CN102977174B - 99mTc(CO)3 nuclear-labeled macrocyclic polyamine triazole ring glucose-based complex as well as preparation and application of complex - Google Patents
99mTc(CO)3 nuclear-labeled macrocyclic polyamine triazole ring glucose-based complex as well as preparation and application of complex Download PDFInfo
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Abstract
The invention discloses a 99mTc(CO)3 nuclear-labeled macrocyclic polyamine triazole ring type glucose-based complex as well as a preparation and an application of the complex. The complex is 99mTc(CO)3-[12]N3-G for short and is formed by taking a 99mTc(CO)3 nuclear as a centronucleus and using three nitrogen atoms in a [12]N3-G ligand molecule to replace 3 H2O molecules on a (99mTc(CO)3(H2O)3)+ intermediate. The complex is prepared by two process steps, namely the synthesis of [12] N3-G and the preparation of a 99mTc(CO)3-[12]N3-G complex. The complex disclosed by the invention has the advantages of high radiochemical purity, good stability, high tumor intake, good tumor/muscle ratio and the like, and is a novel tumor imaging agent with excellent performances.
Description
Technical field
The present invention relates to
99mtc (CO)
3the radiopharmaceutical chemistry of core mark and clinical nuclear medicine technical field, relate to one specifically
99mtc (CO)
3the Macrocyclic polyamine triazole lopps glucosyl group title complex of core mark and preparation method and application.
Background technology
Malignant cell metabolism is vigorous, to the demand of glucose far above normal cell, tumor cell membrane is expressed a large amount of glucose transporter.D-Glucose analogue structure and D-Glucose similar, also can be transported by glucose transporter, the tumour cell vigorous by metabolism absorbs.It is carried out external detection by after radioisotope labeling by PET, SPECT, for diagnosing tumor, treats and therapeutic evaluation by stages.
18f-fluorodeoxyglucose ([
18f] FDG) be current clinical application tumor developer the most widely, enjoy the good reputation of " battle steed ".Due to [
18f] FDG is a kind of pet imaging agent, positron radionuclide [
18f] need to be produced by accelerator, expensive, hinder its widespread use in clinical diagnosis to a certain extent, especially in countries and regions underdeveloped.In view of the foregoing, be necessary that development is a kind of and prepare easy and cheap novel tumor developer.
99mtc, as medical science tracer agent, has very large superiority compared with other nucleic: suitable transformation period (T
1/2=6.02h), the moderate single photon γ (E γ=140kev) of energy launches, decay daughter radiation dose is low, and
99mo-
99msucceeding in developing of Tc producer makes
99mthe preparation of Tc radiopharmaceuticals is simple, can medicine box, cheap and easy to get, reliable in quality.Therefore, study
99mtc labelled glucose class tumor developer is also a general orientation and the focus of Today radiation drug development.
Up to now,
99mtc-ethylenedicysteine-deoxyglucose (is called for short
99mtc-ECDG) be uniquely enter clinical investigation phase
99mtc labelled glucose class tumor developer, but there is tumor uptake value and the shortcoming such as tumour/blood is on the low side, therefore desirable
99mthe glucose tumor metabolic developer of Tc mark still needs to be explored.The advantages such as technetium carbonyl compound has that volume is little, kinetic inertness and good vitro stability, three carbonyl (CO) parts of this kind of complex compound have very high stability, and covalency water molecules easily replaced or mark.Successfully prepare at ambient pressure especially in recent years [
99mtc (CO
3(H
2o
3]
+method make a breakthrough, make the research of technetium carbonyl-complexes also become one of the study hotspot in radiopharmaceutical chemistry field.The research of Macrocyclic polyamine and metal complexes thereof plays a part more and more important in synthetic chemistry, life science.The title complex of some metal of Macrocyclic polyamine shows excellent stability in physiological conditions, therefore in nuclear magnetic resonance diagnosis (human body visualization), x-ray diagnosis, ultrasonic diagnosis, radiodiagnosis and radiation treatment etc., has potential application prospect.Especially Isosorbide-5-Nitrae, 7-7-triazacyclononane (is called for short: [9] N
3) and 1,5,9-triazododecane (abbreviation: [12] N
3) etc. macrocyclic polyamine compound as the less tridentate ligand of volume can with [
99mtc (CO)
3(H
2o)
3]
+caryogamy position generates good stability
99mtc (CO)
3-[9] N
3with
99mtc (CO)
3-[12] N
3title complex.The present invention in conjunction with modern chemistry study hotspot and
99mthe new development of Tc marking method, uses Click chemistry, is nitrine sugar by conversion of glucose, generates triazole lopps glycosyl part containing Macrocyclic polyamine (referred to as [12] N with containing the efficient fast selective of Macrocyclic polyamine alkine compounds
3-G), then utilize nitrogen-atoms in Macrocyclic polyamine with
99mtc (CO)
3caryogamy position is formed stable
99mtc (CO)
3seleroglucar analogue seeks novel tumor developer, has very important scientific research and application and development value.
