CN118045209A - Positron emission computed tomography molecular imaging probe for targeting protein-lost enteropathy and preparation method and application thereof - Google Patents
Positron emission computed tomography molecular imaging probe for targeting protein-lost enteropathy and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of nuclear medicine, and relates to a PET/CT molecular imaging probe for targeting protein-lost enteropathy, and a preparation method and application thereof. The probe comprises a radionuclide, a bifunctional chelating agent and human serum albumin, wherein the bifunctional chelating agent and the human serum albumin are connected through covalent bonds, and the radionuclide and the bifunctional chelating agent are connected through coordination bonds; the radionuclide is a positron nuclide. PET nuclides such as 68Ga/18F/64 Cu and the like are used in the invention, the nuclides can realize the marking of HSA, and the influence on the activity of protein is small; in addition, the nonspecific uptake of the gastrointestinal tract is lower, which is more favorable for detecting PLE lesions.
Description
Technical Field
The invention belongs to the field of nuclear medicine, and particularly relates to a positron emission computed tomography (PET/CT) molecular imaging probe for targeting protein-lost enteropathy, and a preparation method and application thereof.
Background
Protein-loss bowel disease (PLE) is a rare syndrome of gastrointestinal Protein loss that is manifested by a decrease in serum Protein levels in the blood circulation when the loss of plasma proteins in the digestive tract exceeds the body's own synthetic capacity. Almost all plasma proteins are involved in the course of PLE, with medium half-life serum proteins such as albumin, immunoglobulins (IgM, igA and IgG), fibrinogen, lipoproteins, alpha-1 antitrypsin (A1 AT), transferrin and plasmin being the most commonly involved species. The main causes of PLE onset can be divided into two points: (1) increase in interstitial pressure: abnormal expansion of lymphatic vessels, increased lymphatic pressure until rupture, leading to primary or hereditary protein loss diseases caused by loss of protein-rich fluid; (2) intestinal barrier defect, intestinal leakage: erosive or non-erosive gastrointestinal disease causes damage to the mucosal barrier, resulting in free leakage of interstitial proteins within the mucosal lumen to produce secondary lesions, and tight junction complex (Tight junction, TJ) defects are also one of the causes of PLE. PLE is usually manifested by hypoproteinemia and systemic edema. Other signs and symptoms (pericardial and thoracic effusion, malnutrition, systemic edema, unilateral edema during lymphatic expansion, macular edema accompanied by reversible blindness and retinal detachment) are reported in some literature, and gastrointestinal symptoms such as chronic vomiting and diarrhea are common clinical manifestations. Most patients have non-single clinical symptoms, often accompanied by multiple symptoms, which also suggests that the underlying pathological mechanisms of PLE onset are overlapping for multiple reasons.
PLE is associated with more than 85 common diseases, including exudative diseases: such as gastroenteritis, colitis, malignant tumor of gastrointestinal tract, diverticulum diseases and diseases caused by increase of intestinal hydrostatic pressure; and heart diseases with increased central venous pressure, intestinal lymphatic distension, etc., almost all gastrointestinal diseases are associated with PLE. Fecal α1-antitrypsin (AAT) is the primary diagnostic marker of PLE, a broad-spectrum protease inhibitor synthesized in the liver, resistant to proteolytic degradation in intestinal secretions and feces. However, the evaluation of such markers requires collection and handling of faeces and the detection process is cumbersome. In addition, this detection method cannot be used to diagnose PLE caused by stomach illness. Scintillation scanning using 99m Tc or 111 In labeled proteins has been another widely used PLE diagnostic tool since its introduction In 1986. Researches show that the noninvasive detection method is simple and sensitive, can be used for early diagnosis of PLE, and can also locate the lost part of protein in the gastrointestinal tract. Typically 111 In and 99m Tc are used to label serum proteins (mainly transferrin and albumin), 111In-Transferrin、99m Tc-HSA or 99m Tc-Dextran being the currently most widely used radiotracer. When protein loss occurs in the digestive system, these radiotracers accumulate in the gastrointestinal tract for PET imaging.
