CN115057801B - A F-18 labeled PSMA targeted PET probe and preparation method thereof - Google Patents
A F-18 labeled PSMA targeted PET probe and preparation method thereof Download PDFInfo
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Abstract
本发明公开了一种F‑18标记PSMA靶向PET探针及其制备方法，所述PET探针由标记中间体与前体小分子反应得到，所述标记中间体为氟代芳基乙烯砜类标记中间体，所述前体小分子为含巯基的以Lys‑urea‑Glu为母核结构的前体小分子。本发明通过氟代芳基乙烯砜类标记中间体，与含巯基的以Lys‑urea‑Glu为母核结构的前体反应，得到F‑18标记的靶向PSMA用于前列腺癌影像诊断的探针，该探针相比于FDA批准的PET显像剂[68Ga]‑PSMA‑11，其具有更优秀的肿瘤病灶探测能力，肿瘤摄取值约为其三倍，药物通过肝脏和肾脏代谢，代谢速度较慢，图像背景低，靶组织显像清晰，克服了现有显像剂所存在的技术问题。
The present invention discloses an F-18 labeled PSMA targeted PET probe and a preparation method thereof. The PET probe is obtained by reacting a labeled intermediate with a precursor small molecule. The labeled intermediate is a fluoroaryl vinyl sulfone labeled intermediate, and the precursor small molecule is a precursor small molecule containing a thiol group and having Lys-urea-Glu as a parent core structure. The present invention obtains an F-18 labeled targeted PSMA probe for prostate cancer imaging diagnosis by reacting a fluoroaryl vinyl sulfone labeled intermediate with a thiol group-containing precursor with Lys-urea-Glu as a parent core structure. Compared with the FDA-approved PET imaging agent [ 68Ga ]-PSMA-11, the probe has a better tumor lesion detection capability, a tumor uptake value of about three times that of the FDA-approved PET imaging agent [68Ga]-PSMA-11, and the drug is metabolized by the liver and kidneys, with a slower metabolic rate, a low image background, and clear target tissue imaging, thereby overcoming the technical problems existing in existing imaging agents.
Description
Technical Field
The invention relates to the technical field of PET image diagnosis, in particular to an F-18 marked PSMA targeted PET probe and a preparation method thereof.
Background
The Prostate Specific Membrane Antigen (PSMA) is a transmembrane glycoprotein located in prostate epithelial cells. PSMA is expressed at higher levels in 95% of prostate cancer patients, with upregulation of expression levels in Castration Resistant Prostate Cancer (CRPC) and metastatic prostate cancer. Thus, PSMA can be an ideal target for diagnosis and treatment of prostate cancer and metastatic lesions thereof. At present, there are various molecular probes with PSMA as targets in clinical experimental stages, and common PSMA molecular probes include monoclonal antibodies, small analysis inhibitors and the like. For example, 111 In labeled 7E11 is the first radiolabeled PSMA monoclonal antibody, which is the more successful drug for prostate cancer than SPECT imaging currently, but 7E11 binds only to the intramembrane segment of PSMA and is therefore only taken up by necrotic apoptotic cells, and imaging sensitivity is not high. The PSMA small molecular inhibitor has the advantages of good cell permeability, quick blood clearance and the like, and mainly comprises 3 major categories, namely 1, phosphate, phosphonite, phosphonate, phosphoramide and other derivatives, 2, mercapto, indole-mercapto, hydroxamic acid, sulfonamide derivatives and 3, urea derivatives. At present, the urea derivative micromolecular inhibitors entering the clinical experimental stage mainly comprise PSMA-11, PSMAI & T, PSMA-617 and the like. The PSMA small molecule inhibitor can be marked 18F、68 Ga for imaging of prostate cancer and 111Lu、90Y、131 I for treating the prostate cancer (refer to the literature of PET imaging of prostate cancer and nuclide treatment research progress of which PSMA is targeted, feng Yaqi, wang Peng, et al, university of Huazhong science and technology, report of 2020, volume 49, 1). However, the existing PSMA targeted PET imaging agent labeled nuclide Ga-68 has the problems of short half-life period, limited effective utilization time, insignificant tumor uptake in a prostate cancer cell metastasis model and the like, and the imaging effect still needs to be improved.
