CN115057801A - F-18 labeled PSMA (patterned Markov chain) targeted PET (polyethylene terephthalate) probe and preparation method thereof - Google Patents
F-18 labeled PSMA (patterned Markov chain) targeted PET (polyethylene terephthalate) probe and preparation method thereof Download PDFInfo
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- C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
- C07C323/65—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton
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Abstract
The invention discloses an F-18 labeled PSMA (patterned killer nucleic acid) targeted PET (polyethylene terephthalate) probe and a preparation method thereof, wherein the PET probe is obtained by reacting a labeled intermediate and a precursor small molecule, the labeled intermediate is a fluorinated aryl vinyl sulfone labeled intermediate, and the precursor small molecule is a precursor small molecule containing sulfydryl and taking Lys-urea-Glu as a mother nucleus structure. The invention obtains the F-18 labeled targeting PSMA probe for prostate cancer image diagnosis by reacting a fluoro aryl vinyl sulfone labeled intermediate with a precursor containing sulfydryl and taking Lys-urea-Glu as a parent nucleus structure, and the probe is compared with an FDA approved PET imaging agent 68 Ga]PSMA-11, which has more excellent tumor focus detection capability, about three times of tumor uptake value, slow metabolism speed of the drug through liver and kidney metabolism, low image background and clear target tissue development, and overcomes the technical problems of the existing developer.
Description
Technical Field
The invention relates to the technical field of PET image diagnosis, in particular to an F-18 labeled PSMA targeted PET probe and a preparation method thereof.
Background
Prostate specific membrane antigen (abbreviated as PSMA) is located in prostate epithelial cells and is a transmembrane cellular glycoprotein. PSMA is expressed at higher levels in 95% of prostate cancer patients, with upregulation in Castration Resistant Prostate Cancer (CRPC) and metastatic prostate cancer. Therefore, PSMA can be used as an ideal target for diagnosing and treating prostate cancer and metastatic focus thereof. At present, a plurality of molecular probes using PSMA as a target point exist for treating clinical experiment stages, and common PSMA molecular probes comprise monoclonal antibodies, small analysis inhibitors and the like. For example, 111 in-labeled 7E11 is the first radiolabeled PSMA monoclonal antibody, which is a more successful drug for the current SPECT imaging aiming at prostate cancer, but 7E11 can only bind to the membrane inner segment of PSMA, so that the PSMA monoclonal antibody can only be taken up by necrotic and apoptotic cells, and the imaging sensitivity is not high. The PSMA small molecule inhibitor has the advantages of good cell permeability, quick blood clearance and the like, and mainly comprises 3 types: 1. derivatives such as phosphates, phosphinates, phosphonates, phosphoramides, and the like; 2. mercapto, indole-mercapto, hydroxamic acid, sulfonamide derivatives; 3. a urea derivative. At present, the urea derivative small molecular inhibitors entering the clinical experimental stage mainly comprise PSMA-11 and PSMAI&T, PSMA-617, etc. PSMA small molecule inhibitor markable 18 F、 68 Ga is used for prostate cancer imaging and can be labeled 111 Lu、 90 Y、 131 I for prostate cancerThe treatment (can refer to the literature, "PSMA-targeted prostate cancer PET imaging and nuclide therapy research progress", Von sachi, Wang Peng, etc., proceedings of Huazhong university of science and technology, vol. 49, No. 1, 2 months 2020). However, the existing PSMA targeting PET imaging agent labeled nuclide Ga-68 has the problems of short half-life, limited effective utilization time, unobvious tumor uptake in prostate cancer cell metastasis models and the like, and the imaging effect is still to be improved.
Chinese article 'development of prostate cancer PSMA targeting contrast agent 18F-Glu-Urea-Lys and PET scanning research' (the first Hospital affiliated to university of Dalian medical science, Kyoho) 18 The F-Glu-urea-RPET/CT molecular probe is synthesized successfully by marking amino acid to replace R group, determining the structure of the compound by using magnetic resonance spectroscopy and mass spectrometry analysis 18 The F-Glu-Urea-Lys contrast agent has good effect on target tumor imaging, is quick and clear in imaging, has little nonspecific binding, is excreted through the kidney and has high excretion speed. However, the contrast agent has stronger lipophilicity, high background uptake of liver and abdomen, low uptake capacity of tumor tissues to the imaging agent and low target/non-target tissue uptake ratio of the imaging agent compared with the existing Ga-68-PSMA-11.