Although 99m Tc-HSA already has the diagnostic capabilities of PLE, image clarity, signal-to-noise ratio are to be improved due to the low SPECT/CT resolution.
Disclosure of Invention
The invention aims to provide a positron emission computed tomography (PET/CT) molecular imaging probe for targeting protein-lost enteropathy, and a preparation method and application thereof. The probe can be used for diagnosing and researching pathological mechanism of protein-lost enteropathy. A PET/CT imaging diagram with high sensitivity, signal-to-noise ratio and resolution is obtained through the development of PLE-PET nuclide molecular probes, and aims at finding out specific sites of intestinal leakage when diagnosing PLE, and analyzing pathological mechanisms of the intestinal leakage by combining pathology (IHC, HE), so that an imaging guiding basis is provided for the effective diagnosis and treatment of PLE patients.
To achieve the above object, a first aspect of the present invention provides a PET/CT molecular imaging probe for targeting protein-lost enteropathy, the probe comprising a radionuclide, a bifunctional chelator, and human serum albumin, the bifunctional chelator and human serum albumin being covalently linked, the nuclide and bifunctional chelator being linked by a coordinate bond; the radionuclides are positron nuclides, including without limitation: 68Ga、18F、64Cu、124I、89 Zr, etc., preferably at least one of 68Ga、18 F and 64 Cu.
In particular, the bifunctional chelating agent may be coupled to cysteine 34 (Cys 34) or an N-terminal binding site (NTS) of human serum albumin.
The invention is characterized in that: 68Ga(T1/2 =67 min) is a short half-life PET nuclide derived from a germanium gallium generator, compared with the current clinically commonly used SPECT nuclide 99mTc(T1/2 =6.02 h) and 111In(T1/2 =2.8 d), 68 Ga has a relatively short half-life, a patient can complete imaging in a short time, patient compliance is increased, 68 Ga is a positron nuclide, and can be used for PET/CT imaging of PLE, and compared with SPECT/CT, the PET has higher resolution in image quality, and the probe has low uptake in normal gastrointestinal tract, so that the PET is more beneficial to the detection of PLE and the accurate detection of the diseased part. 18 F is the positron nuclide most widely used for PET imaging at present, can be produced by a medical cyclotron, and has the characteristics of simple preparation, high yield, low positron energy, proper physical half-life (T 1/2 =110 min) and the like. 64 Cu has a relatively long half-life (T 1/2 =108 h), allows long-term imaging studies, and is more convenient for transporting nuclides, facilitating long-term monitoring of PLE lesions, and more in-depth analysis of specific causes of protein leakage. The structure and main binding sites of Human Serum Albumin (HSA) are shown in figure 1, a fixed-point coupled bifunctional chelating agent can be used for coupling a cysteine binding site (Cys 34) at position 34 of the HSA, and a non-fixed-point coupled bifunctional chelating agent can be used for coupling an N-terminal binding site (N-terminal binding site, NTS), so that the fixed-point/non-fixed-point labeling of the HSA is realized through a radionuclide. Combining PET/CT imaging data with pathological results can help to theoretically elucidate PLE pathological mechanisms and can also conveniently monitor PLE treatment efficacy. If the positron nuclide labeled HSA is used as a probe, the specific position and distribution of the leakage of the human gastrointestinal tract in the human body can be conveniently determined.
The bifunctional coupling agents of the present invention include, but are not limited to, at least one of DTPA, NOTA, DOTA, RESCA and 3 pC-NETA-NCS.
The bifunctional coupling agents mentioned above can be prepared by methods well known in the art, and 3pC-NETA-NCS can be found in the literature Chong HS,Song HA,Ma X,Milenic DE,Brady ED,Lim S,Lee H,Baidoo K,Cheng D,Brechbiel MW.Novel bimodal bifunctional ligands for radioimmunotherapy and targeted MRI.Bioconjug Chem.2008Jul;19(7):1439-47.doi:10.1021/bc800050x.Epub 2008Jun 20.PMID:18564868;PMCID:PMC2497452.