Summary of the invention
Object of the present invention provides that a kind of radiochemical purity is high, good stability, is applied in tumor imaging field
99mtc (CO)
3core mark Macrocyclic polyamine triazole lopps glucosyl group title complex, also provides its preparation method simultaneously.
Convenient in order to describe, hereafter will
99mtc (CO)
3core mark Macrocyclic polyamine triazole lopps glucosyl group title complex referred to as:
99mtc (CO)
3-[12] N
3-G.
In order to achieve the above object, the present invention by the following technical solutions: a kind of
99mtc (CO)
3-[12] N
3-G title complex, its structural formula is:
In this structural formula: with
99mtc (CO)
3core centered by core, [12] N
33 nitrogen-atoms in-G ligand molecular replace [
99mtc (CO)
3(H
2o)
3]
+3 H on intermediate
2generate after O molecule
99mtc (CO)
3-[12] N
3-G title complex.
99mtc (CO)
3-[12] N
3the preparation method of-G title complex is as follows:
A: part [12] N
3the synthesis of-G:
Take appropriate 1-nitrine-1-deoxidation-β-D-glucopyranoside, Boc-[12] aneN
3in 50mL two mouthfuls of flasks, add tetrahydrofuran (THF) and dissolve, then add a small amount of aqueous solution being dissolved with cupric sulfate pentahydrate, finally add sodium ascorbate, stir, under argon shield condition, reaction is spent the night; Rotary evaporation obtains faint yellow solid, adds a small amount of water dissolution, is extracted with ethyl acetate 3 times, collects ethyl acetate layer, and concentrated, column chromatography method carries out purifying and obtains Aoc-G-Boc-[12] N3; In Aoc-G-Boc-[12] N3, add appropriate anhydrous methanol, then add a small amount of sodium methylate, room temperature reaction 6h, concentrated, add a small amount of water, concentrated, add a small amount of ethanol again, suction filtration, concentrated filtrate, vacuum-drying obtains white solid, adds salt acid for adjusting pH value 3-4 in the product, boiling water bath heating 1h, regulate pH7-8 with the methanol solution of NaOH again, adularescent solid produces, and filters, concentrated filtrate, vacuum 45 DEG C of dried overnight, obtain yellow-brown solid [12] N
3-G;
Synthetic route:
B:
99mtc (CO)
3-[12] N
3the preparation of-G title complex:
5mg Na is added in penicillin bottle
2cO
3, 10mg NaBH
4, 15mg Seignette salt, after shaking up dissolving under adding physiological saline room temperature, pass into CO gas 15 minutes, add Na
99mtcO
4fresh leacheate, at shaking up rear 75-80 DEG C reaction within 30 minutes, namely obtain [
99mtc (CO)
3(H
2o)
3]
+intermediate; Take 2mg [12] N
3-G part, add above-mentioned [
99mtc (CO)
3(H
2o)
3]
+in intermediate, regulator solution pH value is 8-9, and boiling water bath heats 30 minutes, namely obtains of the present invention
99mtc (CO)
3-[12] N
3-G title complex.
Prepared by aforesaid method
99mtc (CO)
3-[12] N
3-G title complex vitro stability is at room temperature good, and its radiochemical purity is greater than 90%.
Will
99mtc (CO)
3-[12] N
3-G with
99mtc-ECDG and [
18f] FDG Biodistribution data (David J.et al.Imaging with in tumor-bearing mice body
99mtc-ECDG Targeted at the Multifunctional Glucose Transport System:Feasibility Study with Rodents [J] .Radiology, 2003,226 (2): 465-473) compare, the results are shown in Table 1.
Table 1
99mtc (CO)
3-[12] N
3-G,
99mtc-ECDG, [
18f] FDG injection 2h after in tumor-bearing mice body Biodistribution data compare (%ID/g, n=3)
As can be seen from the result of above contrast,
99mtc (CO)
3-[12] N
3the tumor uptake value of-G and tumour/muscle ratio all higher than
99mtc-ECDG and [
18f] FDG, can a kind of novel tumor developer be used as.
