CN104324394A - Molecular probe developer, as well as preparation method and application thereof - Google Patents
Molecular probe developer, as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN104324394A CN104324394A CN201410611899.0A CN201410611899A CN104324394A CN 104324394 A CN104324394 A CN 104324394A CN 201410611899 A CN201410611899 A CN 201410611899A CN 104324394 A CN104324394 A CN 104324394A
- Authority
- CN
- China
- Prior art keywords
- trityl
- sulfo
- ethyl
- white solid
- solid product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention belongs to the technical field of radioactive pharmaceutical chemistry and clinical nuclear medicine, and relates to a molecular probe developer, as well as a preparation method and application thereof. The chemical structure of the molecular probe developer is as shown in the specification, wherein M is 99mTc, and NR1R2 is as shown in the specification. The synthesizing route of the preparation method is as shown in the specification. The prepared molecular probe developer has excellent tumor target performance and signal to noise ratio in a tumor mouse body, and can be developed into a tumor developer.
Description
Technical field
The invention belongs to radiopharmaceutical chemistry and clinical nuclear medicine technical field, relate to a kind of molecular probe developer and preparation method thereof, purposes, specifically relate to a kind of molecular probe developer for diagnosing tumor and Lymph node biopsy and preparation method thereof, purposes.
Background technology
The diagnosis of disease is generally divided in vitro and in vivo two kinds.Although in-vitro diagnosis is quick and convenient, its accuracy is poor, needs in-vivo diagnostic to check toward contact.In-vivo diagnostic is divided into again intrusive mood (having misery) and non-intruding in-vivo diagnostic (no pain).Medical Imaging has entered the molecular image epoch, and the research of molecular image comprises imaging device and molecular probe two aspects, and the development of novel molecular probe is the core of molecular image development.Generally speaking positron emission tomography art (PET)/SPECT (single photon emission computed tomography) (SPECT) is functional video picture, is not the anatomical structure video picture of tissue or organ.PET/SPECT video picture needs to use radiopharmaceutical as developer, and wherein the most frequently used is 99mTc and 18F and labelled compound thereof, and therefore its development depends on the development of novel developer.
Tumor is one of disease of serious threat human life, radionuclide image can reflect the change of the physiology of tumor, pathology, metabolism and function, and radionuclide image is a kind of Non-invaive examination method, plurality of advantages makes radionuclide image become the main method of diagnosing tumor.Fluorodeoxyglucose as 18F labelling is the fluoro derivatives of 1,5-anhydroglucitol.Complete chemical name is FDG, usually referred to as 18F-FDG, belongs to positron emission (PET) radioisotopic Value linear.To patient (patient, sufferer) in body after injection FDG, PET scanner can construct the image of reflection FDG distribution in vivo situation, is detecting in tumor cell proliferation as defined the application prospect without there being uniqueness in the diagnosis of lymph metastasis and cancer and classification.But 18F-FDG is barely satisfactory in melanomatous diagnosis and classification.And 18F-FDG is positron tracer, accelerator is needed to produce Value linear expensive; By contrast, 99mTc has half-life short (6.02 hours), gamma ray appropriate energy (140 kilo electron volt), conveniently can obtain from molybdenum PertechnetateSodium Iniection, the remarkable advantage such as cheap, that SPECT (single photon emission computed tomography) (SPECT) video picture uses the most general radionuclide, therefore, succeed in developing SPECT tracer, obviously can reduce inspection fee, alleviate patient's burden, have important economic implications and social meaning.
Fluorescent agent in fluorescent molecular tomography (FMT) not only enables scientist's examination and controlling biological, can also measure therapeutic response with accurate quantitative analysis biological mechanism and body depths in real time in non-intruding mode simultaneously.The 3D result that energy information generated is abundant.
Current is most scholar approval to melanoma ABCDE diagnostic method, but this diagnosis more relies on the experience of doctor.The golden index of diagnosis is histopathologic examination.Melanoma is insensitive to chemotherapy, radiotherapy, and surgical operation is main treatment hands end.Lymph node biopsy (SLNB) is the method comparing recommendation at present.SLN biopsy more and more for melanomatous by stages with the indication of selectivity lymph node dissection.Early discovery Operation in early stage can obtain good curative effect mostly, once metastasis, is difficult to control, poor prognosis.SPECT and fluorescent molecular tomography (FMT) all can be used for detection and the SLNB of the cancers such as breast carcinoma, melanoma, cervical cancer, carcinoma vulvae and colorectal cancer.Lymph node biopsy mainly contains three kinds of tracer methods, biological dye tracer method, namely FMT, and conventional biological dye mainly contains isosulfan blue (Isosulfan blue) and patent blue (Patent blue); Radiocolloid tracer method, i.e. SPECT, conventional radiocolloid has sulfur colloid, the colloidal antimony or human albumin etc. of 99mTc labelling; In fact in order to reduce false positive and false negative, the method adopted at most is associating Tracing detection method, namely combines biological dye tracer method and radiocolloid tracer method.No matter because biological dye tracer method or radiocolloid tracer method do not have a specificity, so false positive and false negative rate are still higher.Be unfavorable for the treatment of disease.