The Chinese paper (the research of a PSMA targeted contrast agent 18F-Glu-Urea-Lys and the research of PET scanning) (Zhang Zhiwei, the first hospital affiliated to university of Dalian medical science) successfully develops a 18 F-Glu-Urea-RPET/CT molecular probe which utilizes a marked amino acid to replace an R group, utilizes a magnetic resonance spectroscopy and a mass spectrometry to analyze and determine a compound structure, and successfully synthesizes the 18 F-Glu-Urea-Lys contrast agent which has good imaging effect on a target tumor, rapid and clear development, less nonspecific combination and rapid excretion through kidneys. However, the contrast agent has strong lipophilicity, high background uptake of liver and abdomen, low uptake capacity of tumor tissues to developer and low target/non-target tissue uptake ratio of the developer compared with the existing Ga-68-PSMA-11.
Disclosure of Invention
Aiming at the problems, the invention provides an F-18 marked PSMA targeted PET probe and a preparation method thereof, wherein the F-18 marked PSMA targeted PET probe is obtained by reacting a fluoro aryl vinyl sulfone marked intermediate with a precursor containing sulfhydryl groups and taking Lys-urea-Glu as a parent nucleus structure, and compared with an FDA approved PET imaging agent [ 68 Ga ] -PSMA-11, the F-18 marked PSMA targeted PET probe has more excellent tumor focus detection capability, the tumor uptake value is about three times of that of the probe, the drug is metabolized by liver and kidney, the non-target tissue uptake is low, the target tissue imaging is clear, and the technical problems of the existing imaging agents are overcome.
The F-18 marked PSMA targeted PET probe is obtained by reacting a marked intermediate with a precursor small molecule, wherein the marked intermediate is a fluorinated aryl vinyl sulfone marked intermediate, and the precursor small molecule is a precursor small molecule which contains sulfhydryl and takes Lys-urea-Glu as a parent nucleus structure.
Further, the labeling intermediate is a labeling intermediate 1 or a labeling 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 molecular structure, m may have a value ranging from 1 to 3, for example, 1, 2, or 3.
Further, the precursor small molecule is precursor small molecule a or precursor small molecule b, and the molecular structure 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 molecular structure, n may have a value ranging from 1 to 3, for example, 1, 2, or 3.
Further, the labeled intermediate is reacted with a precursor small molecule in an alkaline buffer with a pH value of 8-9 (for example, 8.1, 8.2, 8.3, 8.4, 8.5, 8.8, 9.0, etc., preferably 8.5), and the reaction mixture is subjected to high performance liquid chromatography to separate and purify the reaction mixture to obtain the PET probe, wherein 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 PET probe a-1, a-2, b-1 or b-2, and the molecular structure is as follows:
the molecular structure of PET probe a-1 is:
the molecular structure of PET probe a-2 is:
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 may have a value ranging from 1 to 3, for example, 1,2, or 3, and m may have a value ranging from 1 to 3, for example, 1,2, or 3.
Further, the invention also discloses a preparation method of the F-18 marked PSMA targeted PET probe, which comprises the following steps:
S1, adding an F-18 ion compound into vinyl sulfone organic matters, heating for reaction, cooling, and separating a product by HPLC;
S2, diluting a product with water, passing through an alumina column, and then passing through a solid phase extraction column to obtain a fluorinated aryl vinyl sulfone marked intermediate after separation and purification;
S3, adding the precursor small molecules and the fluorinated aryl vinyl sulfone marked 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 organic solvent in the eluent to be below 5% by volume, then hanging the eluent on a solid phase extraction column, washing off the acidic solvent with water, eluting the acidic solvent with ethanol to a product bottle, and finally diluting the eluent with normal saline to the content of ethanol to be below 10% by volume.