The second aspect of the invention provides a preparation method of the PET/CT molecular imaging probe, which comprises the following steps: and (3) modifying the human serum albumin HSA by using the bifunctional chelating agent, and then labeling the radionuclide to obtain the probe.
According to one embodiment of the invention, the method comprises: and coupling the N-terminal binding site of the human serum albumin by adopting the bifunctional chelating agent to obtain the human serum albumin modified with the bifunctional chelating agent, and then forming a coordination bond between the radionuclide and the bifunctional chelating agent by a metal complexing method to obtain the probe.
Specifically, the method comprises the following steps: the p-SCN-Bn-DTPA is adopted to perform non-fixed point coupling on the N-end binding site of the HSA to obtain DTPA-HSA, and then the nuclide 68 Ga and DTPA in the DTPA-HSA form a coordination bond by a metal complexation method, so that the non-fixed point marking of the radionuclide 68 Ga of the HSA is realized.
More specifically, the gallium germanium generator was rinsed with 4mL of 0.05M HCl, the rinse was collected, 1mL (185 MBq) of the rinse was placed in a 1.5mL centrifuge tube, 60. Mu.L of 1M NaAc solution was added thereto, and the pH of the rinse was adjusted to 4.1. 100. Mu.L of DTPA-HSA (10 mg/mL) dissolved in pure water was added to the above solution, and the mixture was stirred and mixed well, and reacted at 37℃for 20 minutes to obtain the objective product. The reaction product was aspirated with a disposable sterile syringe, filtered through a 0.22 μm disposable filter into a 10mL sterile penicillin bottle, and the total activity was determined. Taking 10 mu L/1 mu Ci of quality test, and placing the rest sample in a protective lead tank at 2-8 ℃ for later use.
According to another embodiment of the invention, the method comprises: and adopting the bifunctional chelating agent to perform site-directed coupling on the 34-position cysteine binding site of the human serum albumin to obtain the human serum albumin modified with the bifunctional chelating agent, and complexing the radionuclide with the bifunctional chelating agent by a complexation labeling method to obtain the probe.
Specifically, the method comprises the following steps: site-directed labeling of nuclear species 18 F on HSA was achieved by site-directed coupling of the cysteine binding site at position 34 of HSA (Cys 34) with Maleimido-mono-amide-RESCA to give Mal-RESCA-HSA, which was then complexed with [ Al 18 F ] by aluminum fluoride (18 F-AlF) complexation labeling.
More specifically, a certain amount of 5-10mg/mL of HSA solution was added to the reaction tube, 10 times the molar amount of the prepared 10mg/mL of Maleimido-mono-amide-RESCA solution was added thereto, the pH was adjusted to 8.5 by 1M Tris-HCl buffer solution, the reaction was carried out at room temperature for 2 hours, after the reaction was completed, the target product was collected by Superdex 75 TM increase 100/300GL column, the concentration of the obtained product was measured by nanodrop and packed, one of the tubes was taken for MALDI-TOF measurement, the number of Maleimido-mono-amide-RESCA to which each HSA was attached was detected, and the remaining product was stored in a refrigerator at-80 ℃. The fresh 18 F solution (100 mu L,1110 MBq) obtained by leaching through a QMA column is taken and mixed with AlCl 3 (20 nM, dissolved in NaAC buffer solution with pH=4.0 and 0.1M) solution, the mixture is reacted for 5min at room temperature to obtain { [ 18F]AlF}2+ solution, 200 mu g RESCA-HSA solution is taken and added into { [ 18F]AlF}2+ solution, the mixture is reacted for 15min at 37 ℃ after being mixed uniformly, and the obtained reaction solution is separated and purified through a PD-10 column to obtain the target product 18 F-RESCA-HSA. The reaction product was aspirated with a disposable sterile syringe, filtered through a 0.22 μm disposable filter into a 10mL sterile penicillin bottle, and the total activity was determined. Taking 10 mu L/1 mu Ci of quality test, and placing the rest sample in a protective lead tank at 2-8 ℃ for later use.