Experiment detection shows,
99mtc (CO)
3-[12] N
3the performance of-G title complex is as follows:
1.
99mtc (CO)
3-[12] N
3high performance liquid chromatography (HPLC) qualification of-G
High pressure liquid chromatography (HPLC) is identified: Shimadzu SCL-10AVP type high pressure liquid chromatograph, Kromasil 100-5C18 reversed-phase column (25cm × 4.6mm), and Packard liquid dodges analyser.In table 2, flow velocity is 1.0ml/min to drip washing condition of gradient elution (A is the water of the TFA containing 0.1%, and B is the acetonitrile of the TFA containing 0.1%), and the retention time (Rt) of each component of mensuration is respectively: [
99mtc (CO)
3(H
2o)
3]
+: 18.1min;
99mtc (CO)
3-[12] N
3-G:4.2min, the chromatographic results of gained shows what (t=4.2min has single radioactivity main peak) showed to generate
99mtc (CO)
3-[12] N
3the radiochemical purity of-G title complex is greater than 90%.
The condition of gradient elution of table 2 title complex
2.
99mtc (CO)
3-[12] N
3the mensuration of the lipid of-G title complex
The phosphate buffered saline buffer (0.025mol/L) getting 0.99mLpH7.4, in 10mL centrifuge tube, adds 1.0mL n-Octanol and 0.01mL in centrifuge tube
99mtc (CO)
3-[12] N
3-G solution, covers stopper, vortex, centrifugal 5min (5000r/min).Then from organic phase and aqueous phase, take out 0.1mL respectively, measure the radiocounting of two-phase, and calculate its partition ratio P (radioactive activity of the radioactive activity/aqueous phase of P=organic phase), record log P=-1.22 ± 0.01, explanation
99mtc (CO)
3-[12] N
3-G is a kind of water-soluble substances.
3.
99mtc (CO)
3-[12] N
3the Stability Determination of-G title complex
By what marked
99mtc (CO)
3-[12] N
3-G title complex measures its radiochemical purity after at room temperature placing 6 hours, and experimental result shows
99mtc (CO)
3-[12] N
3-G title complex placement after 6 hours radiochemical purity be greater than 90%, explanation
99mtc (CO)
3-[12] N
3-G title complex at room temperature vitro stability is good, is suitable for the needs of clinical application.
4.
99mtc (CO)
3-[12] N
3the biodistribution experiments of-G title complex in tumor mouse model
From the tail vein injection 0.10mL of the kunming mice (female, body weight is about 18-20g) of lotus S-180 sarcoma model
99mtc (CO)
3-[12] N
3-G complex solution (about 7.4 × 10
5bq), after injection respectively with 0.5h, 2h, 4h sacrificed by decapitation.Get related organization and the organs such as its heart, liver, lung, kidney, spleen, bone, intestines, muscle, blood, tumour, weigh after cleaning, and survey its radiocounting with technetium analyser, the tumor-bearing mice number of each phase is 3.Calculate every gram of percentage injected dose (%ID/g) of each tissue.The results are shown in Table 3.
Table 3
99mtc (CO)
3-[12] N
3the bio distribution of-G title complex in tumor mouse model (x ± s, n=3, %ID/g)
Body embodiment:
Below by embodiment in detail the present invention is described in detail: a kind of
99mtc (CO)
3-[12] N
3-G title complex, its structural formula is:
In this structural formula: with
99mtc (CO)
3core centered by core, [12] N
33 nitrogen-atoms in-G ligand molecular replace [
99mtc (CO)
3(H
2o)
3]
+3 H on intermediate
2generate after O molecule
99mtc (CO)
3-[12] N
3-G title complex.
99mtc (CO)
3-[12] N
3the preparation method of-G title complex is as follows:
(1) part [12] N
3the synthesis of-G
The first step:
Take 1-nitrine-1-deoxidation-β-D-glucopyranoside 186.66mg, Boc-[12] aneN
3204.5mg, in 50mL two mouthfuls of flasks, adds 10mL tetrahydrofuran (THF) and dissolves, then add a small amount of aqueous solution being dissolved with 12.484mg cupric sulfate pentahydrate, finally add the sodium ascorbate of 39.6mg, stir, and under argon shield condition, reaction is spent the night.Rotary evaporation obtains faint yellow solid, adds a small amount of water dissolution, is extracted with ethyl acetate 3 times, collects ethyl acetate layer, and concentrated, column chromatography method carries out purifying and obtains 353.0mg Aoc-G-Boc-[12] N3.