Further, the chromatographic separation conditions of the HPLC are:
the chromatographic column is Eclipse Plus C18-5 μm, 4.6X1250 mm;
the flow rate is 1mL/min, the wavelength is 254nm, and the column temperature is 35 ℃;
mobile phase A, HPLC grade acetonitrile containing 0.1v% TFA, mobile phase B, water containing 0.1v% TFA;
elution conditions:
0.fwdarw.2 min (within the first 2 min) the volume ratio of mobile phase A/mobile phase B is 5/95;
2-15 min (next 15 min) the volume ratio of mobile phase A/mobile phase B was changed to 95/5 at constant speed.
In step S1, F-18 ion compound is dissolved in anhydrous acetonitrile, and then added into vinyl sulfone organic matters for heating reaction at 80-100 ℃ for 5-60min.
Further, the vinyl sulfone organic matter is a labeling precursor 1 or a labeling precursor 2, and the molecular structure of the vinyl sulfone organic matter is as follows:
the molecular structure of the labeling precursor 1 is:
the molecular structure of the labeling precursor 2 is:
in the above, ar=2, 6 diisopropylphenyl.
Further, the marking precursor 1 may specifically be
1,3-diphenyl-2-(4-(vinylsulfonyl)phenoxy)-1H-imidazol-3-ium chloride、1,3-bis(2,6-diisopropylphenyl)-2-(4-(vinylsulfonyl)phenoxy)-1H-imidazol-3-iumchloride、1,3-bis(2,6-dimethylphenyl)-2-(4-(vinylsulfonyl)phenoxy)-1H-imidazol-3-iumchloride Etc.
Accordingly, the labeling precursor 2 may be 2-(4-(vinylsulfonyl)phenoxy)ethyl4-nitrobenzenesulfonate、2-(4-(vinylsulfonyl)phenoxy)ethyl4-methylbenzenesulfonate、2-(4-(vinylsulfonyl)phenoxy)ethyl methanesulfonate、2-(2-(4-(vinylsulfonyl)phenoxy)ethoxy)ethyl 4-nitrobenzenesulfonate、2-(2-(4-(vinylsulfonyl)phenoxy)ethoxy)ethyl 4-methylbenzenesulfonate、2-(2-(4-(vinylsulfonyl)phenoxy)ethoxy)ethyl methanesulfonate、2-(2-(2-(4-(vinylsulfonyl)phenoxy)ethoxy)ethoxy)ethyl 4-nitrobenzenesulfonate、2-(2-(2-(4-(vinylsulfonyl)phenoxy)ethoxy)ethoxy)ethyl4-methylbenzenesulfonate、2-(2-(2-(4-(vinylsulfonyl)phenoxy)ethoxy)ethoxy)ethyl methanesulfonate or the like.
Further, the invention also comprises the application of the F-18 marked PSMA targeted PET probe in preparing PET imaging agents.
In summary, due to the adoption of the technical scheme, the beneficial effects of the invention are as follows:
1. The F-18 marked targeted PSMA probe for prostate cancer image diagnosis is obtained through the reaction of the fluoro aryl vinyl sulfone marked intermediate and a precursor containing sulfhydryl and taking Lys-urea-Glu as a mother nucleus structure, compared with the FDA approved PET imaging agent [ 68 Ga ] -PSMA-11, the probe has more excellent tumor focus detection capability, the tumor uptake value is about three times of that of the PET imaging agent, the medicine is metabolized by liver and kidney, the metabolism speed is lower, the image background is low, the target tissue imaging is clear, and the technical problem of the existing imaging agent is solved;
2. Compared with the prior art, the invention has the special points that the marked small-molecule PET imaging agent has proper log P, high marking efficiency, good in-vivo and in-vitro stability, and difficult occurrence of metabolic F-18 ion removal, and compared with the prior art, the invention has the special points that the marked small-molecule PET imaging agent is different from the prior PET imaging agent in terms of PSMA-11 in animal model imaging, and the imaging agent of the invention has better tumor focus detection capability.
