CN108503695B - Tracer based on GnRH polypeptide derivative and preparation method and application thereof - Google Patents
Tracer based on GnRH polypeptide derivative and preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
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- 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
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
Abstract
The invention discloses a tracer based on a GnRH polypeptide derivative, and a preparation method and application thereof. The structural formula of the derivative based on GnRH polypeptide is
Description
Technical Field
The invention relates to an imaging tracer and a preparation method thereof, in particular to a tracer based on GnRH polypeptide derivatives and a preparation method and application thereof.
Background
Neuropeptide receptors are overexpressed on a variety of human tumors and have been used as a diagnosis of tumorsAnd therapeutic molecular targets. The specific aggregation of radiolabeled neuropeptide analogs in neuropeptide receptor expressing tumors not only provides a good diagnosis of tumors, but also forms the basis for radiation therapy. Somatostatin receptors are representative of successful peptide receptor targeting: receptors in normal and tumor tissues, their function and their expression have been extensively studied, and increasingly optimized radionuclide-labeled receptor-ligands are useful for diagnostic and therapeutic applications1。
Gonadotropin-releasing hormone receptors are members of the glycoprotein receptor subfamily of the G protein-coupled receptor family, and are essential substances for mediating gonadotropin-releasing hormone (GnRH) function2. GnRH, also known as Luteinizing Hormone Releasing Hormone (LHRH), is a hypothalamic hormone decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH)2) It plays a key role in the regulation of the pituitary, gonadal axis and reproduction3. GnRH interacts with gonadotropin-releasing hormone receptors, regulates the secretion of Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH), and participates in the regulation of puberty initiation and maintenance of normal reproductive function. Studies have demonstrated that GnRH receptors are highly expressed in most human reproductive tumors: GnRH receptor is highly expressed in 80% of endometrial, 78% of ovarian, 52% of breast and 86% of prostate cancers, whereas GnRH receptor is not or is under-expressed in normal tissues4. Therefore, the GnRH receptor is a hot target for tumor diagnosis and therapy.
Over the past two decades, a variety of nuclides have been reported, including125I,99mTc,188Re,111In,68Ga, and18f was successfully labelled to GnRH derivatives, but only a few of them were used as tracers for SPECT or PET imaging evaluation. In 2010, Jaliian et al prepared111In-labeled GnRH derivative111In]DTPA-buserelin and biodistribution and SPECT imaging in normal rats (formula 1), showing significant absorption in mammary gland and ovary, but this molecular probe was not further studied in tumor animals5. 2011 prepared by Guo et al111In-labeled GnRH derivatives111In-DOTA-Ahx-(D-Lys6GnRH1) and in vivo SPECT imaging of xenograft human breast cancer tumor-bearing MDA-MB-231 mouse model (formula 2)6. MDA-MB-231 model human breast cancer tumor-bearing nude mouse in vivo injection111In-DOTA-Ahx-(D-Lys6GnRH1)1h later, SPECT/CT clearly shows tumor sites, and the biodistribution result shows that the tumor/muscle ratio is better (at 0.5h, tumor/muscle is 3.5), and the research shows that111In-DOTA-Ahx-(D-Lys6GnRH1) is a potential novel SPECT imaging agent for breast cancer molecules, but111In-DOTA-Ahx-(D-Lys6GnRH1) in the kidney, blood, liver, lung, the pharmacokinetic properties of which in vivo are to be further optimized. The above two imaging agents are single photon imaging agents.
Since PET/CT has a higher sensitivity than SPECT (10)-11–10-12M:10-9–10-10M) and mass. Positive electron nuclides for Zoghi et al in 201668Ga-labelled GnRH derivatives (DOTA-triptorelin) (IC)500.22 ± 0.05nM) as GnRH receptor PET imaging agent7The [ 2 ] is successfully prepared68Ga]DOTA-triptorelin and biodistribution in normal rats and mice harboring 4T1, and is reported68Ga]DOTA-triptorelin has higher intake in liver, kidney, spleen, lung, stomach, intestine, colon, muscle and testis tissues in rats (the intake value is ID/g% at 2 h)>2.9%), no tumor uptake value is reported in the literature, no PET imaging experiment is carried out, errors such as inconsistency between a chart and characters appear in the text, and the existing report data shows that68Ga]The background uptake of DOTA-triptorelin is too high and the specificity is poor, which is not suitable as PET imaging agent.
