CN101775039B - Preparation method and application of 99mTc-marked hydrazino nicotinamide-folate complexs - Google Patents
Preparation method and application of 99mTc-marked hydrazino nicotinamide-folate complexs Download PDFInfo
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- CN101775039B CN101775039B CN2010101011166A CN201010101116A CN101775039B CN 101775039 B CN101775039 B CN 101775039B CN 2010101011166 A CN2010101011166 A CN 2010101011166A CN 201010101116 A CN201010101116 A CN 201010101116A CN 101775039 B CN101775039 B CN 101775039B
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Abstract
The present invention discloses a preparation method and application of a 99mTc-marked hydrazino nicotinamide-folate coordination compound. In the preparation method, the target coordination compound is obtained through two steps of synthesizing ligand hydrazino nicotinamide-folate and marking the hydrazino nicotinamide-folate by 99mTc. The coordination compound has the advantages of high hydrazino nicotinamide-folate, good stability, low cost, high tumor uptaking, good detention and good target/non-target ratio of tumor/blood, tumor/muscle and the like and can be used for preparing a tumor developer as a novel 99mTc-marked folate receptor.
Description
Affiliated technical field
The present invention relates to
99mThe radiopharmaceutical chemistry of Tc mark and clinical nuclear medicine technical field relate to a kind of specifically
99mThe preparation method of the hydrazino nicotinamide-folate coordination compound of Tc mark and application.
Background technology
In medical radioactive pharmaceutical chemistry technical field, folic acid (NHHN-Folate) acceptor is a kind ofly to be connected glycoprotein on the cytolemma by the glycan phosphinositides.The expression high conservative of folacin receptor in the normal health cell, but in many malignant tumours that come from epithelium, express as but having in the tumours such as ovarian cancer, mammary cancer, carcinoma of endometrium, lung cancer, nasopharyngeal carcinoma highly.Folacin receptor has very high affinity and specificity to folacins such as folic acid, methotrexate, 5-methyl tetrahydrofolates, can mediate these material endocytosis and enter cell.Utilize this transport process that has much characteristics, can be with radionuclide or other medicine and folic acid or folacin coupling, enter target cell by folacin receptor mediated.Thereby folacin receptor can be used as radiopharmaceutic " target ", realizes radionuclide image and treatment to the tumour of folacin receptor height expression.
Compare with other target delivery systems such as monoclonal antibodies, folic acid and analogue thereof have affinity height, penetrativity strong, cheap, be easy to characteristics such as structural modification, stable height.Therefore, become a focus of present targeted drug design studies with folic acid and analogue link coupled combination drug thereof.
The current radiopharmaceutic nucleic of labeled leaf acid acceptor target that is used for mainly contains
67/68Ga,
111In,
99mTc,
64Cu, and
18F,
11C etc.Wherein
111In-DTPA-folate (γ) is that first enters and finish clinical folacin receptor target tumor developer (Siegel BA, Dehdashti F, Mutch DG, et al.Evaluationof of II phase
111In-DTPA-folate as a receptor-targeted diagnostic agent for ovarian cancer:initialclinical results.J Nucl Med 2003; 44:700-707), but because
111In nucleic source is inconvenient, and costs an arm and a leg, and has hindered its further application clinically.
99mTc ideal nulcear properties makes it become most widely used nucleic in the nuclear medicine, wherein
99mTc-EC20 successfully has been used for clinical I phase diagnostic tests such as ovarian cancer, cervical cancer, kidney, and the II clinical trial phase carries out (Reddy JA, Xu LC, Parker N, Vetzel M, Leamon CP.Preclinical evaluation of
99mTc-EC20 for imaging folatereceptor-postive tumors.J Nucl Med 2004; 45:857-866).HYNIC (hydrazino nicotinamide), is widely used in because its formed title complex has very high stability and mark rate as a kind of bifunctional linking reagent
99mThe Tc mark.Bibliographical information
99mTc-HYNIC-folate has target to non-target ratio values such as good tumour/blood, tumour/meat, but the definitely picked-up value of tumour in lotus KB mice with tumor model is lower, and the background of liver, spleen etc. higher (W.Guo, G.H.Hinkle, R.J.Lee,
99mTc-HYNIC-folate:a novelreceptor-based targeted radiopharmaceutical for tumor imaging.J Nucl Med1999; 40:1563-1569; Liu Liqin, Wang Shizhen etc. the folacin receptor tumor developer
99mSynthetic and the animal video picture of Tc-hydrazino nicotinamide hydrazides-folic acid. the journal .2006 of the Chinese Academy of Medical Sciences; 28:786-789 Chinese Academy of Medical Sciences journal).Therefore, develop novel
99mThe Tc marked hydrazino nicotinamide-folate coordination compound is used for tumor developer, has great importance.
