate and isotope benzoate.
Optionally, the molar ratio of the coupling agent to the targeting substance is 1-10.
Specifically, in the molar ratio of the coupling agent to the targeting substance, the lower limit of the ratio of the coupling agent can be independently selected from 1, 2, 3,4 and 5; the upper limit of the proportion of the coupling agent may be independently selected from 6, 7, 8, 9, 10.
Optionally, the isotope imaging element source and the coupling agent are used in an amount relationship of 1 × 10-10～1×105mCi/umol；
Wherein the isotope imaging element source is used in an amount based on the content of the isotope imaging element itself.
Specifically, the lower limit of the relationship between the amount of the isotope imaging element source and the coupling agent can be independently selected from 1 × 10-10mCi/umol、4.05×10-4mCi/umol、1×10-2mCi/umol, 0.1mCi/umol, 1 mCi/umol; the upper limit of the amount of isotope imaging element source and coupling agent can be independently selected from 13.5mCi/umol, 47mCi/umol, 1 × 103mCi/umol、1×104mCi/umol、1×105mCi/umol。
Optionally, step S100 includes: and (3) dissolving the coupling agent and the targeting ligand polypeptide in phosphate buffer solution, stirring, and reacting I to obtain the intermediate product.
In the present application, HSA is human serum albumin; FDG is deoxyglucose; DOPA is 3, 4-dihydroxyphenylalanine; DOTA is 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetracarboxylic acid; DTPA is diethyl triaminepentaacetic acid; BA is benzoic acid.
According to yet another aspect of the present application, there is provided the above-described isotope-targeted imaging probe, a molecular imaging probe for use in performing medical diagnosis in vivo.
According to a further aspect of the present application, there is provided the use of an isotope-targeted imaging probe as described above in the preparation of a diagnostic medicament for the prophylaxis and/or treatment of cancer;
preferably, the mode of administration of the medicament includes oral, intratumoral, rectal, parenteral and topical administration.
According to a further aspect of the present application, there is provided the use of the above-described isotope-targeted imaging probe in the preparation of an imaging agent for diagnosing a disease comprising at least one of breast cancer, brain cancer, kidney cancer, endometrial cancer, ovarian cancer, ewing's sarcoma, prostate cancer, liver cancer, and colon cancer.
The beneficial effects that this application can produce include:
1) the isotope targeting imaging probe provided by the application has good targeting property.
2) The isotope targeting imaging probe provided by the application has the characteristics of low dosage and high sensitivity.
3) The isotope targeting imaging probe provided by the application has good in vivo circulation stability and high biocompatibility, and reduces toxic and side effects on normal tissues and organs.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
Unless otherwise specified, the raw materials and the like in the examples of the present application were purchased commercially, wherein the cells involved: breast cancer cells MCF-7, brain cancer cells U87MG, kidney cancer cells 786-O, endometrial adenocarcinoma cells HEC-1-B, ovarian cancer cells a2780, Ewing sarcoma cells SK-ES-1, prostate cancer cells LNCap, colon cancer cells T84, liver cancer cells Huh-7 were purchased from American cell dictionary and tested after culturing according to the instructions.
In the examples, the targeting peptide fragment is from biotech ltd of peptide industry of Nanjing.
EXAMPLE 1 Compound C1[ Pro30, Nle31, Nal32, Leu34]NPY(28-36)-DOTA(64Cu)
Compound C1 was synthesized as follows:
1. DOTA-NHS was dissolved in phosphate buffer to give a solution at a concentration of 10mM, to which was subsequently added a 1: 1 mol ratio of [ Pro30, Nle31, Nal32, Leu34]]Ligand-targeting polypeptide (IIe-Asn-Pro-Nle-Bpa-Arg-Leu-Arg-Tyr-NH) of NPY (28-36)2) Stirring for 24 hours at the temperature of 25 ℃ in the dark, centrifuging to remove suspended matters and foams on the upper layer, redissolving and dispersing by deionized water, then placing in an ice water mixing bath for stirring, taking out after 2 hours, and placing at normal temperature in the dark. Subsequently adding 47mCi/umol of DOTA-NHS64CuCl2After reacting at 80 ℃ for 30min18And C, purifying by using a column C, removing redundant liquid by rotary evaporation, adding deionized water for redissolving, and then placing in a freeze dryer for freeze drying and collecting a sample.