Drawings
FIG. 1 is a spectrum of detection by a radioactive detector of labeled intermediate 2;
FIG. 2 is a UV detector spectrum of labeled intermediate 2 at a detection wavelength of 254nm;
FIG. 3 is a spectrum of detection by the radioactive detector of imaging agent a-2 (n=1, m=1);
FIG. 4 is a graph of the UV detector detection spectrum of imaging agent a-2 (n=1), at 254nm;
FIG. 5 is a PET/CT image evaluation of a small animal with radioactive probe [ 68 Ga ] -PSMA-11 30min, 60min, 120min after intravenous injection in the tail of an LNCaP tumor-bearing mouse;
FIG. 6 is a PET/CT image evaluation of the imaging agent a-2 (n=1, m=1) in mice 30min, 60min, 120min after intravenous injection of LNCaP tumor bearing mice tail;
FIG. 7 is PET/CT image evaluation of the small animals 30min, 60min, 120min after intravenous injection of imaging agent a-1 (n=1) in the tail of LNCaP tumor bearing mice;
Fig. 8 is PET/CT image evaluation of small animals 30min, 60min, 120min after LNCaP tumor bearing mice tail intravenous of imaging agent a-1 (n=3).
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings.
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The F-18 marked PSMA targeted PET probe is obtained by reacting a marked intermediate with a precursor small molecule, wherein the marked intermediate is a fluorinated aryl vinyl sulfone marked intermediate, the precursor small molecule is a precursor small molecule which contains sulfhydryl and takes Lys-urea-Glu as a parent nucleus structure, the fluorinated aryl vinyl sulfone marked intermediate is marked intermediate 1 or marked 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 molecular structure, m may have a value ranging from 1 to 3, for example, 1, 2, or 3.
For the labeled intermediate 1, the specific substance thereof may be [18F]-1-fluoro-4-(vinylsulfonyl)benzene、[18F]-1-fluoro-3-(vinylsulfonyl)benzene、[18F]-1-fluoro-2-(vinylsulfonyl)benzene or the like.
Accordingly, for the labeling intermediate 2, the specific substance thereof may be
[18F]-1-(2-fluoroethoxy)-4-(vinylsulfonyl)benzene、
[18F]-1-(2-(2-fluoroethoxy)ethoxy)-4-(vinylsulfonyl)benzene、
[ 18 F ] -1- (2- (2- (2-fluoroethoxy) ethoxy) ethoxy) -4- (vinylsulfonyl) benzene, etc.
Further, as shown in fig. 1 and 2, the liquid phase diagram of the labeled intermediate 2 shows that the radioactivity detector detects a single radioactivity peak, and the peak time is about 14.5min in fig. 1. The ultraviolet detector is shown in fig. 2 to detect no significant non-radioactive impurity peaks.
For the fluoroaryl vinyl sulfone marked intermediate, generally, an F-18 ionic compound is added into vinyl sulfone organic matters for heating reaction, and then the fluoroaryl vinyl sulfone marked intermediate is obtained through HPLC separation and purification, for example, taking marked intermediate 2 as an example, and the preparation method is as follows:
S1, adding 1-2mg of 1-nitro-4- ((2- (4- (vinylsulfonyl) phenoxy) ethyl) sulfonyl) benzene into anhydrous acetonitrile solution (20 mu L/16 mCi) containing [ 18 F ] fluoride ions, heating to 90 ℃, 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 the diluted product on an HLB solid phase extraction column, washing the HLB column with 10mL of pure water, and eluting the HLB solid phase extraction column with 200 mu L of methanol to obtain purified 1- (2- (18F) ethoxy) -4- (vinylsulfonyl) benzene, wherein the reaction equation is as follows:
further, the precursor small molecule a or the precursor small molecule b has the following molecular structure:
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 molecular structure, n may have a value ranging from 1 to 3, for example, 1, 2, or 3.