1HNMR(500MHz，CDCl3)：δ(ppm)7.62(s，1H)，5.88-5.86(q，1H)，5.46-5.40(m，2H)，5.28-5.23(m，1H)，4.35-4.30(q，1H)，4.14-4.17(d，1H)，4.03-3.99(m，1H)，3.79(s，2H)，3.35-3.33(d，8H)，2.43-2.42(d，4H)，2.09-2.07(d，6H)，2.03(s，3H)，1.86(s，9H)，1.45(s，18H).
13CNMR(500MHz，CDCl3)：δ(ppm)170.46，169.85，169.36，168.77(C＝O-OCH
3)，156.30(C＝O-O(CH
3)
3)，144.48(C-N＝N)，120.60，120.57(C-N-N)，85.80，75.18，72.60，70.28，67.79，61.56(glucose)，79.24(C(CH
3)
3)，49.72，45.46，43.73，27.05，26.23([12]N3)，46.55(CH
2-[12]N3)，28.51(CH
3-C-O-C＝O-[12]N3)，20.52，20.48，20.11，20.08(CH
3-O-C＝O-glucose).HRMS(ESI)：C
18H
35N
6O
5(MH
+)，783.4140.
Second step:
Take 40mg Aoc-G-Boc-[12] N3, add 20mL anhydrous methanol, add a small amount of sodium methylate, room temperature reaction 6h, concentrated, add a small amount of water, concentrated, add a small amount of ethanol again, suction filtration, concentrated filtrate, vacuum-drying obtains white solid 25mg, adds salt acid for adjusting pH value 3-4 in the product, boiling water bath heating 1h, regulate pH7-8 with the methanol solution of NaOH again, adularescent solid produces, and filters, concentrated filtrate, vacuum 45 DEG C of dried overnight, obtain 12mg yellow-brown solid [12] N
3-G.
1HNMR(500MHz，CDCl3)：δ(ppm)8.79(s，1H)，6.22-6.20(d，1H)，4.38-4.33(t，1H)，4.25-4.21(d，1H)，4.-5-4.10(m，4H)，4.02-3.97(t，1H)，3.73-3.68(d，10H)，3.65(s，2H)，2.63-2.49(d，8H).
13CNMR(500MHz，CDCl3)：δ(ppm)139.40(C-N＝N)，130.33(C-N-N)，90.46，90.26，，81.7578.57，78.39，75.06，71.89，63.49(glucose)，51.86(CH
2-[12]N3)，50.34，45.00，44.13，23.11，20.81([12]N3).HRMS(ESI)：C
18H
35N
6O
5(MH
+)，415.2669.
(2)
99mtc (CO)
3-[12] N
3the preparation of-G title complex
5mg Na is added in penicillin bottle
2cO
3, 10mg NaBH
4, 15mg Seignette salt, after shaking up dissolving under adding physiological saline room temperature, pass into CO gas 15 minutes, add Na
99mtcO
4fresh leacheate, at shaking up rear 75-80 DEG C reaction within 30 minutes, namely obtain [
99mtc (CO)
3(H
2o)
3]
+intermediate.Take 2mg [12] N
3-G part, add above-mentioned [
99mtc (CO)
3(H
2o)
3]
+in intermediate, regulator solution pH value is 8-9, and boiling water bath heats 30 minutes, namely obtains of the present invention
99mtc (CO)
3-[12] N
3-G title complex.
By the detection digital proof to above embodiment
99mtc (CO)
3-[12] N
3-G title complex can be applied as a kind of novel tumor developer.
Claims (3)
1. one kind
99mtc (CO)
3-[12] N
3-G title complex, is characterized in that: its structural formula is as follows:
In structural formula: [12] N
3-G is the triazole lopps D-Glucose ylidene ligands containing Macrocyclic polyamine; With
99mtc (CO)
3core centered by core, [12] N
33 nitrogen-atoms in-G ligand molecular replace [
99mtc (CO)
3(H
2o)
3]
+3 H on intermediate
2generate after O molecule
99mtc (CO)
3-[12] N
3-G title complex.