Targeting SPECT or SPECT/FMT combines, not only be beneficial to melanomatous early diagnosis but also with minimum tissue injury's precise ablation sentinel node, and can examination and controlling tumor, can also measure in real time in non-intruding mode and accurate quantitative analysis tumor mechanism and the therapeutic response to tumor simultaneously.
SPECT operation principle injects human body with some special compounds of labelling such as Short half-life nuclides 99mTc through vein, 99mTc can send gamma-rays by decay, gamma-rays can be converted into the signal of telecommunication and input computer, and machine cross sectional reconstruction is section or the 3-D view of a certain organ physiological situation of reflection human body as calculated.SPECT both can become flat image, also can around human body rotating collection, be redeveloped into high-resolution cross-sectional image.
SPECT radionuclide imaging in diagnosis and other imaging diagnosis have the difference of essence.It utilizes the radionuclide energy divergent-ray introduced in body, and by the distribution of external detection instrument sense radiation and amount, reach imaging object.And radionuclide (i.e. developer), absorb in vivo, distribute, blood flow, cell function, cell quantity, the factor such as metabolic activity and excretion drain situation that the process such as excretion depends on again internal organs or tissue, therefore radionuclide imaging is a kind of functional video picture.Although radionuclide imaging also can show the change of its anatomical morphology, the anatomy of image differentiates rate variance, and the definition of its image determines primarily of the functional status of internal organs or tissue, and the focus being usually less than 1cm is difficult to be found by conventional SPECT video picture.But we SPECT of invention will improve noise greatly, thus likely find the focus being less than 1cm.
Sigma-receptor and cell function, bioprocess and numerous disease in close relations, have at least two kinds of hypotypes to be identified at present: i.e. σ 1 type and σ 2 receptor.The development of σ 1 receptor developer will provide responsive special diagnostic method for CNS neuropsychiatric disease, and the early diagnosis for tumor is provided sensitive molecular probe by the research of σ 2 receptor developer.Sigma-receptor is extensively present in central nervous system (CNS), in close relations with the neuropsychiatric disease of CNS.Thus high-affinity is had with sigma-receptor and optionally radioactive indicator can as the sensitive molecular probe of early diagnosis neuropsychiatric disease.Meanwhile, sigma-receptor has highly expression in the many tumor cell lines of the mankind, as melanoma, glioma, breast carcinoma, pulmonary carcinoma and carcinoma of prostate etc.Therefore, with σ 2 receptor have high-affinity and optionally radioactive indicator be excellent tumor developer, be at present technology leading in the world and product.
Summary of the invention
The technical problem solved: use under conventional developer can not be applicable to above two kinds of situations simultaneously.Conventional developer is recall rate and the lower problem of accuracy rate when early diagnosis of cancer such as diagnosing mammary cancer, melanoma, cervical cancer, carcinoma vulvae and colorectal cancer.
Technical solution of the present invention is: the present invention is SPECT developer 99mTc-N2S2-C2NR1R2 SPECT, and its preparation method and application, described 99mTc-N2S2-C2NR1R2 SPECT developer chemical structural formula is as follows:
, wherein M is Tc, NR
1r
2for
Or
.
Synthetic route is as follows:
Described 99mTc-N2S2-C2NR1R2 SPECT developer preparation method is as follows:
Described preparation method comprises the following steps:
A: the compound 3-(synthesis of trityl sulfo-N-(2 – ((2 – (trityl sulfo-) ethyl) is amino) ethyl) propionic acid amide. (1)
By 2-(trityl sulfo-) acetaldehyde (2-(tritylthio) acetaldehyde) and N-(2-aminoethyl)-3-(trityl sulfo-) propionic acid amide. be dissolved in methanol, then by NaCNBH
4add wherein slowly; By reactant liquor in stirred overnight at room temperature; After reaction, organic layer is dry, column chromatography after concentrated, the component recrystallization obtained, the product 1 of obtained white solid;
B: compound N-(2-((2-piperidinoethyl) (2-(trityl sulfo-) ethyl) amino) ethyl)-3-(trityl sulfo-) synthesis of propionic acid amide. (L1)
Get the white solid product 1 of steps A, 2-piperidines bromoethane hydrobromate and potassium carbonate, add second cyanogen, under agitation, be heated to backflow and spend the night, continue stirring reaction, after reacting completely, reactant liquor is cooled to room temperature, respectively with water, acetic acid,diluted washing, separates organic layer, column chromatography after organic over anhydrous dried over sodium sulfate is concentrated, obtained white solid product L1;
C: compound N-(2-((2-diethyl amido) (2-(trityl sulfo-) ethyl) amino) ethyl)-3-(trityl sulfo-) synthesis of propionic acid amide. (L2)
Get white solid product 1,2-(lignocaine) bromoethane hydrobromate, potassium carbonate prepared by steps A; Add second cyanogen, under agitation, be heated to backflow and spend the night, continue stirring reaction, after reacting completely, reactant liquor is cooled to room temperature, respectively with water, acetic acid,diluted washing, separate organic layer, column chromatography after organic over anhydrous dried over sodium sulfate is concentrated, obtained white solid product L2;
The synthesis of L1 or L2 (Tc-L1 or Tc-L2) of D:99m technetium (99mTc) labelling
L1 or L2 is dissolved in trifluoroacetic acid, after stirring at room temperature, drip triethyl silicane, drip and finish, after reactant liquor is concentrated, obtained solid product, is dissolved in ethanol by product, add aqueous solution of salicylic acid and sodium pertechnetate solution and ethanol again, then add stannous chloride and continue stirring reaction, react at 75 DEG C after 30 minutes and take out cooling, obtain Tc-L1 or Tc-L2.