Summary of the invention
The object of the present invention is to provide a kind of have high tumor uptake, radiochemical purity height, good stability, be applied in the tumor imaging field
99mThe hydrazino nicotinamide-folate coordination compound of Tc mark also provides its preparation method simultaneously.
In order to achieve the above object, the present invention by the following technical solutions, and is a kind of
99mThe hydrazino nicotinamide-folate coordination compound of Tc mark, expression formula is:
99mTc-HYNIC-NHHN-Folate, its structural formula is:
In this structural formula: the nitrogen-atoms of diazanyl in part HYNIC-NHHN-Folate (hydrazino nicotinamide--the folic acid) molecule, altogether the Sauerstoffatom in part Tricine and the TPPTS molecule and phosphorus atom and
99mTc carries out coordination and obtains
99mThe Tc-HYNIC-NHHN-Folate title complex.
99mThe preparation method of the hydrazino nicotinamide-folate coordination compound of Tc mark is as follows:
A. part hydrazino nicotinamide--folic acid (HYNIC-NHHN-Folate) synthetic:
Compound folic acid (NHHN-Folate) and succinimide-6-tertiary butyl oxygen carbonyl hydrazide yl pyridines-3-formic acid (NHS-HYNIC-Boc) are dissolved in the dimethyl sulfoxide (DMSO) of 10-50mL, add the 5-25mL pyridine, room temperature reaction 10-24h; Reacted solution is slowly splashed in the ether, and centrifugal collection generates the salmon precipitation thing, uses ether and washed with dichloromethane respectively, and vacuum-drying gets orange red solid; Orange red solid is added in the trifluoroacetic acid of 1-5mL; under nitrogen protection; behind the ice-water bath reaction 2h; revolve to steam and remove trifluoroacetic acid; to remain oily liquids 0.1-2mL N; splash in the 100-500mL pyridine after dinethylformamide (DMF) dissolving, the precipitation that centrifugal collection produces and with the ether washing, vacuum-drying obtains pale brown toner end.Specifically synthetic route is as shown in Figure 1:
B.
99mThe hydrazino nicotinamide-folate coordination compound of Tc mark (
99mTc-HYNIC-NHHN-Folate) preparation:
In the penicillin bottle, add 10-100mg trishydroxymethyl-methylglycine (Tricine) successively, 20-100 μ g tin protochloride (SnCl
22H
2O), (NaAc-HAc 0.2mol/L), shakes up the back to the Tc-99m leacheate 0.1-0.5mL that wherein injects 37～370MBq to the acetate buffer solution of 20-200 μ g part hydrazino nicotinamide-folate and 0.1-1mL, pH=3.6, boiling water bath heating 15min; In the good solution of mark, add 1-5mg trityl phosphine sodium trisulfonate solution (TPPTS), shake up back boiling water bath heating 5-30min, obtain of the present invention
99mThe hydrazino nicotinamide-folate coordination compound of Tc mark.
By method for preparing
99mVitro stability is good under the hydrazino nicotinamide-folate coordination compound room temperature of Tc mark, and radiochemical purity is greater than 90% behind its purifying.The bio distribution experimental result shows in the tumor-bearing mice body:
99mThe delay that the hydrazino nicotinamide-folate coordination compound of Tc mark has very high picked-up to become reconciled in tumour has good tumour/blood, tumour/muscle ratio, and non-target organ picked-up such as liver is low, is applicable to the requirement of clinical video picture.
99mTc-HYNIC-NHHN-Folate,
99mTc-EC20 and
99mTc-HYNIC-Folate bio distribution data contrast in the tumor-bearing mice body is as follows:
Above result shows, with
99mTc-HYNIC-Folate compares,
99mTc-HYNIC-NHHN-Folate has higher tumor uptake and better knurl/meat, knurl/blood ratio; With
99mTc-EC20 compares,
99mThough the absolute picked-up of Tc-HYNIC-NHHN-Folate tumour is low slightly, better knurl/meat ratio and the lower heart, liver, lung picked-up are arranged, so it is as novel
9mThe folacin receptor tumor developer of Tc mark has better bio distribution performance, suitable applying.