Through investigation of the above documents, it can be seen that the GnRH is expressed byReceptors have received increasing attention from many scientists over the last decade as biological targets for tumor therapy and imaging. Currently reported GnRH receptor SPECT molecular probe [ 2 ]111In]DTPA-buserelin remains only in normal rats for the evaluation phase and is not further imaged and studied in model animals; molecular probe111In-DOTA-Ahx-(D-Lys6GnRH1) was shown to be a potential breast cancer molecular imaging agent, but the uptake in the background (kidney, blood, liver, lung) was high and not a good SPECT imaging agent, and the pharmacokinetic properties of the molecular probe in vivo were to be further optimized. Since PET/CT has a higher sensitivity than SPECT (10)-11–10-12M:10-9–10-10M) and mass, a PET imaging agent targeting a GnRH receptor has also been reported, and the reported data show68Ga]The background uptake value of-DOTA-triptorelin is too high, no selectivity and tumor uptake report, and the DOTA-triptorelin is not suitable to be used as a PET imaging agent.
The PET/CT molecular probe prepared by the existing reported targeted GnRH receptor has the defects of high background uptake value, poor selectivity, low sensitivity and the like. The development of a tracer with more excellent performance is of great significance.
Reference documents:
(1)Ginj,M.,Chen,J.,Walter,M.A.,Eltschinger,V.,Reubi,J.C.,and Maecke,H.R.(2005)Preclinical Evaluation of New and Highly Potent Analogues of Octreotide for Predictive Imaging and Targeted Radiotherapy Preclinical Evaluation of New and Highly Potent Analogues of Octreotide for Predictive Imaging and Targeted Radiotherapy 11,1136–1145.
(2)Dufau,M.L.(1998)the Luteinizing Hormone.Annu.Rev.Physiol.60,461–496.
(3)Schally,A.V,Arimura,A.,Kastin,a J.,Matsuo,H.,Baba,Y.,Redding,T.W.,Nair,R.M.,Debeljuk,L.,and White,W.F.(1971)Gonadotropin-releasing hormone:one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones.Science 173,1036–1038.
(4)Schottelius,M.,Berger,S.,Poethko,T.,and Schwaiger,M.(2008)Development of Novel68Ga-and GnRHR-Targeting Efficiency F-Labeled GnRH-I Analogues with High 1256–1268.
(5)Jalilian,A.R.,Shanehsazzadeh,S.,Akhlaghi,M.,Kamali-Dehghan,M.,and Moradkhani,S.(2010)Development of[111In]-DTPA-buserelin for GnRH receptor studies.Radiochim.Acta 98,113–119.
(6)Guo,H.,Lu,J.,Hathaway,H.,Royce,M.E.,Prossnitz,E.R.,and Miao,Y.(2011)Synthesis and evaluation of novel gonadotropin-releasing hormone receptor-targeting peptides.Bioconjug.Chem.22,1682–1689.
(7)Zoghi,M.,Jalilian,A.R.,Niazi,A.,Johari-daha,F.,Alirezapour,B.,and Ramezanpour,S.(2016)Development of a 68Ga-peptide tracer for PET GnRH1-imaging.Ann.Nucl.Med.30,400–408.。
disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a tracer based on a GnRH polypeptide derivative with excellent selectivity as well as a preparation method and application thereof.
The technical scheme adopted by the invention is as follows:
a GnRH polypeptide-based derivative having the structural formula:
wherein R is a group containing a tracer atom.
As a further improvement of the derivative, the derivative has a structural formula
In the formula, X is a tracer atom, and n is an integer between 1 and 10.
As a further improvement of the above-mentioned GnRH polypeptide-based derivatives, X is18F and n are 1-10.
The use of a GnRH polypeptide-based derivative as described above for the preparation of an imaging tracer.
As a further improvement to the above application, the tracer is a PET tracer.
As a further improvement of the above application, the tracer is a tracer for diagnosis of tumor imaging.
As a further improvement of the above application, the tumor is a tumor highly expressing gonadotropin-releasing hormone receptor.