Preferably, described 99mTc-N2S2-C2NR1R2 SPECT developer preparation method is as follows:
A: the compound 3-(synthesis of trityl sulfo-N-(2 – ((2 – (trityl sulfo-) ethyl) is amino) ethyl) propionic acid amide. (1)
2-(trityl sulfo-by 4 grams) N-(2-aminoethyl)-3-(trityl sulfo-) propionic acid amide. of acetaldehyde (2-(tritylthio) acetaldehyde) and 4.5 grams is dissolved in 200 ml methanol, then by 2.25 grams of NaCNBH
4add wherein slowly; By reactant liquor in stirred overnight at room temperature; After reaction, organic layer is dry, column chromatography after concentrated, the component recrystallization obtained, the product (2.0 g, productive rate is 23%) of obtained white solid;
B: compound N-(2-((2-piperidinoethyl) (2-(trityl sulfo-) ethyl) amino) ethyl)-3-(trityl sulfo-) synthesis of propionic acid amide. (L1)
The white solid product 1 that the steps A of getting 200 milligrams prepares, the 2-piperidines bromoethane hydrobromate (2-bromo-piperidinylethylamine hydrobromide) of 75 milligrams and the potassium carbonate of 135 grams join in 500mL three-neck flask, add 100mL second cyanogen, under agitation, be heated to backflow spend the night, continue stirring reaction, after reacting completely, reactant liquor is cooled to room temperature, use water respectively, acetic acid,diluted washs, separate organic layer, column chromatography after organic over anhydrous dried over sodium sulfate is concentrated, obtained 146mg white solid product L1, productive rate is 65%,
C: compound N-(2-((2-diethyl amido) (2-(trityl sulfo-) ethyl) amino) ethyl)-3-(trityl sulfo-) synthesis of propionic acid amide. (L2)
White solid product 1 (200 mg that the steps A of getting 400 milligrams prepares, 0.29 mmol), 2-(lignocaine) the bromoethane hydrobromate (2-bromo-N, N-diethylethylamine hydrobromide) of 150 milligrams and the potassium carbonate K of 280 milligrams
2cO
3join in 500mL three-neck flask, add 100mL second cyanogen, under agitation, be heated to backflow and spend the night, continue stirring reaction, after reacting completely, reactant liquor is cooled to room temperature, respectively with water, acetic acid,diluted washing, separate organic layer, column chromatography after organic over anhydrous dried over sodium sulfate is concentrated, obtained 300 mg white solid product L2, productive rate is 60%;
The synthesis of L1 or L2 (Tc-L1 or Tc-L2) of D:99m technetium (99mTc) labelling
L1 or L2 (0.13 mmol) is dissolved in the trifluoroacetic acid of 15 mL, stir at room temperature after 10 minutes, drip the triethyl silicane of 1 mL, drip and finish, obtained solid product after reactant liquor is concentrated, this product is dissolved in the ethanol of 10 mL, then adds salicylic acid (0.26 mmol) aqueous solution of 2 mL and the sodium pertechnetate solution (lmCi/mL) of 2 mL and 30 mL ethanol, then adds stannous chloride (SnCl
2) (0.26 mmol) continue stirring reaction, take out cooling in 75 DEG C after 30 minutes, obtain Tc-L1 or Tc-L2.
Wherein, the purposes in developer prepared by described molecular probe developer.