According to yet another embodiment of the invention, the method comprises: the 34-position cysteine binding site/N-terminal binding site of HSA is subjected to site-directed/non-site-directed coupling by adopting a bifunctional chelating agent Maleimido-mono-amide-NOTA/p-SCN-Bn-NOTA, and then 64 Cu solution is added, so that site-directed/non-site-directed labeling of 64 Cu on the HSA is realized.
Specifically, an HSA solution with a concentration of 5mg/mL was prepared using 0.1M sodium carbonate/sodium bicarbonate buffer (ph=9), 10mg/mL Maleimido-mono-amide-NOTA/p-SCN-Bn-NOTA solution prepared in DMSO was added thereto, the molar ratio of HSA to Maleimido-mono-amide-NOTA/p-SCN-Bn-NOTA was 1:10, the reaction was carried out at room temperature for 2 hours, then separation and purification were carried out using a PD-10 column, 0.5mL to 1.1mL of eluent was collected, the concentration of the obtained product was measured using nanodrop, and split charging was carried out, one of the tubes was taken for MALDI-TOF measurement, the number of Maleimido-mono-amide-NOTA/p-SCN-Bn-NOTA to which each HSA was attached was detected, and the remaining product was stored in a refrigerator at-80 ℃.15 mug-2 mg of marked Mal-NOTA-HSA/NOTA-HSA is taken and added into 0.1-1.0mL 0.1M pH 5.5 sodium acetate solution, then 25-100MBq of freshly prepared 64 Cu solution is added, the pH value is adjusted to 7.0, and then the temperature is controlled to be 37 ℃ and incubated for 30min; and separating and purifying the obtained reaction liquid by a PD-10 column to obtain a target product.
According to the present invention, there is also provided: when the labeling rate is more than 95%, the radiochemical purity of the target product is more than 99% after the target product is purified by a PD-10 column.
Before use, the PD-10 column balances the column body with PBS solution, and gravity flow velocity is drained, and the process is repeated for a plurality of times; then purifying the target product by using PBS solution; specifically, the PD-10 column is firstly balanced by PBS liquid with the pH of 0.01M and 7.4, 5mL of the PBS liquid is added each time, the PD-10 column is dried by flowing at the gravity flow rate, and the PD-10 column is repeated for 5 times; the target product was then purified with 0.01M PBS pH 7.4. 68 The in vitro stability analysis result of Ga-DTPA-HSA shows that the Ga-DTPA-HSA can keep better stability in PBS solution with the pH of 7.4 and 0.01M, and the radiochemical purity is 98.62+/-0.62% after being incubated for 4 hours at the temperature of 25 ℃.
The third aspect of the invention provides the application of the PET/CT molecular imaging probe in preparing medicines for diagnosing and treating protein-lost enteropathy.
The invention firstly carries out modification on HSA by a bifunctional coupling agent DTPA (diethylenetriamine pentaacetic acid), a bifunctional coupling agent DOTA (1, 4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetracarboxylic acid), a bifunctional coupling agent NOTA (1, 4, 7-triazacyclononane-1, 4, 7-acetic acid), a bifunctional coupling agent RESCA (constraint complexing agent) or a bifunctional ligand 3pC-NETA-NCS, and then carries out labeling of positron nuclein 68Ga/18F/64 Cu and the like to obtain a molecular probe which can be used for positron emission computed tomography (Positron Emission Tomography, PET), so as to obtain a PET/CT imaging diagram with sensitivity, signal to noise ratio and high resolution, and aims at diagnosing PLE, finding a specific site of intestinal leakage and combining pathology (IHC, pathology mechanism) to analyze intestinal leakage, thereby providing a guiding basis for molecular imaging for the treatment of PLE patients.