Embodiment
Below by embodiment in detail the present invention is described in detail: a kind of
99mThe hydrazino nicotinamide-folate coordination compound of Tc mark:
Its structural formula is:
99mThe preparation method of the hydrazino nicotinamide-folate coordination compound of Tc mark is as follows:
A. part hydrazino nicotinamide--folic acid (HYNIC-NHHN-Folate) synthetic:
520mg Folate-NHHN and 532mg NHS-HYNIC-Boc are dissolved in the 25mL dimethyl sulfoxide (DMSO), add the 10mL pyridine, room temperature reaction 16h.Reacted solution is slowly splashed in the 500mL ether, the salmon precipitation that centrifugal collection generates, use respectively ether (3 * 5mL) and methylene dichloride (3 * 5mL) wash, and vacuum-drying gets the orange red solid of 363mg, productive rate 48.8%.
Its nucleus magnetic hydrogen spectrum (
1HNMR, DMSO-d
6) be:
δ：8.94(s，1H)，8.65(s，1H)，8.53(s，1H)，8.19(m，2H)，7.85(m，2H)6.98(m.1H)，6.61(d，J＝8.3Hz，2H)，4.48(d，J＝5.4Hz，2H)，4.32(m，2H)，3.1-1.8(m，16H)，1.42(s，9H)；
Nuclear-magnetism carbon spectrum (
13CNMR, DMSO-d
6) be: δ: 174.0,171.5,166.2,158.6,155.0,153.8,150.7,148.5,147.6,136.5,130.3,129.0,128.8,121.3,115.6,111.1,79.1,54.8,45.7,30.7,30.5,28.7,25.7.
Its mass-spectrometric data (ESI-MS) is: m/z[M+H]
+Calculated value is 775.4, and product records 775.1.
The above-mentioned orange red solid of 72mg is added in the trifluoroacetic acid of 1mL, under nitrogen protection, behind the ice-water bath reaction 2h, revolve to steam and remove trifluoroacetic acid, to remain oily liquids 0.5mLN, splash in the 200mL pyridine after dinethylformamide (DMF) dissolving, the precipitation that centrifugal collection produces and with ether washing (3 * 5mL), vacuum-drying obtains the pale brown toner of 37mg end, productive rate 59.7%;
Its nucleus magnetic hydrogen spectrum (
1HNMR, DMSO-d
6) be:
δ：8.62(s，1H)，7.96(br，1H)，7.78(m，1H)，7.63(m，2H)，6.90(m，1H)，6.62(d，J＝7.32，2H)，4.46(m，1H)，4.31(m，2H)，2.01-3.01(m，10H)，1.02-1.70(m，8H).
Nuclear-magnetism carbon spectrum (
13CNMR, DMSO-d
6) be:
δ：174.0，171.5，166.2，158.3，153.8，150.7，148.5，147.4，138.5，130.3，129.0，128.8，121.4，115.6，111.1，54.8，45.9，30.7，30.5，25.7.
Its mass-spectrometric data (ESI-MS) is: m/z[M+H]
+Calculated value is 675.3, and product records 675.2.
B.
99mThe preparation of the hydrazino nicotinamide-folate coordination compound of Tc mark:
This title complex adopts two-step approach to carry out mark, adds 0.5mL Tricine solution (80mg/mL) successively in the penicillin bottle, 0.02mL SnCl
2Solution (2mg/mL), (0.2mol/L pH=3.6), shakes up the back to wherein injecting Tc-99m leacheate 0.2mL (about 1mCi), boiling water bath heating 15min for 0.05mL HYNIC-NHHN-Folate solution (1mg/mL) and 0.5mLNaAc-HAc buffered soln.After being cooled to room temperature, in the good solution of mark, add 0.2mLTPPTS solution (5mg/mL), shake up back boiling water bath heating 15min, can obtain of the present invention
99mTc-HYNIC-NHHN-Folate.
Through adopting high performance liquid chromatography (HPLC) right
99mThe marker of Tc-HYNIC-NHHN-Folate is identified and purifying, the ALLTECH high performance liquid chromatograph, Kromasi C-18 reversed-phase column (5mm, 250mm * 4.6mm).The HPLC condition is: A:90%NH
4HCO
3(0.05mol/LpH=7.0)/10%CH
3OH, B:100%CH
3OH; 0～30min, 20～50%B; Flow velocity: 1mL/min.Each component retention time is:
99mTcO
4 -: 2.8min,
99mTc-Tricine:3.5min,
99mTc-HYNIC-NHHN-Folate:8.7min.It is 78% that HPLC measures mark rate, and radiochemical purity is greater than 90% after the separation and purification.