Wherein, the synthetic method of the rhenium complex (Re-L1 or Re-L2) of reference substance L1 and L2 is as follows:
L1 or L2 (0.13 mmol) is dissolved in the trifluoroacetic acid of 15 mL, stir at room temperature after 10 minutes, drip the triethyl silicane of 1 mL, drip and finish, obtained solid product after reactant liquor is concentrated, product is dissolved in the methanol of 10 mL, then adds salicylic acid (0.26 mmol) aqueous solution of 2 mL and the perrhenic acid sodium (NaReO of 2 mL
4) aqueous solution and 30 mL methanol, then add SnCl
2(0.26 mmol) continues stirring reaction, 75 DEG C of reactions, after within 4 hours, reacting completely, reactant liquor is cooled to rt while stirring overnight, dry concentrated rear column chromatography, product Re-L1 or Re-L2 of obtained violet solid shape.
Alpha-melanocyte stimulating hormone (α – melanocyte stimulating hormore, α-MSH) peptide is as Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-α-MSH) and melanocortin receptor 1(Melanocotin-1 receptors, MC1R) there is very high affinity.RDG (Arg-Gly-Asp, arginine-glycine-aspartic acid) this polypeptide be made up of 3 aminoacid and α v β 3 receptor have very high affinity, and MC1R and α v β 3 receptor has very high expression in melanoma.
beneficial effect:the present invention is all better than the 18F-FDG of current Clinical practice on the ratio of melanoma intake and tumor/blood or muscle.The present invention will not only be beneficial to the early diagnosis of cancer such as melanoma, breast carcinoma, cervical cancer, carcinoma vulvae and colorectal cancer but also with minimum tissue injury's precise ablation sentinel node, and can determine that whether excision is complete, greatly reduces the false negative of SLNB.To cancer particularly breast carcinoma, melanoma, cervical cancer, carcinoma vulvae and colorectal cancer test-and-treat method bring revolutionary change, to the formulation of targeted therapy scheme, there is extremely important directive significance, produce huge economic results in society.On the one hand, to cancer particularly breast carcinoma, melanoma, cervical cancer, carcinoma vulvae and PATIENTS WITH LARGE BOWEL, further improve recall rate and accuracy rate, the foundation of molecular biology and pathological diagnosis can be provided for the selection of clinical treatment and formulation; The present invention will improve the level of domestic medical inspection industry, China is made to be in first place in the world at molecular image and molecular probe field, shorten China for a long time and external existing gap between molecular image and molecular probe technology, be conducive to the Medical standard theory improving people, build a Harmonious Society.
Of the present invention
tc-L1with
tc-L2biodistribution experiments in mice with tumor body:
Get 18 melanoma cancer mices, be divided into 3 groups (often organizing 6), every mice is respectively by tail vein note 0.2mL (0.1mCi)
tc-L1or
tc-L2often organize mice to slaughter at corresponding time point (1,3 and 6h) respectively, take out corresponding internal organs (brain, the heart, liver, spleen, lung, kidney, tumor, muscle, bone and blood etc.), weigh after cleaning respectively, radiocounting measured by Y-enumerator, calculates the radioactivity (%ID/g) of every gram of internal organs.
1 h, 3 h and 6h after Tc-L1 intravenous injection, tumor uptake amount reaches 9.61%, 8.19% and 7.05% respectively.Tumor/blood ratio reaches 14.71,23.4 and 47.25 respectively.Tumor/liver ratio reaches 0.75,1.55 and 2.00 respectively.1 h, 3 h and 6h after Tc-L2 intravenous injection, tumor uptake amount reaches 8.52%, 7.56% and 5.39% respectively.Tumor/blood ratio reaches 16.49,34.8 and 43.14 respectively.Tumor/liver ratio reaches 0.64,2.29 and 1.71 respectively.Tc-1 and Tc-2 has excellent tumor-targeting and signal to noise ratio in tumor mouse body, can develop into tumor developer.
Detailed description of the invention
The present invention includes but be not limited to following example:
Embodiment 1
Molecular probe developer preparation process for diagnosing tumor and Lymph node biopsy of the present invention is as follows:
Compound 3-(trityl sulfo-N-(2 – ((2 – (trityl sulfo-) ethyl) is amino) ethyl) propionic acid amide. (
1) synthesis
2-(trityl sulfo-by 4 grams) N-(2-aminoethyl)-3-(trityl sulfo-) propionic acid amide. of acetaldehyde (2-(tritylthio) acetaldehyde) and 4.5 grams is dissolved in 200 ml methanol, then by 2.25 grams of NaCNBH
4add slowly wherein.By reactant liquor in stirred overnight at room temperature.After reaction, organic layer is dry, column chromatography after concentrated, the component recrystallization obtained, the product (2.0 g, 23%) of obtained white solid:
1h NMR (CDCl
3) δ 1.98 (t, 2H, J=7.2 Hz), 2.34 (t, 2H, J=6.6 Hz), 2.45-2.50 (m, 4H), 2.51 (t, 2H, J=6.0 Hz), 3.16 (q, 2H, J=6.0 Hz), 5.82 (s, 1H), 7.16-7.22 (m, 6H), 7.23-7.30 (m, 12H), 7.39-7.44 (m, 12H). MS, m/z (M+H)
+c
45h
45n
2oS
2theoretical value: 693.30; Actual measurement: 693.29.