A method for the synthesis of a tracer based on a derivative of a GnRH polypeptide by reacting a GnRH analogue D-Lys6-GnRH[(Glp)-HWSY(D)KLRPG-NH2]The epsilon amino group of lysine at position 6 is introduced
Or
The preparation method is that X is tracer atom, and the structural formula of the tracer of GnRH polypeptide derivative is shown in the specification
As a further improvement of the above synthesis process, X is18F。
Method for the synthesis of tracers based on derivatives of GnRH polypeptides, using the polypeptide NOTA-P-D-Lys6The GnRH, aluminum salt and trace atom react to obtain the derivative with the structural formula
In the formula, X is a tracer atom, and n is an integer between 1 and 10.
As a further improvement of the above synthesis process, X is18F and n are integers between 1 and 10.
The invention has the beneficial effects that:
the GnRH polypeptide derivative has good specificity, and has low uptake in organs and low background uptake value; meanwhile, the compound has higher uptake in tumor tissues with high GnRH receptor expression, and is particularly suitable for being used as a tumor imaging agent.
The result of the experiment of PET imaging and in vivo stability of the tracer in tumor-bearing nude mice shows that the tracer has high tumor specificity and in vivo stability.
Drawings
FIG. 1 is18F-FP-D-Lys6-GnRH and standard FP-D-Lys6HPLC plot of GnRH.
FIG. 2 is18F-FP-D-Lys6PET visualization of GnRH by tail vein injection of prostate cancer PC-3 tumor-bearing nude mouse model in vivo for 1h (white arrows indicate tumor);
FIG. 3 is an immunohistochemical staining of GnRH receptor expression in prostate cancer PC-3 xenograft tumors. A. High GnRH receptor expression in the cytoplasm was shown in prostate cancer PC-3 xenograft tumors (brown,. times.400). B. Prostate cancer PC-3 xenograft tumors stained without the addition of the original GnRH antibody (x 400).
Detailed Description
A GnRH polypeptide-based derivative having the structural formula:
in the formula, X is a tracer atom, and n is an integer between 1 and 10.
As a further improvement of the above-mentioned GnRH polypeptide-based derivatives, X is18F and n are integers between 1 and 10.
The use of a GnRH polypeptide-based derivative as described above for the preparation of an imaging tracer.
As a further improvement to the above application, the tracer is a PET tracer.
As a further improvement of the above application, the tracer is a tracer for diagnosis of tumor imaging.
As a further improvement of the above application, the tumor is a tumor highly expressing gonadotropin-releasing hormone receptor.
A method for the synthesis of a tracer based on a derivative of a GnRH polypeptide byGnRH analogues D-Lys6-GnRH[(Glp)-HWSY(D)KLRPG-NH2]The epsilon amino group of lysine at position 6 is introduced
Or
The preparation method is characterized in that X is a tracer atom, and the structural formula of the tracer of the GnRH polypeptide derivative is as described above.
As a further improvement of the above synthesis process, X is18F。
Method for the synthesis of tracers based on derivatives of GnRH polypeptides, using the polypeptide NOTA-P-D-Lys6The GnRH, aluminum salt and trace atom react to obtain the derivative with the structural formula
In the formula, X is a tracer atom, and n is an integer between 1 and 10.
As a further improvement of the above synthesis process, X is18F and n are integers between 1 and 10.
The following was combined with a molecular probe18F-FP-D-Lys6Preparation of GnRH and its standard products are used as examples to further illustrate the technical scheme of the invention.