Right
99mPerformance and the parametric measurement of Tc-HYNIC-NHHN-Folate are as follows:
1.
99mThe Tc-HYNIC-NHHN-Folate lipid is measured
The mark complex solution of getting behind the 0.1mL purifying adds in phosphate buffer soln (PBS)-n-Octanol mixed solution (0.6mL PBS and 0.7mL n-Octanol), behind the 3～5min that fully vibrates, places the centrifugal 5min of whizzer again.Get 0.1mL organic phase and water respectively and measure radiocounting, calculate lipid mean value and LogP thereof.(radioactive activity of the radioactive activity/water of P=organic phase) records logP=-3.26, explanation
99mTc-HYNIC-NHHN-Folate is a hydroaropic substance.
2.
99mThe Tc-HYNIC-NHHN-Folate vitro stability is measured
Marker ligand compound behind the purifying is placed 4h respectively under room temperature, during adopt the HPLC method to measure the radiochemical purity of marker, observe the vitro stability of marker ligand compound.Experiment shows this title complex after placing 4h, and radiochemical purity shows still greater than 90%
99mTc-HYNIC-NHHN-Folate at room temperature vitro stability is good, is suitable for the needs of clinical application.
3.
99mThe Tc-HYNIC-NHHN-Folate charge property is measured
Utilize paper electrophoresis method to measure the charge property of marker ligand compound.Adopting chromatographic paper of Xinhua is support, and electrophoresis liquid is the PBS (pH=7.4) of 0.025mol/L.In the chromatographic paper center of having got ready, regulating voltage is to 150V with the marker ligand compound point sample behind the purifying.Electrophoresis carries out powered-down behind the 120min, takes out the chromatography paper slip, dries the increased radioactivity of back measuring mark title complex on chromatographic paper.Calculate the relative percentage value of shifting to positive pole, negative pole and being detained the initial point component respectively.The result shows that the radiocounting more than 90% concentrates on positive pole, shows
99mTc-HYNIC-NHHN-Folate is the electronegativity material.
4.
99mThe cell in vitro associativity of Tc-HYNIC-NHHN-Folate is measured
Cultivate the KB cell (human oral cavity epithelial cancer cells) of folacin receptor high expression level in orifice plate, it is 2 * 10 that the adjustment cell concn makes every porocyte number
5～4 * 10
5After treating the 12h cell attachment, cell is divided into three groups of A, B, C, is respectively total absorption, internalization and inhibition group, every group three hole.A, B group adds the weary folic acid substratum 975 μ L that prepare, and the C group adds 475 μ L substratum and 500 μ L folic acid solution (100 μ M), 37 ℃ hatch 40min after, A, B, C group add the marker ligand compound 25 μ L (1MBq/mL) after the separation and purification respectively, hatch 1h for 37 ℃.Orifice plate is taken out back sucking-off substratum from incubator, A, the C group is organized (0.15M NaCl and 0.1M HAc with stripping buffer with freezing PBS (pH=7.4) flushing three times, B, pH=3) flushing is three times, and the substratum of collection sucking-off and the solution of flushing are as water.Orifice plate is washed with the 1mL trypsin digestion and cell and with PBS in every hole, changes centrifuge tube after the collection over to as solid phase, measures water and solid phase radiocounting respectively.The result shows that this title complex and folacin receptor have good binding ability, the cell total binding account for add up radioactively 24%, after the inhibition group added excessive folic acid, picked-up was subjected to remarkable inhibition, illustrated that folacin receptor is the specificity combination to the combination of this title complex.
5.
99mTc-HYNIC-NHHN-Folate measures in the intravital bio distribution of normal mouse
Select 12 of the female normal kunming mices of 18～20g, be divided into 4 groups at random, every group of 3 mouse.Feed mouse after one week with the food of weary folic acid, inject mark complex solution (about 185kBq, radiochemical purity is greater than 90%) behind the 0.1mL purifying respectively from mouse tail vein, the disconnected neck of mouse is put to death in injection back different time, get its blood, the heart, liver, spleen, organs such as lung, weigh after cleaning, and place trap type gamma ray probe to measure its radiocounting, the radiocounting of calculating every gram tissue accounts for the percentage ratio of total injected dose (%ID/g).The inhibition group is injected 0.1mL folic acid solution (1mg/mL) simultaneously.Experimental result sees Table 2.