Disclosure of Invention
The invention aims to: aiming at the existing problems, the invention provides an F-18 labeled PSMA targeted PET probe and a preparation method thereof, the invention obtains the F-18 labeled targeted PSMA probe for prostate cancer image diagnosis by reacting a fluorinated aryl vinyl sulfone labeled intermediate with a precursor containing sulfhydryl and taking Lys-urea-Glu as a mother nucleus structure, and the probe is compared with PET imaging agent approved by FDA 68 Ga]PSMA-11, which has more excellent tumor focus detection capability, about three times of tumor uptake value, low non-target tissue uptake and clear target tissue imaging by the metabolism of the drug through liver and kidney, and overcomes the technical problems of the existing imaging agents.
The technical scheme adopted by the invention is as follows: an F-18 labeled PSMA targeted PET probe is obtained by reacting a labeled intermediate with a precursor small molecule, wherein the labeled intermediate is a fluorinated aryl vinyl sulfone labeled intermediate, and the precursor small molecule is a sulfydryl-containing precursor small molecule with Lys-urea-Glu as a mother nucleus structure.
Further, the labeled intermediate is labeled intermediate 1 or labeled intermediate 2, and the molecular structure is as follows:
the molecular structure of the labeled intermediate 1 is:
the molecular structure of the labeled intermediate 2 is:
in the above molecular structure, m is in the range of 1 to 3, and may be, for example, 1, 2 or 3.
Further, the precursor small molecule is a precursor small molecule a or a precursor small molecule b, and the molecular structure of the precursor small molecule is as follows:
the molecular structure of the precursor small molecule a is as follows:
the molecular structure of the precursor small molecule b is as follows:
in the above molecular structure, n is a value in the range of 1 to 3, and may be 1, 2 or 3, for example.
Further, the labeled intermediate and the precursor small molecule react in an alkaline buffer solution with the pH value of 8-9 (for example, 8.1, 8.2, 8.3, 8.4, 8.5, 8.8, 9.0, and the like, preferably 8.5), and are separated and purified by high performance liquid chromatography to obtain a PET probe; the alkaline buffer is selected from sodium carbonate buffer, sodium borate buffer, potassium bicarbonate buffer, phosphate buffer, HEPES buffer or MES buffer.
Further, the PET probe is a PET probe a-1, a-2, b-1 or b-2, and the molecular structure of the PET probe is as follows:
the molecular structure of the PET probe a-1 is as follows:
the molecular structure of the PET probe a-2 is as follows:
the molecular structure of the PET probe b-1 is as follows:
the molecular structure of the PET probe b-2 is as follows:
in the above molecular structure, n has a value in the range of 1 to 3, and may be, for example, 1, 2 or 3; the value of m is in the range of 1-3, and may be, for example, 1, 2, or 3.
Further, the invention also comprises a preparation method of the F-18 labeled PSMA targeted PET probe, which comprises the following steps:
s1, adding the F-18 ionic compound into a vinyl sulfone organic substance for heating reaction, cooling, and separating a product through HPLC;
s2, diluting the product with water, passing through an alumina column, and then passing through a solid phase extraction column to obtain a separated and purified fluoro aryl vinyl sulfone labeled intermediate;
s3, adding the precursor small molecules and the fluoro aryl vinyl sulfone labeled intermediate into an alkaline buffer solution together, reacting for 5-60min at 100 ℃, and purifying the product by HPLC after the reaction is finished;
s4, collecting the eluent, diluting the eluent with water, controlling the content of the organic solvent in the eluent to be below 5 v%, then hanging the eluent on a solid phase extraction column, washing away the acidic solvent with water, rinsing the eluent with ethanol to a product bottle, and finally diluting the eluent with normal saline until the content of the ethanol is below 10 v%, thus obtaining the product.
Further, the chromatographic separation conditions of the HPLC are as follows:
a chromatographic column: eclipse Plus C185 μm, 4.6X 250 mm;
flow rate: 1 mL/min; wavelength: 254nm, column temperature: 35 ℃;
mobile phase A: HPLC grade acetonitrile with 0.1 v% TFA; mobile phase B: water with 0.1 v% TFA;
elution conditions:
0 → 2min (within the first 2 min): the volume ratio of mobile phase a/mobile phase B was 5/95;
2 → 15min (within the next 15 min): the volume ratio mobile phase a/mobile phase B varied uniformly to 95/5.
