CN101289466B - <99>Tc<m>N nucleus marked ciprofloxacin dithiocarbamate complexes, preparation and applications - Google Patents

<99>Tc<m>N nucleus marked ciprofloxacin dithiocarbamate complexes, preparation and applications Download PDF

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CN101289466B
CN101289466B CN2008101061539A CN200810106153A CN101289466B CN 101289466 B CN101289466 B CN 101289466B CN 2008101061539 A CN2008101061539 A CN 2008101061539A CN 200810106153 A CN200810106153 A CN 200810106153A CN 101289466 B CN101289466 B CN 101289466B
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cpfxdtc
preparation
title complex
ciprofloxacin
inflammation
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CN101289466A (en
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张俊波
郭海勋
张仕坚
林艳
王学斌
唐志刚
张现忠
陆洁
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Beijing Shihong Pharmaceutical Research Center
Beijing Normal University
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Beijing Normal University
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Abstract

The invention discloses a <99>Tc<m>N nucleus label ciprofloxacin ammonia famine chlordimeform-hydrochloride complex, a preparation method and applications thereof. The complex uses the <99>Tc<m>N nucleus as a centronucleus, and the organic ligand which is coordinated with the <99>Tc<m>N nucleus is ciprofloxacin ammonia famine chlordimeform-hydrochloride (CPFXDTC). The complex is provided with an irregular square pyramidal geometry; wherein, N atom in the triple bond of Tc equivalent to N is arranged in the apical position, and four sulfur atoms provided by two ligands CPFXDTC molecules are arranged in four points at the bottom surface. The complex has the advantages of the high radiochemical purity, the good stability, the high inflammation uptaking and the good target or non-target ratioof inflammation or muscle, inflammation or blood, etc., which is a novel inflammation tracer with the popularization using value.