The result shows that this marker ligand compound has higher picked-up and well delay in kidney, picked-up in its hetero-organization and organ is all lower, this is because in healthy tissues, and the folacin receptor of uriniferous tubules is expressed higher, and the expression of the folacin receptor of its hetero-organization and organ is relative conservative.When injecting excessive folic acid, the picked-up of marker ligand compound in kidney obviously suppressed, and shows that this marker ligand compound has higher affinity to folacin receptor and has than highly selective.
6.
99mThe bio distribution of Tc-HYNIC-NHHN-Folate in bearing mouse model measured
Get the nude mice of the about 18～20g of physique amount, in left upper extremity subcutaneous vaccination KB tumor cell line 0.1mL (6 * 10
6), fed 10～14 days with the food of weary folic acid inoculation back, can be used for experiment when treating knurl path length to 0.8～1.0cm.Get 10 of lotus KB mice with tumor, be divided into 2 groups, tail vein injection 0.1mL (about 185KBq, radiochemical purity is greater than 90%) marker solution, 4h takes out tissues such as the heart, liver, spleen, lung, kidney, brain, bone, tumour, muscle and blood with the mouse sacrificed by decapitation after injection, weighs and its radiocounting of survey in the technetium analyser, the radiocounting of calculating every gram tissue accounts for the percentage ratio of total injected dose (%ID/g), and the inhibition group is injected 0.1mL folic acid solution (1mg/mL) simultaneously.Experimental result is as shown in table 3:
By the detection data declaration of above embodiment,
99mTc-HYNIC-NHHN-Folate can be used as a kind of novel
99mTc labeled leaf acid acceptor tumor developer is applied.
Claims (3)
1. one kind
99mThe hydrazino nicotinamide-folate coordination compound of Tc mark is characterized in that: expression formula is
99mTc-HYNIC-NHHN-Folate, its structural formula is:
In this structural formula: the nitrogen-atoms in the part HYNIC-NHHN-Folate molecule in the diazanyl, altogether the Sauerstoffatom in part Tricine and the TPPTS molecule and phosphorus atom and
99mTc carries out coordination and obtains
99mThe Tc-HYNIC-NHHN-Folate title complex.
2. preparation according to claim 1
99mThe method of the hydrazino nicotinamide-folate coordination compound of Tc mark, its step is as follows:
A. part hydrazino nicotinamide--folic acid synthetic:
Compound folic acid and succinimide-6-tertiary butyl oxygen carbonyl hydrazide yl pyridines-3-formic acid are dissolved in the dimethyl sulfoxide (DMSO) of 10-50mL, add the 5-25mL pyridine, room temperature reaction 10-24h; Reacted solution is slowly splashed in the ether, and centrifugal collection generates the salmon precipitation thing, uses ether and washed with dichloromethane respectively, and vacuum-drying gets orange red solid; Orange red solid is added in the trifluoroacetic acid of 1-5mL, under nitrogen protection, behind the ice-water bath reaction 2h, revolve to steam and remove trifluoroacetic acid, to remain oily liquids 0.1-2mL N, splash into behind the dinethylformamide solution in the 100-500mL pyridine, the precipitation that centrifugal collection produces and with the ether washing, vacuum-drying obtains pale brown toner end; Synthetic route is:
B.
99mThe preparation of the hydrazino nicotinamide-folate coordination compound of Tc mark:
In the penicillin bottle, add 10-100mg trishydroxymethyl-methylglycine successively, 20-100 μ g tin protochloride, 20-200 μ g part hydrazino nicotinamide--the acetate buffer solution of folic acid and 0.1-1mL, pH=3.6, shake up the back to the Tc-99m leacheate 0.1-0.5mL that wherein injects 37～370MBq, boiling water bath heating 15min; Add 1-5mg trityl phosphine sodium trisulfonate solution in the good solution of mark, shake up back boiling water bath heating 5-30min, it is described to obtain claim 1
99mThe hydrazino nicotinamide-folate coordination compound of Tc mark.
3. as claimed in claim 1
99mThe hydrazino nicotinamide-folate coordination compound of Tc mark is characterized in that: described title complex can be used as folacin receptor and is used to prepare tumor developer.
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| CN102526775B (en) * | 2012-01-18 | 2013-03-13 | 江苏省原子医学研究所 | 99Tcm-labeled folate-polyhydroxyethyl acrylate-diethylenetriaminepentaacetic acid and preparation method thereof |
| CN103342724B (en) * | 2013-06-26 | 2015-07-08 | 北京师范大学 | Preparation method and application for 99mTc-labelled hydrazino-nicotinamide-5-aminopentanoic acid-pteroyl lysine complex |
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