The compound of example 2 [ Asn28, Pro30, Trp32]NPY(25-36)-HSA(124I)
Compound C2 was synthesized as follows:
according to HSA and a targeting group [ Asn28, Pro30, Trp32]]The targeted ligand polypeptide (Arg-His-Pro-Asn-Asn-Pro-Ile-Trp-Arg-Gln-Arg-Tyr-NH2) mole ratio of NPY (25-36) is 1: 1, SMCC activated HSA and targeting ligand polypeptide are dissolved in phosphate buffered saline at a concentration of 0.08mM, stirred at 4 ℃ for 24 hours, and centrifuged to remove impurities. Then adding Na with the dosage of 13.5mCi/umol according to the dosage of HSA124Solid I, stirred in an EP tube previously coated with iodine for 10min, purified by dialysis bag with molecular weight of 10KD, and then freeze-dried in a freeze-dryer to collect the sample.
Example 3 Compound C3[ Asn28, Pro30, Trp32]NPY(25-36)-DOTATATE(111In)
Compound C3 was synthesized as follows:
DOTATATE-NHS was dissolved in PBS to give a solution with a concentration of 10mM, to which was subsequently added a 1: 1 molar ratio of targeting group containing [ Asn28, Pro30, Trp32]Ligand-targeting polypeptide of NPY (25-36) (Arg-His-Pro-Asn-Asn-Pro-Ile-Trp-Arg-Gln-Arg-Tyr-NH)2) Stirring for 24 hr at 25 deg.C in the dark, centrifuging to remove upper layer suspended matter and foam, and deionizingAfter redissolving and dispersing, placing the mixture in an ice water mixed bath for stirring, taking the mixture out after 2 hours, and placing the mixture at normal temperature in a dark place. The subsequent addition was 4.05X 10 relative to the amount of DOTATATE-4mCi/umol111InCl3And continuously stirring for 24 hours in a dark place, centrifuging to remove upper-layer suspended matters and foams after stirring is finished, adding deionized water, redissolving and dispersing, placing in a freeze dryer, freeze-drying, and collecting samples.
Example 4 Synthesis of Compounds C4-C473
The specific procedures for synthesizing the compounds C4-C473 in this example were the same as in example 1; see table 1 for the remaining conditions.
TABLE 1
Example 5 in vivo tumor imaging experiment samples C1-473 of examples 1-4 were subjected to a mouse nuclide imaging experiment.
Selecting 3 tumor-bearing mice, injecting a sample C1-473 with the radioactive dose of 100 mu Ci, and imaging after 24h by using a small animal PET scanner. The imaging effect is shown in table 2. Wherein the effective imaging time refers to a time period in which the signal-to-noise ratio is greater than 1.
In clinical studies of imaging techniques, the signal-to-noise ratio parameter must be used to evaluate the quality of the image. The signal is the average value of pixels in a certain interested region, the noise is the difference of the same amount of pixels deviating from the reality in the same interested region, and the signal-to-noise ratio is the ratio of the signal to the noise.
TABLE 2
Note: + + + + + + indicates a signal-to-noise ratio greater than 3.5; + + + + represents a signal-to-noise ratio of 2.5-3.5; + represents a signal-to-noise ratio of 1.5-2.5; + denotes a signal-to-noise ratio of 1-1.5
Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.
Claims (10)
1. An isotope-targeted imaging probe, characterized in that the isotope-targeted imaging probe comprises a targeting group, a coupling group and an isotope imaging element;
the targeting group, the coupling group and the isotope imaging element are connected in sequence;
the targeting group is bound to the coupling group via an amide bond;
the isotope imaging element is connected with the coupling group through a chemical coupling mode or a chemical coordination mode.
2. The isotopically targeted imaging probe of claim 1, wherein said targeting group is derived from a ligand for a neuropeptide Y receptor;
the ligand of the neuropeptide Y receptor is a targeting ligand polypeptide;
preferably, the targeting ligand polypeptide comprises a peptide chain selected from at least one of the following: NPY (28-36), [ Arg6, Pro34] pNPY, [ Phe6, Pro34] pNPY, [ Asn6, Pro34] pNPY, [ Cys 34, Pro34] pNPY, [ D-His 34, Pro34] NPY, [ Phe 34, Pro34] pNPY, [ Pro34, Nle 34, Bpa 34, Leu34] NPY (28-36), [ Pro34, Nal 34, Leu34] NPY (28-36), [ Pro34, Nle 34, Nal 34, Leu34] NPY (28-36), [ D-Arg 34] -NPY, [ D-His 34] -Pro 34, [ Arg 34, Pro 36Leu 34] NPY, [ Pro34] pNPY, [ Pro34], pNPY, [ Pro34] pNPY, [ Pro34, Pro34] pNPY, [ Pro34], pNPY, [ Pro 34-P34 ], pNPY, [ Pro34] Pro34, Pro34] NPY, [ P34, pNPY (28-34, pNPY, pP 34, pNPY-34, pNPY-34, pP 34, pNPY (28-34, pNPY-34, Pro34, pNPY-34, pNPY (28-34, pNPY-34, pNPY-34, pNPY (28-34, pNPY-34, pP 34, pNPY-34, pP 34, pNPY-34, pNPY 34, pNPY 34, pNPY-34, pNPY 34, pNPY (28-34, pP 34, pNPY 34, pNPY 36, [ Asn28, Pro30, Trp32] NPY (25-36), [ Pro30, Tyr31, Trp32] NPY (25-36), NPY (3-36) and NPY (22-36);
preferably, the coupling group is derived from a coupling agent selected from at least one of choline, HSA, FDG, benzoic acid, DOPA, acyclovir, AV45, DOTA, citric acid, dotate, DTPA, dotacoc.