68 The imaging results of Ga-DTPA-HSA in KM mice are shown in FIG. 2, the distribution of 68 Ga-DTPA-HSA in KM rats changes with time, the probe flows through the heart through blood circulation, then enters liver metabolism, the uptake of the heart and the liver is reduced with time, and no gastrointestinal tract is ingested within 6 hours. PET imaging through the constructed intestinal stress model is shown in FIG. 4, and the 68 Ga-DTPA-HSA can be observed to have obvious three concentrated areas at the intestinal part in the second imaging of the experimental group. Serum protein content was measured in both experimental and control KM rats, with a significant decrease in ALB in each rat group, with the average decreasing gradually over time in the experimental group (fig. 5A-C). It can be seen that the probe can be used as an imaging agent for detecting the intestinal leakage of plasma protein at PLE disease sites in a noninvasive manner with high sensitivity, specificity and resolution.
The invention has at least the following advantages and beneficial effects:
The novel PET/CT molecular probe 68Ga/18F/64 Cu-HSA provided by the invention has stable property, good imaging effect, low uptake in intestinal tracts of normal mice, high image resolution, and contribution to accurately positioning PLE disease parts, is expected to be used for monitoring the treatment effect of PLE patients in real time and noninvasively, monitoring the intestinal leakage condition of PLE of the same focus and different focuses, and provides imaging agents with higher sensitivity and specificity for PLE diagnosis and treatment processes, patient screening and treatment effect monitoring.
PET nuclides such as 68Ga/18F/64 Cu and the like are used in the invention, the nuclides can realize the marking of HSA, and the influence on the activity of protein is small; in addition, the nonspecific uptake of the gastrointestinal tract is lower, which is more favorable for detecting PLE lesions.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
The above and other objects, features and advantages of the present invention will become more apparent by describing in more detail exemplary embodiments thereof with reference to the attached drawings.
FIG. 1 is a schematic representation of the structure of human serum albumin and its bifunctional chelator binding sites.
FIG. 2 shows the results of the analysis of the radiolabeling rate, radiochemical purity and in vitro stability of 68 Ga-DTPA-HSA probe in example 1 of the present invention.
FIG. 3 shows the results of Micro-PET imaging in KM rat model of 68 Ga-DTPA-HSA labeled compound in example 2 of the present invention.
FIG. 4 shows the results of Micro-PET imaging of 68 Ga-DTPA-HSA labeled compound in KM rat stress model in example 3 of the present invention.
FIG. 5 shows serum albumin content change (FIGS. 5A-C) and biodistribution analysis (FIG. 5D) of 68 Ga-DTPA-HSA labeled compound in KM rat stress model in example 3 of the present invention. Wherein A: serum albumin content detection of each KM rat (EG-1, EG-2, EG-3, EG-4) in the Experimental Group (EG) stress model; b: detecting the serum albumin content of each KM rat (CG-1, CG-2) in a Control Group (CG) stress model; c: detecting the average content of serum albumin in the KM rats of the two groups of stress models; d: and (5) detecting the biodistribution of the stress KM rats constructed by two injections.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below. While the preferred embodiments of the present invention are described below, it should be understood that the present invention may be embodied in various forms and should not be limited to the embodiments set forth herein.
The DTPA-HSA kit of the present invention is provided by North capital of a country Hongjingku pharmaceutical Co. PD-10 preloaded gel column was purchased from GE company (USA)
EXAMPLE 1 68 preparation of Ga-DTPA-HSA
The gallium germanium generator was rinsed with 4mL of 0.05M HCl, the rinse was collected, and the radioactivity was measured using an activity meter. 1mL (185 MBq) of the eluent was taken, 60. Mu.L of 1M NaAc solution was added thereto, and the pH of the eluent was adjusted to 4.1. 100. Mu.L of DTPA-HSA (10 mg/mL) dissolved in pure water was added to the above solution, and the mixture was stirred and mixed well, and reacted at 37℃for 20 minutes.
A PD-10 column was taken, rinsed with 0.01M pH 7.2PBS (5 mL. Times.5), and then the PD-10 column was placed on an expanded bottle. The solution after completion of the reaction was fed into the PD-10 column after the equilibration treatment in a total volume of about 1.1mL, the sample was fed to 2.5mL and all of the sample was fed into the column, 2.5mL of the liquid from the beginning was discarded, 0.01M pH 7.2PBS was added for elution, and the sample solution eluted next was taken out.