Further, in step S1, dissolving the F-18 ionic compound in anhydrous acetonitrile, adding into the vinylsulfone organic substance, and heating to react at 80-100 deg.C for 5-60 min.
Further, the vinylsulfone organic matter is a labeled precursor 1 or a labeled precursor 2, and the molecular structure is as follows:
the molecular structure of the label precursor 1 is:
the molecular structure of the label precursor 2 is:
in the above, Ar ═ 2,6 diisopropylphenyl.
Further, the labeling precursor 1 may specifically be
1,3-diphenyl-2- (4- (phenylsulfonyl) phenoxy) -1H-imidozol-3-ium chloride, 1,3-bis (2, 6-dimethylphenylyl) -2- (4- (phenylsulfonyl) phenoxy) -1H-imidozol-3-ium chloride, and the like.
Accordingly, the labeling precursor 2 may specifically be 2- (4- (vinylsulfonyl) phenoxy) ethyl4-nitrobenzenesulfonate, 2- (4- (vinylsulfonyl) phenoxy) ethyl4-methylbenzenesulfonate, 2- (4- (vinylsulfonyl) phenoxy) ethyl) ethoxy) ethyl4-nitrobenzenesulfonate, 2- (2- (4- (vinylsulfonyl) phenoxy) ethoxy) ethyl4-methylbenzenesulfonate, 2- (2- (4- (phenylsulfonyl) phenoxy) ethoxy) ethyl methyl sulfonate, 2- (2- (2- (4- (phenylsulfonyl) phenoxy) ethoxy) ethoxy) ethyl4-nitrobenzenesulfonate, 2- (2- (2- (4- (phenylsulfonyl) phenoxy) ethoxy) ethoxy) ethyl 4-tolylnenesulfonate, 2- (2- (2- (4- (phenylsulfonyl) phenoxy) ethoxy) ethoxy) ethoxy) methyl sulfonate, and the like.
Furthermore, the invention also comprises the application of the F-18 labeled PSMA targeted PET probe in the preparation of PET imaging agents.
In summary, due to the adoption of the technical scheme, the invention has the beneficial effects that:
1. the invention obtains the F-18 labeled targeting PSMA probe for prostate cancer image diagnosis by reacting a fluoro aryl vinyl sulfone labeled intermediate with a precursor containing sulfydryl and taking Lys-urea-Glu as a parent nucleus structure, and the probe is compared with an FDA approved PET imaging agent 68 Ga]PSMA-11, which has more excellent tumor focus detection capability, about three times of tumor uptake value, slow metabolism speed of the drug through liver and kidney metabolism, low image background and clear target tissue development, and overcomes the technical problems of the existing developer;
2. the invention is characterized in that the F-18 marking method ensures that the marked micromolecule PET imaging agent has proper logP, high marking efficiency, good stability of the imaging agent in vitro and in vivo, and difficult occurrence of metabolism and F-18 ion removal, compared with the prior art, the invention has the special point that the imaging agent of the invention is different from the prior PET imaging agent representing PSMA-11 on the imaging of an animal model, and the imaging agent of the invention shows better tumor focus detection capability.
Drawings
FIG. 1 is a spectrum of the detection of the radioactive detector of the labeled intermediate 2;
FIG. 2 is a detection spectrum of a UV detector for labeling the intermediate 2, with a detection wavelength of 254 nm;
fig. 3 is a spectrum of the detection of the imaging agent a-2 (n-1, m-1) by a radioactive detector;
fig. 4 is a UV-detector detection spectrum of imaging agent a-2(n ═ 1), with a detection wavelength of 254 nm;
FIG. 5 is a view of a radioactive probe [ 2 ] 68 Ga]-PSMA-11 small animal PET/CT image assessment 30min, 60min, 120min after tail vein injection in LNCaP tumor bearing mice;
fig. 6 is a PET/CT image assessment of small animals 30min, 60min, 120min after tail vein injection of imaging agent a-2 (n-1, m-1) in LNCaP tumor bearing mice;
FIG. 7 is a PET/CT image assessment of small animals with imaging agent a-1 (n-1) at 30min, 60min, 120min post tail vein injection in LNCaP tumor bearing mice;
fig. 8 is a PET/CT image assessment of small animals 30min, 60min, 120min after tail vein injection of imaging agent a-1 (n-3) in LNCaP tumor bearing mice.