For the precursor small molecule a, a specific substance thereof may be (S)-2-(3-((S)-1-carboxy-3-(2-mercaptoacetamido)propyl)ureido)pentanedioic acid、(S)-2-(3-((S)-1-carboxy-3-(3-mercaptopropanamido)propyl)ureido)pentanedioic acid、(S)-2-(3-((S)-1-carboxy-3-(4-mercaptobutanamido)propyl)ureido)pentanedioic acid or the like.
Accordingly, for the precursor small molecule b, the specific substance thereof may be (S)-2-(3-((S)-3-((R)-2-amino-3-mercaptopropanamido)-1-carboxypropyl)ureido)pentanedioic acid、(S)-2-(3-((S)-3-((S)-2-amino-4-mercaptobutanamido)-1-carboxypropyl)ureido)pentanedioic acid、(S)-2-(3-((S)-3-((S)-2-amino-5-mercaptopentanamido)-1-carboxypropyl)ureido)pentanedioic acid or the like.
The labeled intermediate reacts with the precursor micromolecules in alkaline buffer solution with the pH value of 8-9, and the PET probe is obtained through high performance liquid chromatography separation and purification. The alkaline buffer is selected from sodium carbonate buffer, sodium borate buffer, potassium bicarbonate buffer, phosphate buffer, HEPES buffer or MES buffer. Since the labeling intermediates and the precursor small molecules are two, after being combined in pairs, 4 PET probes can be obtained, and the molecular structures of the labeling intermediates and the precursor small molecules are respectively 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 may have a value ranging from 1 to 3, for example, 1,2, or 3, and m may have a value ranging from 1 to 3, for example, 1,2, or 3. Taking the developer a-2 as an example, the reaction equation is as follows:
further, for better illustration of the present invention, specific examples are set forth below:
example 1 (imaging agent a-2, m=1, n=1)
An F-18 labeled PSMA-targeted PET probe (a-2), the preparation method of which comprises the following steps:
S1, adding 1-2mg of marked precursor 2 into anhydrous acetonitrile solution (20 mu L/16 mCi) containing [ 18 F ] fluoride ions, heating to 90 ℃, 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, eluting with 200 mu L of methanol from the HLB solid phase extraction column to obtain purified 1- (2- (18F) ethoxy) -4- (vinylsulfonyl) benzene,
S3, adding 100-200 mug of precursor small molecule a into 100 mug of sodium borate buffer solution (pH=8.5), then adding 100 mug of the prepared methanol solution containing 1- (2- (18F) ethoxy) -4- (vinylsulfonyl) benzene, and heating and reacting for 15min at 85 ℃;
S4, purifying the product by HPLC after the reaction is finished, and confirming the identity of the labeled compound by co-injection with a corresponding non-radioactive standard;
S5, collecting eluent with peak time of 11.8min, diluting the collected eluent with water until the acetonitrile content of an organic solvent is below 5%, then hanging the eluent on an HLB solid phase extraction column, washing the eluent with 10mL of water to remove redundant acidic solvent, finally leaching the eluent with 200 mu L of ethanol to a product bottle, and diluting the eluent with normal saline until the ethanol content is below 10%, thus obtaining the PET probe a-2.
Among the above, shimadzu analytical HPLC was used, and the HPLC conditions were:
the chromatographic column is Eclipse Plus C18-5 μm, 4.6X1250 mm;
The flow rate is 1mL/min, the wavelength of PDA is 254nm, and the column temperature is 35 ℃;
Mobile phase A, HPLC grade acetonitrile containing 0.1v% TFA (trifluoroacetic acid), mobile phase B, water containing 0.1v% TFA;
elution conditions:
Mobile phase a/mobile phase b=5/95 (v/v) during the initial 2min, mobile phase a/mobile phase b=5/95 (v/v) changed to mobile phase a/mobile phase b=95/5 (v/v) at a constant rate over 2-15 min.