Compound N-(2-((2-piperidinoethyl) (2-(trityl sulfo-) ethyl) is amino) ethyl)-3-(trityl sulfo-) propionic acid amide. (
l1)synthesis
The compound of 200 milligrams
1, the 2-piperidines bromoethane hydrobromate (2-bromo-piperidinylethylamine hydrobromide) of 75 milligrams and the potassium carbonate K of 135 grams
2cO
3join in 500mL three-neck flask, add 100mL second cyanogen, under agitation, be heated to backflow and spend the night, continue stirring reaction, after reacting completely, reactant liquor is cooled to room temperature, respectively with water, acetic acid,diluted washing, separates organic layer, column chromatography after organic over anhydrous dried over sodium sulfate is concentrated, obtained 146 mg white solid product
l1, productive rate is 65%:
1h NMR (CDCl
3) δ 1.40-1.44 (m, 2H), 1.50-1.63 (m, 4H), 2.02 (t, 2H, J=7.2 Hz), 2.27 (t, 2H, J=7.2 Hz), 2.26-2.51 (m, 14H), 3.14 (q, 2H, J=4.8 Hz), 6.57 (s, 1H), 7.14-7.22 (m, 6H), 7.24-7.31 (m, 12H), 7.40-7.47 (m, 12H). MS, m/z (M+H)
+c
52h
58n
3oS
2theoretical value: 804.40; Actual measurement: 804.40.
Compound N-(2-((2-diethyl amido) (2-(trityl sulfo-) ethyl) is amino) ethyl)-3-(trityl sulfo-) propionic acid amide. (
l2)synthesis
The compound of 400 milligrams
1(200 mg, 0.29 mmol), 2-(lignocaine) the bromoethane hydrobromate (2-bromo-N, N-diethylethylamine hydrobromide) of 150 milligrams and the potassium carbonate K of 280 milligrams
2cO
3join in 500mL three-neck flask, add 100mL second cyanogen, under agitation, be heated to backflow and spend the night, continue stirring reaction, after reacting completely, reactant liquor is cooled to room temperature, respectively with water, acetic acid,diluted washing, separates organic layer, column chromatography after organic over anhydrous dried over sodium sulfate is concentrated, obtained 300 mg white solid product
l2, productive rate is 60%:
1h NMR (CDCl
3) δ 1.40-1.44 (m, 2H), 1.50-1.63 (m, 4H), 2.02 (t, 2H, J=7.2 Hz), 2.27 (t, 2H, J=7.2 Hz), 2.26-2.51 (m, 14H), 3.14 (q, 2H, J=4.8 Hz), 6.57 (s, 1H), 7.14-7.22 (m, 6H), 7.24-7.31 (m, 12H), 7.40-7.47 (m, 12H). MS, m/z (M+H)
+c
52h
58n
3oS
2theoretical value: 804.40; Actual measurement: 804.40.
l1with
l2rhenium complex (
re-L1or
re-L2) synthesis
Will
l1or
l2(0.13 mmol) is dissolved in the trifluoroacetic acid of 15 mL, stir at room temperature after 10 minutes, drip the triethyl silicane of 1 mL, drip and finish, obtained solid product after reactant liquor is concentrated, this product is dissolved in the methanol of 10 mL, then adds salicylic acid (0.26 mmol) aqueous solution of 2 mL and the perrhenic acid sodium (NaReO of 2 mL
4) aqueous solution and 30 mL methanol, then add SnCl
2(0.26 mmol
)continue stirring reaction, 75 DEG C of reactions, after within 4 hours, reacting completely, reactant liquor is cooled to rt while stirring overnight, dry concentrated rear column chromatography, product Re-L1 or Re-L2 of obtained violet solid shape.
: productive rate 62%:
1h NMR (CDCl
3) δ 1.40-1.50 (m 2H), 1.85-2.01 (m, 2H), 2.18-2.31 (m, 3H), 2.60-2.80 (m, 5H), 3.09 (t, 2H, J=7.8 Hz), 3.42-3.48 (m, 2H), 3.55-3.70 (m, 3H), 3.70-3.77 (m, 1H), 3.77-3.82 (m, 1H), 3.84-3.90 (m, 1H), 3.93 (X of AX, 1H, J=16.8 Hz), 4.03-4.18 (m, 1H), 4.23-4.28 (m, 1H), 4.69 (A of AX, 1H, J=16.2 Hz). MS, m/z (M+H)
+c
14h
27n
3o
2reS
2theoretical value: 520.11, actual measurement: 520.10.
re-L2: productive rate 52%:
1h NMR (CDCl
3) δ 1.40-1.50 (m 2H), 1.85-2.01 (m, 2H), 2.18-2.31 (m, 3H), 2.60-2.80 (m, 5H), 3.09 (t, 2H, J=7.8 Hz), 3.42-3.48 (m, 2H), 3.55-3.70 (m, 3H), 3.70-3.77 (m, 1H), 3.77-3.82 (m, 1H), 3.84-3.90 (m, 1H), 3.93 (X of AX, 1H, J=16.8 Hz), 4.03-4.18 (m, 1H), 4.23-4.28 (m, 1H), 4.69 (A of AX, 1H, J=16.2 Hz). MS, m/z (M+H)
+c
13h
27n
3o
2reS
2theoretical value: 508.1102, actual measurement: 508.1100.