Detailed Description
The present invention will be described in detail below with reference to the accompanying drawings.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The F-18 labeled PSMA targeted PET probe is obtained by reacting a labeled intermediate with a precursor small molecule, wherein the labeled intermediate is a fluorinated aryl vinyl sulfone labeled intermediate, the precursor small molecule is a precursor small molecule containing sulfydryl and taking Lys-urea-Glu as a parent nucleus structure, the fluorinated aryl vinyl sulfone labeled intermediate is a labeled intermediate 1 or a labeled intermediate 2, and the molecular structure is as follows:
the molecular structure of the labeled intermediate 1 is:
the molecular structure of the labeled intermediate 2 is:
in the above molecular structure, m is in the range of 1 to 3, and may be, for example, 1, 2 or 3.
As the labeled intermediate 1, a specific substance thereof may be [ 2 ], [ 18 F]-1-fluoro-4-(vinylsulfonyl)benzene、[ 18 F]-1-fluoro-3-(vinylsulfonyl)benzene、[ 18 F]-1-fluoro-2- (vinylsulfonyl) bezene and the like.
Accordingly, for the labeled intermediate 2, a specific substance thereof may be
[ 18 F]-1-(2-fluoroethoxy)-4-(vinylsulfonyl)benzene、
[ 18 F]-1-(2-(2-fluoroethoxy)ethoxy)-4-(vinylsulfonyl)benzene、
[ 18 F]-1- (2- (2- (2-fluoroethoxy) ethoxy) ethoxy) -4- (vinylsulfonyl) bezene, etc.
Further, the liquid phase spectrum of the labeled intermediate 2 is shown in fig. 1 and fig. 2, and in fig. 1, it is shown that a single radioactive peak is detected by the radioactivity detector, and the peak-off time is about 14.5 min. The absence of a distinct nonradioactive impurity peak detected by the UV detector is shown in FIG. 2.
For the fluoro aryl vinyl sulfone labeled intermediate, generally, F-18 ionic compound is added into vinyl sulfone organic matter for heating reaction, and then separated and purified by HPLC, for example, taking labeled intermediate 2 as an example, as a preparation example, the preparation method is as follows:
s1, adding 1-2mg of 1-nitro-4- ((2- (4- (vinylsulfonyl) phenoxy) ethyl) sulfonyl) benzene to a solution containing [ alpha ], [ beta ] -n-butyl ] benzene 18 F]In anhydrous acetonitrile (20. mu.L/16 mCi) of fluoride ion, heating to 90 deg.C, reacting for 20min, cooling, and separating by HPLCObtaining a product;
s2, collecting a product peak, diluting the product peak with 10mL of water, passing the product peak through a Sep-Pak alumina column, loading the product peak on an HLB solid phase extraction column, washing the HLB column with 10mL of pure water, and eluting the product peak from the HLB solid phase extraction column with 200 μ L of methanol to obtain the purified 1- (2- (18F) ethoxy) -4- (vinylsulfonyl) benzene, wherein the reaction equation is as follows:
further, the molecular structure of the precursor small molecule a or the precursor small molecule b is as follows:
the molecular structure of the precursor small molecule a is as follows:
the molecular structure of the precursor small molecule b is as follows:
in the above molecular structure, n is a value in the range of 1 to 3, and may be 1, 2 or 3, for example.
As the precursor small molecule a, specific substances thereof may be (S) -2- (3- ((S) -1-carboxy-3- (2-merictoacetamido) propyl) ureido) pentandioic acid, (S) -2- (3- ((S) -1-carboxy-3- (3-merictopyramido) propyl) ureido) pentandioic acid, (S) -2- (3- ((S) -1-carboxy-3- (4-merictoacetamido) propyl) ureido) pentandioic acid, and the like.
Accordingly, as for the precursor small molecule b, a specific substance thereof may be (S) -2- (3- ((S) -3- ((R) -2-amino-3-meroptopanamido) -1-carboxypropyl) ureido) pentandioic acid, (S) -2- (3- ((S) -2-amino-4-meroptobutanamido) -1-carboxypropyl) ureido) pentandioic acid, (S) -2- (3- ((S) -2-amino-5-meroptopanamido) -1-carboxypropyl) ureido) pentandioic acid, or the like.