Molecular probe18F-FP-D-Lys6The labeling route for GnRH is as follows:
in the formula (I), the compound is shown in the specification,
the reaction was completed in a PET-MF-2V-IT-I type fluoro-18 multifunctional Synthesis Module (Beijing Pat, China). The method comprises the following specific steps:
1) cyclotron pass18O(p,n)18F nuclear reaction to produce18F-Ions, trapped by QMA column and then captured by K222Solution (2.7mg of K)2CO3In 0.1mL of water, 12mg of K222In 0.9mL MeCN) to the reaction flask;
2) introducing nitrogen (80mL/min) and removing the solvent under heating at 116 deg.C;
3) anhydrous acetonitrile (1.5mL) was added, nitrogen was purged and heated to 116 ℃, and the solvent was evaporated again;
4) a methyl 2-bromopropionate solution (5mg in 1mL of acetonitrile) was added to a solution containing the active [ alpha ], [ alpha ]18F]KF/K222Heating to 100 ℃ in a closed reaction tube and keeping for 10 min;
5) after cooling the reaction tube, KOH aqueous solution (0.1M, 0.5mL) was added to the reaction tube and heated to 100 ℃ under sealed conditions for 20min to obtain 2-18Introducing nitrogen into F-potassium propionate, heating to 100 ℃, and evaporating the liquid to dryness;
6) adding NPC solution (40mg dissolved in 1.5mL acetonitrile) into a reaction bottle, and heating to 100 ℃ under a sealed condition to react for 20 min; cooling the reaction tube to room temperature;
7) adding 5% acetic acid aqueous solution (1mL) into the reaction bottle to quench the reaction, and fully and uniformly mixing;
8) separating the mixed solution by semi-preparative HPLC, and collecting18F-NFP was diluted with 0.1% aqueous TFA (40mL) and passed through an Oasis HLB column;
9)18adsorbing the F-NFP on an Oasis HLB column, and leaching the HLB column by using 1mL of water;
10) blowing the Oasis HLB column after washing by using nitrogen (80 mL/min);
11)18the F-NFP was washed off the Oasis HLB column with dry ether (8mL) and dried over a home-made sodium sulfate column;18collecting the F-NFP in a second reaction flask, and blow-drying the ether with nitrogen at room temperature to obtain a dry product18F-NFP, radiochemical purity>99% and standardArticle (A)19The F-NFP comparison was consistently retained in HPCL;
12) polypeptide D-Lys6GnRH was dissolved in DMSO (200. mu.L) and DIPEA (40. mu.L) and added to the dried suspension18Keeping the reaction solution at 40 ℃ for 10min in an F-NFP reaction bottle;
13) the reaction was quenched with aqueous solution (0.7mL) and diluted with water (10mL), the dilution passed through a C18 column and the C18 column was rinsed with 5mL of water. Eluting the product adsorbed on the C18 column with ethanol (2mL), blowing the ethanol with nitrogen,18F-FP-D-Lys6GnRH was used as a solution in physiological saline through a 0.22 μm sterile filter.
From18Starting with F negative ion for 120min, and obtaining the product with specific activity of 20-100 GBq/mu mol with the radiochemical yield of 10 +/-5% (n-10) after the decay correction18F-FP-D-Lys6-a GnRH tracer.
Prepared by18F-FP-D-Lys6-GnRH radiochemical purity>95%, consistent with its standard retention time in HPCL.
Standard substance FP-D-Lys6The synthetic route of-GnRH is identical to the above-mentioned labeling route. Separating standard substance with semi-preparative HPLC, concentrating in freeze dryer to obtain white powder, detecting purity with analytical HPLC, and detecting molecular weight FP-D-Lys with ultra-high resolution three-in-one mass spectrometer6HRMS (ESI-TOF) (m/z) theoretical molecular weight of GnRH calcd for C62H87FN18O14([M+2H]2+)664.3383, molecular weight determined, 664.3389.
Similarly, can be synthesized
Imaging agent18F-FP-D-Lys6Labelling route for GnRH
Polypeptide NOTA-P-D-Lys6-GnRH(300μg) Dissolving in pure water (100 μ L) and AlCl3The mixed solution of (0.01M, 12. mu.L), AcOH (12.5. mu.L) and DMF (650. mu.L) was added to the solution18F-The reaction mixture was kept at 100 ℃ for 10min, cooled and then subjected to semi-preparative HPLC separation, the collected radioactive product was diluted with an aqueous solution (30mL), the diluted solution was passed through a C18 column, the product adsorbed on the C18 column was eluted with ethanol (1.5mL, containing 10. mu.L hydrochloric acid), and the ethanol was dried with nitrogen to obtain18F-NOTA-P-D-Lys6GnRH was used as a solution in physiological saline through a 0.22 μm sterile filter. From18Starting from F negative ions for 40 minutes, obtaining the radiochemical yield of 42 +/-10% (n is 6) after the decay correction, and obtaining the product with the specific activity of 120-GBq/mu mol18F-NOTA-P-D-Lys6-a GnRH tracer.18F-NOTA-P-D-Lys6-GnRH radiochemical purity>95%, consistent with its standard retention time in HPCL.