3. The isotope-targeted imaging probe of claim 1, wherein the isotope imaging element is selected from the group consisting of radioisotopes11C、64Cu、67Cu、124I、125I、131I、111In、213Bi、68Ga、18F、99mAt least one of Tc.
4. The isotope-targeted imaging probe of claim 3, wherein the isotope imaging element is selected from the group consisting of radioisotopes11C、124I、125I、131I、18At least one of F;
the coupling agent is selected from at least one of choline, HSA, FDG, benzoic acid, DOPA, acyclovir and AV 45;
the isotope imaging element is connected with the coupling agent through chemical coupling;
preferably, the isotopic imaging element is selected from the group consisting of radioisotopes67Cu、64Cu、111In、68Ga、213Bi、99mAt least one of Tc;
the coupling agent is at least one of citric acid, DTPA, DOTA and derivatives thereof;
the isotope imaging element is connected with the coupling agent through chemical coordination;
preferably, the DOTA derivative is selected from at least one of dotate, dotoc.
5. The method for preparing an isotopically targeted imaging probe of any one of claims 1 to 4, comprising at least the steps of:
s100, reacting a mixture containing a coupling agent and a target substance to obtain an intermediate product;
s200, adding an isotope imaging element source into the intermediate product, reacting II, washing and drying to obtain the isotope targeted imaging probe;
the isotope imaging element source is an isotope salt substance.
6. The preparation method according to claim 5, wherein the molar ratio of the coupling agent to the targeting substance is 1-10;
preferably, the dosage relation of the isotope imaging element source and the coupling agent is 1 x 10-10～1×105mCi/umol。
Wherein the isotope imaging element source is used in an amount based on the content of the isotope imaging element itself.
7. The method according to claim 5, wherein the step S100 includes: and (3) dissolving the coupling agent and the targeting ligand polypeptide in phosphate buffer solution, stirring, and reacting I to obtain the intermediate product.
8. The isotope-targeted imaging probe of any one of claims 1 to 4, for use as a molecular imaging probe for performing medical diagnosis in vivo.
9. Use of the isotope-targeted imaging probe of any one of claims 1 to 4 for the preparation of a diagnostic medicament for the prophylaxis and/or treatment of cancer;
preferably, the mode of administration of the medicament includes oral, intratumoral, rectal, parenteral and topical administration.
10. Use of the isotope-targeted imaging probe of any one of claims 1 to 4 in the preparation of an imaging agent for diagnosing a disease including at least one of breast cancer, brain cancer, kidney cancer, endometrial cancer, ovarian cancer, ewing's sarcoma, prostate cancer, liver cancer, and colon cancer.
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| CN111744022A (en) * | 2019-03-27 | 2020-10-09 | 中国科学院宁波材料技术与工程研究所 | Active targeting response type imaging probe, and preparation method and application thereof |
| CN111744020A (en) * | 2019-03-27 | 2020-10-09 | 中国科学院宁波材料技术与工程研究所 | Active targeting response type polypeptide drug, preparation method and application thereof |
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| TW201912184A (en) * | 2017-09-08 | 2019-04-01 | 行政院原子能委員會核能研究所 | A radioactive labeling method for neuropeptide Y compounds and derivatives thereof |
| CN111744022A (en) * | 2019-03-27 | 2020-10-09 | 中国科学院宁波材料技术与工程研究所 | Active targeting response type imaging probe, and preparation method and application thereof |
| CN111744020A (en) * | 2019-03-27 | 2020-10-09 | 中国科学院宁波材料技术与工程研究所 | Active targeting response type polypeptide drug, preparation method and application thereof |
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