99m technetium (
99mtc) labelling
l1with
l2(
tc-L1with
tc-L2) synthesis
Will
l1or
l2(0.13 mmol) is dissolved in the trifluoroacetic acid of 15 mL, stir at room temperature after 10 minutes, drip the triethyl silicane of 1 mL, drip and finish, obtained solid product after reactant liquor is concentrated, this product is dissolved in the ethanol of 10 mL, then adds salicylic acid (0.26 mmol) aqueous solution of 2 mL and the sodium pertechnetate solution (lmCi/mL) of 2 mL and 30 mL ethanol, then adds stannous chloride (SnCl
2) (0.26 mmol
)continue stirring reaction, take out cooling in 75 DEG C after 30 minutes, obtain Tc-L1 or Tc-L2.
Tc-L1 and Tc-L2 of the present invention be biodistribution experiments in mice with tumor body:
Get 18 melanoma cancer mices, be divided into 3 groups (often organizing 6), every mice is respectively by tail vein note 0.2mL (0.1mCi) Tc-L1 or Tc-L2, often organize mice to slaughter at corresponding time point (1,3 and 6h) respectively, take out corresponding internal organs (brain, the heart, liver, spleen, lung, kidney, tumor, muscle, bone and blood etc.), weigh after cleaning respectively, radiocounting measured by Y-enumerator, calculates the radioactivity (%ID/g) of every gram of internal organs.Experimental result is in table 1.
1 h, 3 h and 6h after Tc-L1 intravenous injection, tumor uptake amount reaches 9.61%, 8.19% and 7.05% respectively.Tumor/blood ratio reaches 14.71,23.4 and 47.25 respectively.Tumor/liver ratio reaches 0.75,1.55 and 2.00 respectively.1 h, 3 h and 6h after Tc-L2 intravenous injection, tumor uptake amount reaches 8.52%, 7.56% and 5.39% respectively.Tumor/blood ratio reaches 16.49,34.8 and 43.14 respectively.Tumor/liver ratio reaches 0.64,2.29 and 1.71 respectively.Tc-1 and Tc-2 has excellent tumor-targeting and signal to noise ratio in tumor mouse body, can develop into tumor developer.
Table 1
The foregoing is only the specific embodiment of the present invention; but these are the simple description to mentality of designing of the present invention; instead of the restriction to mentality of designing of the present invention, any do not exceed mentality of designing of the present invention combination, increase or amendment, all fall into protection scope of the present invention.
Claims (7)
1. a molecular probe developer, is characterized in that described molecular probe developer chemical structural formula is as follows:
, wherein M is Tc, NR
1r
2for
or
.
2. a preparation method for molecular probe developer, is characterized in that, the synthetic route of described preparation method is as follows:
Described preparation method comprises the following steps:
A: the compound 3-(synthesis of trityl sulfo-N-(2 – ((2 – (trityl sulfo-) ethyl) is amino) ethyl) propionic acid amide. (1)
By 2-(trityl sulfo-) acetaldehyde and N-(2-aminoethyl)-3-(trityl sulfo-) propionic acid amide. be dissolved in methanol, then by NaCNBH
4add wherein slowly; By reactant liquor in stirred overnight at room temperature; After reaction, organic layer is dry, column chromatography after concentrated, the component recrystallization obtained, the product 1 of obtained white solid;
B: compound N-(2-((2-piperidinoethyl) (2-(trityl sulfo-) ethyl) amino) ethyl)-3-(trityl sulfo-) synthesis of propionic acid amide. (L1)
Get the white solid product 1 of steps A, 2-piperidines bromoethane hydrobromate and potassium carbonate, add second cyanogen, under agitation, be heated to backflow and spend the night, continue stirring reaction, after reacting completely, reactant liquor is cooled to room temperature, respectively with water, acetic acid,diluted washing, separates organic layer, column chromatography after organic over anhydrous dried over sodium sulfate is concentrated, obtained white solid product L1;
C: compound N-(2-((2-diethyl amido) (2-(trityl sulfo-) ethyl) amino) ethyl)-3-(trityl sulfo-) synthesis of propionic acid amide. (L2)
Get white solid product 1,2-(lignocaine) bromoethane hydrobromate, potassium carbonate prepared by steps A; Add second cyanogen, under agitation, be heated to backflow and spend the night, continue stirring reaction, after reacting completely, reactant liquor is cooled to room temperature, respectively with water, acetic acid,diluted washing, separate organic layer, column chromatography after organic over anhydrous dried over sodium sulfate is concentrated, obtained white solid product L2;
The synthesis of L1 or L2 (Tc-L1 or Tc-L2) of D:99m technetium (99mTc) labelling
L1 or L2 is dissolved in trifluoroacetic acid, after stirring at room temperature, drip triethyl silicane, drip and finish, after reactant liquor is concentrated, obtained solid product, is dissolved in ethanol by product, add aqueous solution of salicylic acid and sodium pertechnetate solution and ethanol again, then add stannous chloride and continue stirring reaction, react at 75 DEG C after 30 minutes and take out cooling, obtain Tc-L1 or Tc-L2.