The radiochemical purity of 68 Ga-DTPA-HSA was examined by Radio-iTLC method. The labeled product 68 Ga-DTPA-HSA was spotted onto silica gel impregnated glass fiber strips, developed up in a 0.5M citric acid/sodium citrate (ph=5) system, and scanned with an AR-2000 thin layer radiation scanner; the radiochemical purity of 68 Ga-HSA was calculated using the instrument's own software. 68 The radiochemical purity of Ga-DTPA-HSA is not lower than 95%, and the radiochemical purity is not obviously changed after the probe is placed in PBS for 48 hours, and is still kept at about 98.6% (figure 2).
EXAMPLE 2 PET imaging study of 68 Ga-DTPA-HSA in animal
KM rats were purchased from viton ritwa (beijing) stock. KM rats were injected by tail vein with 14.8MBq 68 Ga-DTPA-HSA, and at 0.5h,1h,2h, and 4h post injection, anesthetized with isoflurane (2% isoflurane-30% oxygen/air), and subjected to imaging studies on small animals Micro-PET/CT.
As shown in FIG. 3, the distribution of 68 Ga-DTPA-HSA in KM rats changes with time, and the probe flows through the heart via blood circulation and then enters the liver for metabolism, so that the uptake of the heart and the liver is reduced with time, and no gastrointestinal tract is ingested within 6 hours. The probe was circulated through the heart by blood circulation and then into the liver for metabolism, and the uptake increased over time, and no uptake was seen in the gastrointestinal tract within 6 hours.
EXAMPLE 3 68 investigation of Ga-DTPA-HSA in animal models
Stress object model construction:
KM rats were purchased from Vetong Liwa (Beijing) Inc., 4 rats from the experimental group (experimental group; EG) and 2 rats from the Control Group (CG). The rat models of the experimental group and the control group are respectively constructed by respectively taking 30mg/Kg as a standard and respectively administering medicaments corresponding to the intravenous injection of the tail of the rat, and the three doses are administered at intervals of 2 days. The injection dates were noted Day0, day3 and Day6, respectively.
68 PET imaging study of Ga-DTPA-HSA in animal model:
The KM rats were anesthetized with isoflurane (2% isoflurane-30% oxygen/air) at 4h post injection on Day1 (Day 1, day4 and Day 7) after each drug injection via tail vein injection of 19.98-32.375MBq 68 Ga-DTPA-HSA, and imaging studies were performed on small animals Micro-PET/CT (fig. 4), showing that the experimental group had a significant region of concentrate of 68 Ga-DTPA-HSA in the KM rat intestinal tract after the second injection and no significant concentrate was detected in the control KM rat abdominal cavity.
Serum Albumin (ALB) study:
Blood samples of about 0.5mL (about 250uL serum) were collected from the jugular vein of the rat within 30min before dosing and 30min before each imaging time point in 3mL vacuum yellow cap blood collection tube (sephadex + procoagulant tube) and allowed to stand at room temperature for at least 30min after blood sample collection. Serum was obtained for ALB assay (A-C of FIG. 5) by centrifugation at 2000g and 4℃for 10 minutes in two hours after blood collection, and the results showed a significant decrease in serum albumin content (reference range: 31.70-43.70) in the experimental group KM rats, with a minimum of 25.9g/L, and a decrease in serum albumin content in the control group injected with IgG but still within the normal range, and an average value of ALB gradually decreased with time in the experimental group.
Animal model biodistribution study:
Experimental group KM rats were used for biodistribution studies on day 1 after the end of the two injections, as follows: each rat was injected with 7.4MBq 68 Ga-DTPA-has, 4h after injection, the rats were sacrificed, dissected from their blood, heart, liver, spleen, lung, kidney, stomach, bone, muscle, etc., PET/CT imaging was performed after stomach and intestinal tract dissection, gamma-Counter detection was then performed on small intestine and large intestine tissues (with probe imaging region preference), respectively, the organ weights were weighed, and then their radioactivity was measured with gamma-Counter for ID%/g calculation (D of fig. 5), and the results showed higher radioactivity (ID%/g) in the bones, and in addition, higher radioactivity was present in the large intestine and small intestine of rats in the experimental group relative to the control group.