2. as claimed in claim 1
99mtc (CO)
3-[12] N
3the preparation method of-G title complex, its processing step is as follows:
A: part [12] N
3the synthesis of-G:
Take appropriate 1-nitrine-1-deoxidation-β-D-glucopyranoside, Boc-[12] aneN
3in 50mL two mouthfuls of flasks, add tetrahydrofuran (THF) and dissolve, then add a small amount of aqueous solution being dissolved with cupric sulfate pentahydrate, finally add sodium ascorbate, stir, under argon shield condition, reaction is spent the night; Rotary evaporation obtains faint yellow solid, adds a small amount of water dissolution, is extracted with ethyl acetate 3 times, collects ethyl acetate layer, and concentrated, column chromatography method carries out purifying and obtains Aoc-G-Boc-[12] N3; In Aoc-G-Boc-[12] N3, add appropriate anhydrous methanol, then add a small amount of sodium methylate, room temperature reaction 6h, concentrated, add a small amount of water, concentrated, add a small amount of ethanol again, suction filtration, concentrated filtrate, vacuum-drying obtains white solid, adds salt acid for adjusting pH value 3-4 in the product, boiling water bath heating 1h, regulate pH7-8 with the methanol solution of NaOH again, adularescent solid produces, and filters, concentrated filtrate, vacuum 45 DEG C of dried overnight, obtain yellow-brown solid [12] N
3-G;
B:
99mtc (CO)
3-[12] N
3the preparation of-G title complex:
5mgNa is added in penicillin bottle
2cO
3, 10mgNaBH
4, 15mg Seignette salt, then after shaking up dissolving under adding physiological saline room temperature, pass into CO gas 15 minutes, add Na
99mtcO
4fresh leacheate, at shaking up rear 75-80 DEG C reaction within 30 minutes, namely obtain [
99mtc (CO)
3(H
2o)
3]
+intermediate; Take 2mg [12] N
3-G part, add above-mentioned [
99mtc (CO)
3(H
2o)
3]
+in intermediate, regulator solution pH value is 8-9, and boiling water bath heats 30 minutes, namely obtains described
99mtc (CO)
3-[12] N
3-G title complex.
3. as claimed in claim 1
99mtc (CO)
3-[12] N
3-G title complex prepares the purposes in tumor developer in radiopharmaceutical chemistry field.
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| CN105001274B (en) * | 2015-07-31 | 2018-01-19 | 中国科学院高能物理研究所 | Complex, the Preparation method and use of a kind of Glucosamine derived ligand compound and preparation method, three carbonyl Tc 99ms mark |
| CN106806908A (en) * | 2015-11-30 | 2017-06-09 | 天津朋德药业有限公司 | A kind of glucose metabolism imageable agents box |
| CN105541799B (en) * | 2015-12-10 | 2017-10-24 | 北京师范大学 | [12] aneN containing targeting group and fluorophor3Cationoid lipid, transgene carrier and preparation method thereof |
| CN105524113B (en) * | 2016-03-04 | 2018-04-10 | 北京师范大学 | 99mTcN cores mark glucose dithiocarbamate complexes and preparation method and application containing triazole ring |
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|---|---|---|---|---|
| WO2001015746A1 (en) * | 1999-09-01 | 2001-03-08 | Schering Aktiengesellschaft | Radiopharmaceutical products and their preparation procedure |
| CN101316615A (en) * | 2005-11-29 | 2008-12-03 | 马林克罗特公司 | Bifunctional metal chelating conjugates |
| CN101555263A (en) * | 2009-05-21 | 2009-10-14 | 北京师范大学 | D-glucose dithiocarbamate complex marked by <99m>TcO, preparation method and applications thereof |
| CN102060880A (en) * | 2010-12-06 | 2011-05-18 | 北京师范大学 | 99mTc(CO)3-DGDTC complex as well as preparation method and application thereof |
| CN102219818A (en) * | 2011-05-05 | 2011-10-19 | 江苏省原子医学研究所 | Thymidine derivates as well as preparation method and applications thereof in preparing tumor developing agents as ligand |
-
2012
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001015746A1 (en) * | 1999-09-01 | 2001-03-08 | Schering Aktiengesellschaft | Radiopharmaceutical products and their preparation procedure |
| CN101316615A (en) * | 2005-11-29 | 2008-12-03 | 马林克罗特公司 | Bifunctional metal chelating conjugates |
| CN101555263A (en) * | 2009-05-21 | 2009-10-14 | 北京师范大学 | D-glucose dithiocarbamate complex marked by <99m>TcO, preparation method and applications thereof |
| CN102060880A (en) * | 2010-12-06 | 2011-05-18 | 北京师范大学 | 99mTc(CO)3-DGDTC complex as well as preparation method and application thereof |
| CN102219818A (en) * | 2011-05-05 | 2011-10-19 | 江苏省原子医学研究所 | Thymidine derivates as well as preparation method and applications thereof in preparing tumor developing agents as ligand |
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