3. the preparation method of a kind of molecular probe developer according to claim 2, is characterized in that the synthetic route of described preparation method is as follows:
Described preparation method comprises the following steps:
A: the compound 3-(synthesis of trityl sulfo-N-(2 – ((2 – (trityl sulfo-) ethyl) is amino) ethyl) propionic acid amide. (1)
2-(trityl sulfo-by 4 grams) N-(2-aminoethyl)-3-(trityl sulfo-) propionic acid amide. of acetaldehyde and 4.5 grams is dissolved in 200 ml methanol, then by 2.25 grams of NaCNBH
4add wherein slowly; By reactant liquor in stirred overnight at room temperature; After reaction, organic layer is dry, column chromatography after concentrated, the component recrystallization obtained, the product 1 of obtained white solid;
B: compound N-(2-((2-piperidinoethyl) (2-(trityl sulfo-) ethyl) amino) ethyl)-3-(trityl sulfo-) synthesis of propionic acid amide. (L1)
White solid product 1 prepared by the steps A of getting 200 milligrams, the 2-piperidines bromoethane hydrobromate of 75 milligrams and the potassium carbonate of 135 grams join in 500mL three-neck flask, add 100mL second cyanogen, under agitation, be heated to backflow spend the night, continue stirring reaction, after reacting completely, reactant liquor is cooled to room temperature, respectively with water, acetic acid,diluted washing, separate organic layer, column chromatography after organic over anhydrous dried over sodium sulfate is concentrated, obtained white solid product L1;
C: compound N-(2-((2-diethyl amido) (2-(trityl sulfo-) ethyl) amino) ethyl)-3-(trityl sulfo-) synthesis of propionic acid amide. (L2)
White solid product 1 (200 mg that the steps A of getting 400 milligrams prepares, 0.29 mmol), 2-(lignocaine) the bromoethane hydrobromate of 150 milligrams and the potassium carbonate of 280 milligrams join in 500mL three-neck flask, add 100mL second cyanogen, under agitation, be heated to backflow spend the night, continue stirring reaction, after reacting completely, reactant liquor is cooled to room temperature, respectively with water, acetic acid,diluted washing, separates organic layer, column chromatography after organic over anhydrous dried over sodium sulfate is concentrated, obtained white solid product L2;
The synthesis of L1 or L2 (Tc-L1 or Tc-L2) of D:99m technetium (99mTc) labelling
L1 or L2 (0.13 mmol) is dissolved in the trifluoroacetic acid of 15 mL, stir at room temperature after 10 minutes, drip the triethyl silicane of 1 mL, drip and finish, obtained solid product after reactant liquor is concentrated, product is dissolved in the ethanol of 10 mL, then adds salicylic acid (0.26 mmol) aqueous solution of 2 mL and the sodium pertechnetate solution (lmCi/mL) of 2 mL and 30 mL ethanol, then add stannous chloride (SnCl
2) (0.26 mmol) continue stirring reaction, react at 75 DEG C after 30 minutes and take out cooling, obtain Tc-L1 or Tc-L2.
4. the preparation method of a kind of molecular probe developer according to claim 2, it is characterized in that the white solid product that in described preparation method, steps A prepares is 2.0 g, productive rate is 23%.
5. the preparation method of a kind of molecular probe developer according to claim 2, it is characterized in that the white solid product L1 that in described preparation method, step B prepares is 146mg, productive rate is 65%.
6. the preparation method of a kind of molecular probe developer according to claim 2, it is characterized in that in described preparation method that step B prepares white solid product L2 is 300 mg, and productive rate is 60%.