And (3) reacting the labeled intermediate with the precursor micromolecule in an alkaline buffer solution with the pH value of 8-9, and separating and purifying by high performance liquid chromatography to obtain the PET probe. The alkaline buffer is selected from sodium carbonate buffer, sodium borate buffer, potassium bicarbonate buffer, phosphate buffer, HEPES buffer or MES buffer. Because the labeled intermediate and the precursor small molecule are both of two types, after being combined in pairs, 4 PET probes can be obtained, and the molecular structures of the probes are as follows:
PET probe a-1 (obtained by reacting labeled intermediate 1 with precursor small molecule a):
PET probe a-2 (obtained by reacting labeled intermediate 2 with precursor small molecule a):
PET probe b-1 (obtained by reacting labeled intermediate 1 with precursor small molecule b):
PET probe b-2 (obtained by reacting labeled intermediate 2 with precursor small molecule b):
in the above molecular structure, n has a value in the range of 1 to 3, and may be, for example, 1, 2 or 3; the value of m is in the range of 1-3, and may be, for example, 1, 2, or 3. Taking developer a-2 as an example, the reaction equation is:
further, for better illustrating the present invention, specific examples are listed below:
example 1 (developer a-2, m ═ 1, n ═ 1)
An F-18 labeled PSMA targeting PET probe (a-2) is prepared by the following steps:
s1, adding 1-2mg of the tag precursor 2 to a solution containing [ solution ] 18 F]Heating to 90 deg.C in anhydrous acetonitrile solution (20 μ L/16mCi) of fluoride ion, reacting for 20min, cooling, and separating the obtained product by HPLC;
s2, collecting a product peak, diluting the product peak with 10mL of water, passing through a Sep-Pak alumina column, loading the product peak on an HLB solid-phase extraction column, washing the HLB column with 10mL of pure water, leaching the product peak from the HLB solid-phase extraction column with 200 mu L of methanol to obtain the purified 1- (2- (18F) ethoxy) -4- (vinylsulfonyl) benzene,
s3, adding 100 μ g of precursor small molecule a into 100 μ g of sodium borate buffer (pH 8.5), adding 100 μ g of the prepared methanol solution containing 1- (2- (18F) ethoxy) -4- (vinylsulfonyl) benzene, and heating at 85 ℃ for 15 min;
s4, after the reaction is finished, purifying the product by HPLC, and confirming the identity of the labeled compound by co-injection with corresponding non-radioactive standard;
s5, collecting the eluent with the peak time of 11.8min, diluting the collected eluent with water until the content of the organic solvent acetonitrile is below 5%, hanging the eluent on an HLB solid phase extraction column, washing with 10mL of water to remove the redundant acidic solvent, finally leaching with 200 mu L of ethanol to a product bottle, and diluting with normal saline until the content of the ethanol is below 10%, thus obtaining the PET probe a-2.
In the above, Shimadzu analytical HPLC was used, and the HPLC conditions were:
a chromatographic column: eclipse Plus C185 μm, 4.6X 250 mm;
flow rate: 1 mL/min; the wavelength of the PDA was set to: 254nm, column temperature: 35 ℃;
mobile phase A: HPLC grade acetonitrile with 0.1 v% TFA (trifluoroacetic acid); mobile phase B: water with 0.1 v% TFA;
elution conditions:
within the initial 2min, the mobile phase a/mobile phase B was 5/95(v/v), and within 2-15min, the mobile phase a/mobile phase B was changed at a constant speed to 5/95(v/v) to 95/5 (v/v).
The F-19 standard corresponding to the PET probe obtained above is characterized by mass spectrum m/z: [ M + H ]]:Calcd for C 24 H 34 18 FN 3 O 11 S 2 624.18, find 624.10. The prepared probe is subjected to radioactive HPLC analysis, and the detected spectrum of the radioactive detector and the detected spectrum of the UV detector are shown in figures 3 and 4. In fig. 3, it is shown that the radioactivity detector detects a single product (imaging agent a-2, m is 1, n is 1) radioactivity peak, and the peak-off time is about 12 min. The absence of a distinct non-radioactive impurity peak in the sample detected by the uv detector is shown in figure 4.