The F-19 standard corresponding to the obtained PET probe represents M/z: [ M+H ]: calcd for C 24H34 18FN3O11S2 624.18,find 624.10 by mass spectrum. The prepared probe was subjected to radioactive HPLC analysis, and the spectra detected by the radioactive detector and the UV detector are shown in FIGS. 3 and 4. In fig. 3, the radioactivity detector detects a single radioactive peak of the product (imaging agent a-2, m=1, n=1), and the peak-out time is about 12 min. The ultraviolet detector in fig. 4 shows that the sample does not contain significant peaks of non-radioactive impurities.
Example 2
An F-18 labeled PSMA-targeted PET probe a-1 (n=1), the preparation method of which comprises the following steps:
S1, adding 1-2mg of labeled precursor 1 into anhydrous acetonitrile solution (20 mu L/16 mCi) containing [ 18 F ] fluoride ions, heating to 90 ℃, 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 the diluted product peak onto an HLB solid phase extraction column, washing the HLB column with 10mL of pure water, and eluting the HLB solid phase extraction column with 200 mu L of methanol to obtain purified 1-18 fluoro-4- (vinylsulfonyl) benzene;
S3, adding 100-200 mug of precursor small molecule a (n=1) into 100 mug of sodium borate buffer solution (pH=8.5), then adding 100 mug of the prepared methanol solution containing 1-18 fluorine-4- (vinylsulfonyl) benzene, and heating and reacting for 15min at 85 ℃;
S4, purifying the product by HPLC after the reaction is finished, and confirming the identity of the labeled compound by co-injection with a corresponding non-radioactive standard;
S5, collecting eluent with peak time of 12.6min, diluting the collected eluent with water until the acetonitrile content of an organic solvent is below 5%, then hanging the eluent on an HLB solid phase extraction column, washing the eluent with 10mL of water to remove redundant acidic solvent, finally leaching the eluent with 200 mu L of ethanol to a product bottle, and diluting the eluent with normal saline until the ethanol content is below 10%, thus obtaining the PET probe a-1 (n=1).
Example 3
An F-18 labeled PSMA-targeted PET probe a-1 (n=3), the preparation method of which comprises the following steps:
S1, adding 1-2mg of labeled precursor 1 into anhydrous acetonitrile solution (20 mu L/16 mCi) containing [ 18 F ] fluoride ions, heating to 90 ℃, 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 the diluted product peak onto an HLB solid phase extraction column, washing the HLB column with 10mL of pure water, and eluting the HLB solid phase extraction column with 200 mu L of methanol to obtain purified 1-18 fluoro-4- (vinylsulfonyl) benzene;
S3, adding 100-200 mug of precursor small molecule a (n=3) into 100 mug of sodium borate buffer solution (pH=8.5), then adding 100 mug of the prepared methanol solution containing 1-18 fluorine-4- (vinylsulfonyl) benzene, and heating and reacting for 15min at 85 ℃;
S4, purifying the product by HPLC after the reaction is finished, and confirming the identity of the labeled compound by co-injection with a corresponding non-radioactive standard;
S5, collecting eluent with peak time of 14min, diluting the collected eluent with water until the acetonitrile content of an organic solvent is below 5%, then hanging the eluent on an HLB solid phase extraction column, washing the excessive acidic solvent with 10mL of water, finally leaching the eluent with 200 mu L of ethanol to a product bottle, and diluting the eluent with normal saline until the ethanol content is below 10%, thus obtaining the PET probe a-1 (n=3).