The experimental result shows that the probe can be used as an imaging agent for detecting the intestinal leakage condition of plasma protein at PLE disease sites in a noninvasive manner with high sensitivity, high resolution and high specificity.
The foregoing description of embodiments of the invention has been presented for purposes of illustration and description, and is not intended to be exhaustive or limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the various embodiments described.
Claims (10)
1. A positron emission computed tomography molecular imaging probe for targeting a protein-lost enteropathy, wherein the probe comprises a radionuclide, a bifunctional chelator and human serum albumin, wherein the bifunctional chelator and the human serum albumin are connected by a covalent bond, and the radionuclide and the bifunctional chelator are connected by a coordinate bond; the radionuclide is a positron nuclide, preferably at least one of 68Ga、18 F and 64Cu、124I、89 Zr, more preferably at least one of 68Ga、18 F and 64 Cu.
2. The positron emission computed tomography molecular imaging probe of claim 1, wherein the bifunctional chelating agent is coupled to a cysteine 34 or an N-terminal binding site of human serum albumin;
the bifunctional coupling agent is at least one of DTPA, NOTA, DOTA, RESCA and 3 pC-NETA-NCS.
3. A method of preparing a positron emission computed tomography molecular imaging probe as claimed in any one of claims 1-2, comprising the steps of: and (3) modifying the human serum albumin HSA by using the bifunctional chelating agent, and then labeling the radionuclide to obtain the probe.
4. A method of preparing according to claim 3, characterized in that the method comprises: and coupling the N-terminal binding site of the human serum albumin by adopting the bifunctional chelating agent to obtain the human serum albumin modified with the bifunctional chelating agent, and then forming a coordination bond between the radionuclide and the bifunctional chelating agent by a metal complexing method to obtain the probe.
5. The method of manufacturing according to claim 4, characterized in that the method comprises: the p-SCN-Bn-DTPA is adopted to perform non-fixed point coupling on the N-end binding site of the HSA to obtain DTPA-HSA, and then the nuclide 68 Ga and DTPA in the DTPA-HSA form a coordination bond by a metal complexation method, so that the non-fixed point marking of the radionuclide 68 Ga of the HSA is realized.
6. A method of preparing according to claim 3, characterized in that the method comprises: and adopting the bifunctional chelating agent to perform site-directed coupling on the 34-position cysteine binding site of the human serum albumin to obtain the human serum albumin modified with the bifunctional chelating agent, and complexing the radionuclide with the bifunctional chelating agent by a complexation labeling method to obtain the probe.
7. The method of manufacturing according to claim 6, characterized in that the method comprises: the Maleimido-mono-amide-RESCA is adopted to carry out site-directed coupling on the 34-position cysteine binding site of HSA to obtain Mal-RESCA-HSA, and then Mal-RESCA-HSA and [ Al 18 F ] are complexed by a 18 F-AlF complexing labeling method, so that the site-directed labeling of the nuclide 18 F on the HSA is realized.
8. A method of preparing according to claim 3, characterized in that the method comprises: the 34-position cysteine binding site/N-terminal binding site of HSA is subjected to site-directed/non-site-directed coupling by adopting a bifunctional chelating agent Maleimido-mono-amide-NOTA/p-SCN-Bn-NOTA, and then 64 Cu solution is added, so that site-directed/non-site-directed labeling of 64 Cu on the HSA is realized.
9. The method according to any one of claims 3 to 8, characterized by further comprising: purifying by PD-10 column to make the radiochemical purity of target product greater than 99%; before use, the PD-10 column balances the column body with PBS solution, and gravity flow velocity is drained, and the process is repeated for a plurality of times; then purifying the target product by using PBS solution.
10. Use of the positron emission computed tomography molecular imaging probe of claim 1 in the manufacture of a medicament for diagnosis and treatment of protein-lost bowel disease.
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