Example 2
An F-18 labeled PSMA targeting PET probe a-1(n is 1), and the preparation method comprises the following steps:
s1, adding 1-2mg of the tag precursor 1 to a solution containing [ solution ] 18 F]Heating to 90 deg.C in anhydrous acetonitrile solution (20 μ L/16mCi) of fluoride ion, reacting for 20min, cooling, and separating the obtained product by HPLC;
s2, collecting a product peak, diluting the product peak with 10mL of water, passing through a Sep-Pak alumina column, loading the product peak on an HLB solid-phase extraction column, washing the HLB column with 10mL of pure water, and leaching the HLB solid-phase extraction column with 200 mu L of methanol to obtain purified 1-18 fluoro-4- (vinylsulfonyl) benzene;
s3, adding 100 μ g of precursor small molecule a (n ═ 1) into 100 μ g of sodium borate buffer (pH 8.5), adding 100 μ g of the above prepared methanol solution containing 1-18 fluoro-4- (vinylsulfonyl) benzene, and heating at 85 ℃ for 15 min;
s4, after the reaction is finished, purifying the product by HPLC, and confirming the identity of the labeled compound by co-injection with corresponding non-radioactive standard;
and S5, collecting the eluent with the peak time of 12.6min, diluting the collected eluent with water until the content of the organic solvent acetonitrile is below 5%, hanging the eluent on an HLB solid phase extraction column, washing the eluent with 10mL of water to remove the redundant acidic solvent, finally leaching the eluent with 200 mu L of ethanol to a product bottle, and diluting the product bottle with physiological saline until the content of the ethanol is below 10%, thereby obtaining the PET probe a-1(n is 1).
Example 3
An F-18 labeled PSMA targeting PET probe a-1 (n-3), which is prepared by the following steps:
s1, adding 1 to 2mg of the label precursor 1 to a solution containing 18 F]Heating to 90 deg.C in anhydrous acetonitrile solution (20 μ L/16mCi) of fluoride ion, reacting for 20min, cooling, and separating the obtained product by HPLC;
s2, collecting a product peak, diluting with 10mL of water, passing through a Sep-Pak alumina column, loading onto an HLB solid-phase extraction column, washing the HLB column with 10mL of pure water, and leaching from the HLB solid-phase extraction column with 200 mu L of methanol to obtain purified 1-18 fluoro-4- (vinylsulfonyl) benzene;
s3, adding 100 μ g of precursor small molecule a (n ═ 3) into 100 μ g of sodium borate buffer (pH 8.5), adding 100 μ g of the prepared methanol solution containing 1-18 fluoro-4- (vinylsulfonyl) benzene, and heating at 85 ℃ for 15 min;
s4, after the reaction is finished, purifying the product by HPLC, and confirming the identity of the labeled compound by co-injection with corresponding non-radioactive standard;
and S5, collecting the eluent with the peak time of 14min, diluting the collected eluent with water until the content of the organic solvent acetonitrile is below 5%, hanging the eluent on an HLB solid phase extraction column, washing the eluent with 10mL of water to remove the redundant acidic solvent, finally leaching the eluent with 200 mu L of ethanol to a product bottle, and diluting the product bottle with physiological saline until the content of the ethanol is below 10%, thereby obtaining the PET probe a-1 (n-3).
Example 4
An F-18 labeled PSMA targeting PET probe b-1(n is 1), and the preparation method comprises the following steps:
s1, adding 1 to 2mg of the label precursor 1 to a solution containing 18 F]Heating to 90 deg.C in anhydrous acetonitrile solution (20 μ L/16mCi) of fluoride ion, reacting for 20min, cooling,separating the resulting product by HPLC;
s2, collecting a product peak, diluting with 10mL of water, passing through a Sep-Pak alumina column, loading onto an HLB solid-phase extraction column, washing the HLB column with 10mL of pure water, and leaching from the HLB solid-phase extraction column with 200 mu L of methanol to obtain purified 1-18 fluoro-4- (vinylsulfonyl) benzene;
s3, adding 100 μ g of precursor small molecule b (n ═ 1) into 100 μ g of sodium borate buffer (pH 8.5), then adding 100 μ g of the above prepared methanol solution containing 1-18 fluoro-4- (vinylsulfonyl) benzene, and heating at 85 ℃ for 15 min;
s4, after the reaction is finished, purifying the product through HPLC, and confirming the identity of the labeled compound through co-injection with a corresponding non-radioactive standard;
and S5, collecting the eluent with the peak time of 14.6min, diluting the collected eluent with water until the content of the organic solvent acetonitrile is below 5%, hanging the eluent on an HLB solid phase extraction column, washing the column with 10mL of water to remove the redundant acidic solvent, finally rinsing the column with 200 mu L of ethanol to a product bottle, and diluting the product bottle with normal saline until the content of the ethanol is below 10%, thereby obtaining the PET probe b-1(n is 1).