Example 4
An F-18 labeled PSMA-targeted PET probe b-1 (n=1), the preparation method of which comprises the following steps:
S1, adding 1-2mg of labeled precursor 1 into anhydrous acetonitrile solution (20 mu L/16 mCi) containing [ 18 F ] fluoride ions, heating to 90 ℃, 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 the diluted product peak onto an HLB solid phase extraction column, washing the HLB column with 10mL of pure water, and eluting the HLB solid phase extraction column with 200 mu L of methanol to obtain purified 1-18 fluoro-4- (vinylsulfonyl) benzene;
S3, adding 100-200 mug of precursor small molecule b (n=1) into 100 mug of sodium borate buffer solution (pH=8.5), then adding 100 mug of the prepared methanol solution containing 1-18 fluorine-4- (vinylsulfonyl) benzene, and heating and reacting for 15min at 85 ℃;
S4, purifying the product by HPLC after the reaction is finished, and confirming the identity of the labeled compound by co-injection with a corresponding non-radioactive standard;
S5, collecting eluent with peak time of 14.6min, diluting the collected eluent with water until the acetonitrile content of an organic solvent is below 5%, then hanging the eluent on an HLB solid phase extraction column, washing the eluent with 10mL of water to remove redundant acidic solvent, finally leaching the eluent with 200 mu L of ethanol to a product bottle, and diluting the eluent with normal saline until the ethanol content is below 10%, thus obtaining the PET probe b-1 (n=1).
Test procedure and results
Modeling of experimental animals:
LNCaP cells are typically cultured in ATCC 1640 medium containing 10% fetal bovine serum and 1% diabodies in 37℃and 5% CO 2 incubator at 1-2 day intervals at a rate of one-to-three passages. Nod/scid male mice were vaccinated with a total volume of 100. Mu.L of a solution of 2X 10 6 LNCaP cells mixed with RPMI 1640 pure medium and matrigel at a 1:1 ratio. One month after inoculation, tumors grow to 500-1000mm 3 and experiments can be performed.
PET/CT imaging of small animals:
tumor-bearing model mice were subjected to gas anesthesia (0.8 mL/min oxygen, 1.5% isoflurane), and were injected with an imaging agent via the tail vein at a dose of 25-35 μCi, and PET/CT images were acquired by static scanning at 0.5h, 1h, and 2h after injection, PET was acquired for 20min, and after image acquisition and reconstruction, the region of interest (ROI) was delineated, and the% ID/g of intake dose was calculated there.
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 mice. 2h after tail vein injection, the tumor uptake of the probe can reach 5.32% ID/g through the imaging of PET/CT static scanning of small animals, the muscle uptake is 0.07ID/g, and the tumor/muscle ratio is quite high (76).
Example 2 imaging agent a-1 (n=1) was visualized in a tumor-bearing LnCap mouse small animal PET/CT as shown in fig. 7. 2h after tail vein injection, the tumor uptake of the probe can reach 11.37% ID/g and the muscle uptake is 0.10% ID/g through imaging of PET/CT static scanning of small animals, and the probe has quite high tumor/muscle ratio (113.70).
Example 3 imaging agent a-1 (n=3) was visualized in a tumor-bearing LnCap mouse small animal PET/CT as shown in fig. 8. 2h after tail vein injection, the tumor uptake of the probe can reach 2.86% ID/g and the muscle uptake is 0.13% ID/g through the imaging of PET/CT static scanning of small animals, and the probe has a higher tumor/muscle ratio of (22).
Comparative example 1 As shown in FIG. 5, on the same batch of LNCaP tumor-bearing mice, [ 68 Ga ] -PSMA-11 was subjected to imaging at a time point of 2 hours after injection, tumor uptake was 3.85% ID/g, muscle uptake was 0.07% ID/g, and tumor/muscle ratio was 55.
As can be seen from the above structure, compared with FDA-approved prostate cancer imaging agent [ 68 Ga ] -PSMA-11, the tumor uptake value of agent a-1 (n=1) is about 3 times, the tumor uptake value of agent a-2 (n=1, m=1) is about 1.5 times, and both agents are metabolized by the liver and kidney, resulting in low image background and clear imaging of the target tissue.