In vitro stability test of molecular probes
20 μ L (60 μ Ci) of the labeled probe was taken and placed in 1mL phosphate buffered saline PBS and bovine serum BSA, respectively, and incubated at 37 ℃ for 60 and 120min, and then the radiochemical purity was measured by Radio-HPLC. Tracer agent18F-FP-D-Lys6GnRH and18F-NOTA-P-D-Lys6GnRH was stable in PBS and calf serum BSA at 37 ℃ for 60min and 120min, prototypes>98％。
FIG. 1 is18F-FP-D-Lys6-GnRH and standard FP-D-Lys6HPLC plot of GnRH. A, Standard FP-D-Lys6HPLC plot of GnRH at 214 nm. B, the number of the first and second groups,18F-FP-D-Lys6-radio-HPLC plot of GnRH. C, performing a chemical reaction on the mixture to obtain a reaction product,18F-FP-D-Lys6-radio-HPLC plot of GnRH at 37 ℃ for 2h in PBS. D, performing a Chemical Mechanical Polishing (CMP) process,18F-FP-D-Lys6-radio-HPLC plot of GnRH in fetal bovine serum at 37 ℃ for 2 h. It can be seen from the figure that the preparation yields radiochemical purity>98% of tracer18F-FP-D-Lys6GnRH and the tracer has a high stability in vitro.
Experiment of lipid-water partition coefficient of molecular probe
The molecular probe (20. mu. Ci, 5. mu.L) injection was added to a mixed solution of n-octanol and PBS (volume ratio: 1,5mL), vigorously stirred for 3min, and centrifuged at 6000 rpm for 4min to ensure separation of the ester water. The radioactivity was measured in three separate 300. mu.L lipid and 300. mu.L aqueous layers using a gamma counter. Calculation formula of logP:
log10P＝log10(radiation count in 0.3mL n-octanol/radiation count in 0.3mL water).18F-FP-D-Lys6The logP value of-GnRH is-2.13 ± 0.04(n ═ 3), indicating that the tracer has high hydrophilicity.
PET imaging of tumor-bearing model animal
Tracer agent18F-FP-D-Lys6Injecting GnRH (150-200 mu Ci) into a PC-3 tumor-bearing nude mouse model of prostate cancer for 1h through tail vein, and then imaging by using a small animal PET-CT scanning (figure 2). From the figure, the tracer can be seen18F-FP-D-Lys6The GnRH is specifically gathered at the tumor site of the PC-3 prostate cancer, clearly shows the tumor, and is a potential PC-3PET imaging agent for the prostate cancer.
Pathological organization experiment
After the prostate cancer PC-3 model animal PET imaging, the animal is sacrificed to take out the tissue organ, and the histomorphosis pathological detection and the pathological immunohistochemical experiment are carried out. Hematoxylin staining of the nuclei was blue, DAB showed a positive expression of tan (fig. 3), in which a.prostate cancer PC-3 xenograft tumors showed a high cytoplasmic GnRH receptor expression (brown, × 400). B. Prostate cancer PC-3 xenograft tumors stained without the addition of the original GnRH antibody (x 400). It can be seen from the figure that the GnRH receptor in the prostate cancer PC-3 model is highly expressed, which shows that the highly expressed GnRH model is successfully made.
Claims (2)
1. Use of a GnRH polypeptide-based derivative for the preparation of an imaging tracer, wherein the derivative is as follows:
in the formula, X is18F and n are integers between 1 and 10.
The tracer is a tracer for tumor imaging diagnosis;
the tumor is a tumor highly expressing a gonadotropin releasing hormone receptor;
the tumor is prostate cancer.
2. Use according to claim 1, characterized in that said tracer based on a derivative of a GnRH polypeptide is synthesized by reacting the GnRH analogue D-Lys6-GnRH[(Glp)-HWSY(D)KLRPG-NH2]The epsilon amino group of lysine at position 6 is introduced
The preparation method is characterized in that X is a tracer atom, and the structural formula of the tracer of the GnRH polypeptide derivative is as follows:
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