Test procedures and results
Modeling an experimental animal:
LNCaP cells are typically grown in ATCC 1640 medium containing 10% fetal bovine serum and 1% diabody at 37 deg.C with 5% CO 2 Culturing in an incubator, and carrying out passage at intervals of 1-2 days, wherein the passage ratio is one to three. Nod/scid male mice were inoculated with 2X 10 in a total volume of 100. mu.L 6 LNCaP cells were mixed with RPMI 1640 pure medium and matrigel in a 1:1 ratio. The tumors grew 500-1000mm one month after inoculation 3 Experiments can be performed.
PET/CT imaging of small animals:
carrying out gas anesthesia (0.8mL/min oxygen, 1.5% isoflurane) on a tumor-bearing model mouse, injecting an imaging agent through tail vein, wherein the dosage is 25-35 mu Ci, statically scanning and acquiring PET/CT images at time points of 0.5h, 1h and 2h after acquisition and injection, acquiring the PET for 20min, delineating a region of interest (ROI) after image collection and reconstruction, and calculating the% ID/g of the absorbed dosage at the position.
Test results
Example 1: as shown in fig. 6, imaging agent a-2(n ═ 1, m ═ 1) was PET/CT imaged in tumor bearing LnCap mouse animals. 2h after tail vein injection, the probe can achieve the tumor uptake of 5.32% ID/g and the muscle uptake of 0.07ID/g through the imaging of PET/CT static scanning of small animals, and has a quite high tumor/muscle ratio (76).
Example 2: as shown in fig. 7, imaging agent a-1(n ═ 1) was PET/CT imaged in tumor-bearing LnCap mouse animals. 2h after tail vein injection, the probe can achieve 11.37% ID/g of tumor uptake and 0.10% ID/g of muscle uptake by imaging of PET/CT static scanning of small animals, and has a quite high (113.70) tumor/muscle ratio.
Example 3: as shown in fig. 8, imaging agent a-1(n ═ 3) was PET/CT imaged in tumor-bearing LnCap mouse animals. 2h after tail vein injection, the probe is obtained by imaging of PET/CT static scanning of small animals, the tumor uptake of the probe can reach 2.86% ID/g, the muscle uptake is 0.13% ID/g, and the tumor/muscle ratio is higher (22).
Comparative example 1: as shown in FIG. 5, the treatment was carried out on the same batch of LNCaP tumor-bearing mice 68 Ga]Imaging at 2h time point after injection of PSMA-11, tumor uptake was 3.85% ID/g, muscle uptake was 0.07% ID/g, and tumor/muscle ratio was 55.
From the above structure, it can be obtained that compared with the FDA-approved prostate cancer imaging agent 68 Ga]PSMA-11, the tumor uptake of imaging agent a-1(n ═ 1) is about 3 times, the tumor uptake of imaging agent a-2(n ═ 1, m ═ 1) is about 1.5 times, the two imaging agents are metabolized by liver and kidney, the image background is low, and the target tissue is clearly imaged.
Meanwhile, in the article "research on development of PSMA (prostate cancer PSMA targeted contrast agent 18F-Glu-Urea-Lys and PET scanning research", the published images show that the original literature (ONCOLOGY LETTERS, 10: 2299-2302,2015) does not have definite uptake values and image color bar, and cannot provide contrast of specific uptake values, but from the image point of view, the liver and abdomen of the mouse have a large amount of imaging agent concentration, the image target/non-target ratio is low, and the background is unclear) The uptake of the imaging agent is high in the liver and intestinal tract, while the uptake of the target tissue tumor is only slightly higher than that of the muscle tissue. In contrast, the developer of the present invention is compared with 18 The F-Glu-Urea-Lys contrast agent has the advantages of mild labeling condition, good in-vivo distribution characteristic and high tumor target tissue uptake.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. The F-18 labeled PSMA targeted PET probe is characterized by being obtained by reacting a labeled intermediate with a precursor small molecule, wherein the labeled intermediate is a fluorinated aryl vinyl sulfone labeled intermediate, and the precursor small molecule is a sulfydryl-containing precursor small molecule with Lys-urea-Glu as a parent nucleus structure.