Meanwhile, in the paper of research and PET scanning research of a PSMA targeted contrast agent 18F-Glu-Urea-Lys, images disclosed in the paper show that (original document (ONCOLOGY LETTERS,10:2299-2302,2015) does not have a clear uptake value and an image color bar, and specific uptake value contrast cannot be provided, but from the image, the liver and the abdomen of a mouse have a large amount of concentrated imaging agent, the image target/non-target ratio is low, the background is unclear), the uptake of the imaging agent in the liver and the intestinal tract is high, and the uptake of the tumor of a target tissue is only slightly higher than that of muscle tissue. Compared with 18 F-Glu-Urea-Lys contrast medium, the contrast medium of the invention has the advantages of mild labeling condition, good in vivo distribution characteristic and high tumor target tissue uptake.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (6)
1. The F-18 marked PSMA targeted PET probe is characterized in that the PET probe is obtained by reacting a marked intermediate with a precursor small molecule, wherein the marked intermediate is a fluorinated aryl vinyl sulfone marked intermediate, the precursor small molecule is a precursor small molecule which contains sulfhydryl and takes Lys-urea-Glu as a parent nucleus structure, and the marked intermediate is marked intermediate 1 or marked intermediate 2, and has the molecular structure as follows:
The molecular structure of the labeled intermediate 1 is:
The molecular structure of the labeled intermediate 2 is:
in the molecular structure, the value range of m is 1-3;
The precursor small molecule is precursor small molecule a or precursor small molecule b, and the molecular structure 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 molecular structure, the value range of n is 1-3;
The labeling intermediate reacts with precursor small molecules in an alkaline buffer solution with the pH value of 8-9, and the PET probe is obtained through high performance liquid chromatography separation and purification, wherein the alkaline buffer solution is selected from sodium carbonate buffer solution, sodium borate buffer solution, potassium bicarbonate buffer solution, phosphoric acid buffer solution, HEPES buffer solution or MES buffer solution.
2. The F-18 labeled PSMA-targeted PET probe of claim 1, wherein the PET probe is PET probe a-1, a-2, b-1, or b-2, having a molecular structure of:
the molecular structure of PET probe a-1 is:
the molecular structure of PET probe a-2 is:
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 molecular structure, the value range of n is 1-3, and the value range of m is 1-3.
3. The method of preparing an F-18 labeled PSMA-targeted PET probe of claim 1, comprising the steps of:
S1, adding an F-18 ion compound into vinyl sulfone organic matters, heating for reaction, cooling, and separating a product by HPLC;
S2, diluting a product with water, passing through an alumina column, and then passing through a solid phase extraction column to obtain a fluorinated aryl vinyl sulfone marked intermediate after separation and purification;
S3, adding the precursor small molecules and the fluorinated aryl vinyl sulfone marked 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 organic solvent in the eluent to be below 5% by volume, then hanging the eluent on a solid phase extraction column, washing off the acidic solvent with water, eluting the acidic solvent with ethanol to a product bottle, and finally diluting the eluent with normal saline to the content of ethanol to be below 10% by volume.
4. A method of preparation according to claim 3, wherein the chromatographic separation conditions of the HPLC are:
the chromatographic column is Eclipse Plus C18-5 μm, 4.6X1250 mm;
the flow rate is 1mL/min, the wavelength is 254nm, and the column temperature is 35 ℃;
mobile phase A, HPLC grade acetonitrile containing 0.1v% TFA, mobile phase B, water containing 0.1v% TFA;
elution conditions:
0 to 2min, wherein the volume ratio of the mobile phase A to the mobile phase B is 5/95;
2-15 min, wherein the volume ratio of the mobile phase A to the mobile phase B is changed to 95/5 at a constant speed.
5. The process according to claim 3, wherein in step S1, F-18 ion compound is dissolved in anhydrous acetonitrile and then added into vinyl sulfone organic compound for heating reaction at 80-100deg.C for 5-60min.
6. The method according to claim 3, wherein the vinyl sulfone organic compound is a labeling precursor 1 or a labeling precursor 2, and has a molecular structure of:
the molecular structure of the labeling precursor 1 is:
the molecular structure of the labeling precursor 2 is:
in the above, ar=2, 6 diisopropylphenyl.
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