7. the purposes in developer prepared by a kind of molecular probe developer according to claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410611899.0A CN104324394A (en) | 2014-11-05 | 2014-11-05 | Molecular probe developer, as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410611899.0A CN104324394A (en) | 2014-11-05 | 2014-11-05 | Molecular probe developer, as well as preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104324394A true CN104324394A (en) | 2015-02-04 |
Family
ID=52399278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410611899.0A Pending CN104324394A (en) | 2014-11-05 | 2014-11-05 | Molecular probe developer, as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104324394A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106729779A (en) * | 2016-11-16 | 2017-05-31 | 中国科学院苏州生物医学工程技术研究所 | Molecular probe developer and preparation method thereof |
| CN115536705A (en) * | 2022-09-23 | 2022-12-30 | 江苏省原子医学研究所 | Targeting II-type vesicle monoamine transporter molecular probe and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2010003829A (en) * | 2010-04-08 | 2011-10-31 | Inst Nac De Investigaciones Nucleares | 99-mtc-tat-bombesin as a novel radiopharmaceutical for the early detection of breast cancer. |
| US20120269724A1 (en) * | 2009-06-13 | 2012-10-25 | President And Fellows Of Harvard College | Compositions and methods for imaging tissues, organs and tumors |
-
2014
- 2014-11-05 CN CN201410611899.0A patent/CN104324394A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120269724A1 (en) * | 2009-06-13 | 2012-10-25 | President And Fellows Of Harvard College | Compositions and methods for imaging tissues, organs and tumors |
| MX2010003829A (en) * | 2010-04-08 | 2011-10-31 | Inst Nac De Investigaciones Nucleares | 99-mtc-tat-bombesin as a novel radiopharmaceutical for the early detection of breast cancer. |
Non-Patent Citations (1)
| Title |
|---|
| 林培喜等，: "《无机化学与分析化学》", 30 September 2010, 哈尔滨工程大学出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106729779A (en) * | 2016-11-16 | 2017-05-31 | 中国科学院苏州生物医学工程技术研究所 | Molecular probe developer and preparation method thereof |
| CN106729779B (en) * | 2016-11-16 | 2019-07-23 | 中国科学院苏州生物医学工程技术研究所 | Molecular probe imaging agent and preparation method thereof |
| CN115536705A (en) * | 2022-09-23 | 2022-12-30 | 江苏省原子医学研究所 | Targeting II-type vesicle monoamine transporter molecular probe and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Rice et al. | The next generation of positron emission tomography radiopharmaceuticals in oncology | |
| CN111592584B (en) | HER2 affinity body and diagnosis and treatment nuclide marker as well as preparation method and application thereof | |
| CN113583089B (en) | Tumor PD-L1 targeted PET imaging agent, labeling precursor, preparation method and application thereof | |
| CN112851637B (en) | PSMA inhibitor, compound, preparation method and application thereof | |
| CN107245087A (en) | 99mGlucosan derivative and preparation method and application of the Tc marks containing isonitrile | |
| CN105126128A (en) | Novel tumor VEGFR-3 molecular photographic developer and application thereof | |
| CN106581700A (en) | Novel HER2-targeting polypeptide radioactive medicine and preparation method and application thereof | |
| Liu et al. | PET imaging of VEGFR and integrins in glioma tumor xenografts using 89Zr labelled heterodimeric peptide | |
| CN104324394A (en) | Molecular probe developer, as well as preparation method and application thereof | |
| CN110339375A (en) | A kind of rk polypeptide radiopharmaceutical and preparation method thereof targeting HER2 | |
| CN108434469A (en) | A kind of HER2 affinities body68Ga markers and preparation method thereof, application | |
| CN117209476A (en) | The method comprises the following steps of 99m Tc-labeled radioactive probe for targeting fibroblast activation protein and preparation method and application thereof | |
| CN105963724A (en) | {0><}0{>Radio-labeled tumor developing agent as well as preparation method and application thereof | |
| CN111407900B (en) | Estrogen receptor targeted radioactive tracer, preparation method and application | |
| CN100363371C (en) | Application of 99TcmN (CPEDTC)2 compounding agent in tumour imaging field | |
| CN104844806B (en) | It is a kind of for target compound of isotope labeling and its preparation method and application | |
| CN106729779B (en) | Molecular probe imaging agent and preparation method thereof | |
| Kong et al. | Development of Tyrosine‐Based Radiotracer 99mTc‐N4‐Tyrosine for Breast Cancer Imaging | |
| CN101085787B (en) | Technetium-99m signed dimercaptosuccinate complexes, preparing method and application thereof | |
| CN114617983B (en) | Fluorine-18 labeled CEA molecular targeting compound and preparation method and application thereof | |
| LU504784B1 (en) | Radiolabeled tumor imaging agent and preparation method thereof | |
| CN115448856B (en) | EuK dimer compound and derivative for targeting PSMA and application thereof | |
| CN112409436B (en) | Radionuclide-labeled estrogen receptor molecule targeting compound and application thereof | |
| Qu et al. | 68 Ga labeled EphA2-targeted cyclic peptide: a novel positron imaging tracer for triple-negative breast cancer? | |
| CN116763946A (en) | Cyclic peptide radiopharmaceuticals for targeting PD-L1 and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150204 |