2. The F-18 labeled PSMA-targeted PET probe of claim 1, wherein the labeled intermediate is labeled intermediate 1 or labeled intermediate 2, and the molecular structure thereof is as follows:
the molecular structure of the labeled intermediate 1 is:
the molecular structure of the labeled intermediate 2 is:
in the above molecular structure, m has a value ranging from 1 to 3.
3. The F-18 labeled PSMA-targeted PET probe of claim 1, wherein the precursor small molecule is precursor small molecule a or precursor small molecule b, and the molecular structure thereof is as follows:
the molecular structure of the precursor small molecule a is as follows:
the molecular structure of the precursor small molecule b is as follows:
in the above molecular structure, n has a value ranging from 1 to 3.
4. The F-18 labeled PSMA targeted PET probe as claimed in claim 1, wherein the labeled intermediate reacts with the precursor small molecule in an alkaline buffer solution with the pH value of 8-9, and the PET probe is obtained by separation and purification through high performance liquid chromatography; the alkaline buffer is selected from sodium carbonate buffer, sodium borate buffer, potassium bicarbonate buffer, phosphate buffer, HEPES buffer or MES buffer.
5. The F-18 labeled PSMA-targeted PET probe of claim 1, wherein the PET probe is a PET probe a-1, a-2, b-1, or b-2, having a molecular structure of:
the molecular structure of the PET probe a-1 is as follows:
the molecular structure of the PET probe a-2 is as follows:
the molecular structure of the PET probe b-1 is as follows:
the molecular structure of the PET probe b-2 is as follows:
in the above molecular structure, n has a value ranging from 1 to 3, and m has a value ranging from 1 to 3.
6. The method for preparing the F-18 labeled PSMA-targeted PET probe of claim 1, comprising the steps of:
s1, adding the F-18 ionic compound into a vinyl sulfone organic substance for heating reaction, cooling, and separating a product through HPLC;
s2, diluting the product with water, passing through an alumina column, and then passing through a solid phase extraction column to obtain a separated and purified fluoro aryl vinyl sulfone labeled intermediate;
s3, adding the precursor small molecules and the fluoro aryl vinyl sulfone labeled intermediate into an alkaline buffer solution together, reacting for 5-60min at 100 ℃, and purifying the product by HPLC after the reaction is finished;
s4, collecting the eluent, diluting the eluent with water, controlling the content of an organic solvent in the eluent to be below 5 v%, hanging the eluent on a solid phase extraction column, washing the acidic solvent with water, rinsing the eluent with ethanol to a product bottle, and finally diluting the eluent with normal saline until the content of the ethanol is below 10 v%.
7. The method of claim 6, wherein the chromatographic conditions of the HPLC are:
a chromatographic column: eclipse Plus C185 μm, 4.6X 250 mm;
flow rate: 1 mL/min; wavelength: 254nm, column temperature: 35 ℃;
a mobile phase A: HPLC grade acetonitrile with 0.1 v% TFA; mobile phase B: water with 0.1 v% TFA;
elution conditions:
0 → 2 min: the volume ratio of mobile phase a/mobile phase B was 5/95;
2 → 15 min: the volume ratio mobile phase a/mobile phase B varied uniformly to 95/5.
8. The preparation method according to claim 6, wherein in step S1, the F-18 ionic compound is dissolved in anhydrous acetonitrile, and then added to the vinylsulfone organic substance to perform a heating reaction at a temperature of 80-100 ℃ for 5-60 min.
9. The preparation method according to claim 6, wherein the vinylsulfone organic compound is a labeled precursor 1 or a labeled precursor 2, and the molecular structure thereof is as follows:
the molecular structure of the label precursor 1 is:
the molecular structure of the label precursor 2 is:
in the above, Ar ═ 2,6 diisopropylphenyl.
10. Use of the F-18 labeled PSMA-targeted PET probe of any of claims 1-5 for the preparation of a PET imaging agent.
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