Description

99Tc mN nucleus marked ciprofloxacin dithiocarbamate complexes and preparation method and application
Affiliated technical field
The present invention relates to 99Tc mThe radiopharmaceutical chemistry and the clinical nuclear medicine technical field of N nuclear mark relate to a kind of specifically 99Tc mN nucleus marked ciprofloxacin dithiocarbamate complexes and preparation method and application.
Background technology
As everyone knows, the video picture of nucleic inflammation is an important means checking focus in early days.It is highly sensitive that acute chronic inflammatory diseases focus is surveyed in the white corpuscle video picture of radioisotope labeling, and high specificity have the title of " gold standard ", but cross infection takes place easily again its labeling process complexity, so be subjected to certain limitation on its clinical application.Because 99Tc mHas short (T of transformation period 1/2=6.02 hours), the energy of (E that suits γ=140kev) etc. good nulcear properties and conveniently be easy to get, cheap advantage, make it become the first-selected nucleic of radiopharmaceuticals research.In recent years, 99Tc mMark antibiotic is one of focus of nuclear medicine inflammation video picture, wherein 99Tc m-Ciprofloxacin ( 99Tc m-ciprofloxacin) research is more, and it can not only diagnose inflammation, and can also distinguish bacillary and non-bacterial infection, and clinical value is preferably arranged.But 99Tc mStill there is certain shortcoming in-Ciprofloxacin, the radiochemical purity that at first is title complex is not high, can form the colloid technetium of non-quantitative during mark and influence the video picture quality, and title complex needs the millipore filtration purification process, cause the radiological chemistry productive rate to reduce clinical application inconvenience (Seung JO, Jin-Sook R, Joong WS, et al.Synthesis of 99mTc-ciprofloxacinby different methods and its biodistribution[J], Applied Radiation and Isotopes, 2002,57:193-200), therefore develop the novel inflammation developer that makes things convenient for clinical application and have great importance.
Because 99Tc mThe N triple bond has very high chemical stability, and the bio distribution character of its corresponding title complex obviously be different from [ 99Tc mO] 3+Nuclear or [ 99Tc mO 2] +The caryogamy compound, thereby 99Tc mN caryogamy compound has caused people's extensive concern.Especially with SDH (succinyl two hydrazides, H 2NNHCOCH 2CH 2CONHNH 2) as N 3-The ion donor, SnCl 2As reductive agent at room temperature successfully prepare [ 99Tc m≡ N] 2+The method of intermediate makes a breakthrough, for [ 99Tc m≡ N] 2+Convenience has been opened in radiopharmaceutic research and application.The Ciprofloxacin that how will contain quinolones drug effect group be converted into can with 99Tc m(Ciprofloxacin dithiocarbamate, be called for short: CPFXDTC), preparation is corresponding then for the ciprofloxacin dithiocarbamate part of N complexing 99Tc mN nuclear ciprofloxacin dithiocarbamate complexes ( 99Tc mN-CPFXDTC) coming as novel inflammation developer, is the important topic that current present technique field need solve.
Summary of the invention
Purpose of the present invention provides a kind of radiochemical purity height, good stability, is applied in inflammation video picture field 99Tc mThe N nucleus marked ciprofloxacin dithiocarbamate complexes also provides simultaneously 99Tc mThe preparation method of N nucleus marked ciprofloxacin dithiocarbamate complexes.
In order to achieve the above object, the present invention by the following technical solutions: a kind of 99Tc mThe N nucleus marked ciprofloxacin dithiocarbamate complexes ( 99Tc mN-CPFXDTC), its structural formula is:
This title complex has a PYR geometric configuration of irregular pros, and wherein the N atom in the Tc ≡ N triple bond is positioned at vertex position, and four sulphur atoms that two part CPFXDTC molecules provide are positioned at four points of bottom surface.
99Tc mThe preparation method of N-CPFXDTC title complex is as follows:
A. part CPFXDTC's is synthetic:
Get a certain amount of ciprofloxacin HCl and place reaction flask, add the water and the tetrahydrofuran solution that are dissolved with an amount of sodium hydroxide,, dropwise add dithiocarbonic anhydride in being cooled under the ice-water bath about 0 ℃, and under this temperature stirring reaction 2 hours, remove ice bath and under room temperature, react and spend the night.Have yellow solid to generate, filter, drying with methyl alcohol/anhydrous diethyl ether recrystallization, gets pale yellow crystals, is part CPFXDTC.
Its synthetic route is:
Figure DEST_PATH_GA20192684200810106153901D00012
B. 99Tc mThe preparation of N-CPFXDTC:
With 37～370MBq's 99Tc mO 4 -Leacheate 1-5mL joins in SDH (the succinyl two hydrazides) froze-dried kit and fully shakes up, and after the solid dissolving, 20～30 ℃ of following reactions obtained in 15～30 minutes 99Tc mThe N midbody solution.With 1mL concentration is that the CPFXDTC aqueous solution of 1g/L joins above-mentioned 99Tc mIn the N midbody solution, under 20～30 ℃, left standstill 15～30 minutes behind the mixing, promptly obtain described 99Tc mThe N-CPFXDTC title complex.
99Tc mLigand exchange reaction is adopted in the preparation of N-CPFXDTC, and its reaction scheme is as follows:
99Tc mO 4 -+SDH+SnCl 2·2H 2O+PDTA→[ 99Tc mN] int 2+
[ 99Tc mN] int 2++CPFXDTC→ 99Tc mN-CPFXDTC
Above-mentioned described chemosynthesis reagent all is commercial goods, and wide material sources obtain easily.
By method for preparing 99Tc mVitro stability is good under the N-CPFXDTC title complex room temperature, and its radiochemical purity is greater than 90%.
Above-mentioned described 99Tc mThe N-CPFXDTC title complex is a kind of novel 99Tc mMark inflammation developer, it and tradition 99Tc mThe difference of-Ciprofloxacin be it be with [ 99Tc m≡ N] 2+Nuclear is centronucleus, and radiochemical purity height, good stability, mark do not need filtering with microporous membrane, is convenient to clinical expansion and uses.External bacterium shows in conjunction with experimental result 99Tc mThe bacterium combination rate of N-CPFXDTC is 59.7%, and 99Tc mThe bacterium combination rate of-Ciprofloxacin is 40% (Seung JO, Jin-Sook R, Joong WS, et al.Synthesis of 99mTc-ciprofloxacin by differentmethods and its biodistribution[J], Applied Radiation and Isotopes, 2002,57:193-200), show 99Tc mN-CPFXDTC has better external bacterium binding characteristic, possesses the value as the inflammation developer.
Will 99Tc mThe N-CPFXDTC title complex with clinically as the inflammation video picture 99Tc m-Ciprofloxacin bio distribution data in the small white mouse body of infectation of bacteria model Kunming compare [Zhang Hong, Jiang Ningyi, Zhu Lin etc. 99mThe experimental study [J] of Tc marked ciprofloxacin inflammation video picture, Chinese clinical medicine image magazine, 2006,17:42-44], result such as table 1:
Table 1 99Tc mN-CPFXDTC with 99Tc m-Ciprofloxacin is bio distribution in the small white mouse body of 4h infectation of bacteria model Kunming [(X ± S, n=4) %ID/g] after injection
Figure DEST_PATH_GA20192684200810106153901D00021
Above result shows, although 99Tc mInflammation tissue/the muscle ratio of N-CPFXDTC title complex will be lower than 99Tc m-Ciprofloxacin, but the former picked-up value in inflammation and inflammation tissue/blood ratio will be apparently higher than the latter, so, 99Tc mThe N-CPFXDTC title complex is better than in the intravital bio distribution result of inflammation mouse 99Tc m-Ciprofloxacin can be used as a kind of novel inflammation developer and applies.
Experiment shows, 99Tc mThe performance of N-CPFXDTC title complex is as follows:
1. 99Tc mThe chromatography of N-CPFXDTC is identified:
Thin-layer chromatography chromatogram (TLC) is identified: making support with polyamide layer, is that 9: 1 methylene chloride-methanol mixed solvent is made developping agent with physiological saline and volume ratio respectively, and the tomographic results of mensuration sees Table 2.
The tomographic results of each component of table 2 (Rf value)
Identify that by above-mentioned chromatography the radiochemical purity of measured marker is greater than 90%.
High pressure liquid chromatography (HPLC) is identified: Shimadzu SCL-10AVP type high pressure liquid chromatograph, (25cm * 4.6mm), Packard liquid dodges analyser to the Kromasil100-5C18 reversed-phase column.Drip washing condition of gradient elution (A is a water, and B is the methyl alcohol phase) sees Table 3, and flow velocity is 1.0ml/min, and the retention time of each component of mensuration (Rt) is respectively: [ 99Tc mN] 2+: 2.9min; 99Tc mN-CPFXDTC:23.9min, the chromatogram result of gained show, 99Tc mThe radiochemical purity of N-CPFXDTC title complex is greater than 95%.
The condition of gradient elution of table 3 title complex
Figure G200810106153901D00042
2. 99Tc mThe mensuration of the lipid of N-CPFXDTC title complex
The phosphate buffered saline buffer (0.025mol/L) of getting 1.0mLpH7.4 adds 1.0mL n-Octanol and 0.01mL in centrifuge tube in the 10mL centrifuge tube 99Tc mN-CPFXDTC solution covers stopper, fully shakes up, centrifugal 5min (5000r/min).Take out 0.1mL from organic phase and aqueous phase respectively then, measure the radiocounting of two-phase, and calculate its partition ratio P (radioactive activity of the radioactive activity/water of P=organic phase), record logP=1.02, explanation 99Tc mN-CPFXDTC is a lipid-soluble substance.
(3) 99Tc mThe stability of N-CPFXDTC title complex is measured
Mark is good 99Tc mThe N-CPFXDTC title complex is at room temperature placed different time (1,2,3,4,5,6 hour) back and is measured its radiochemical purity, and experimental result shows 99Tc mThe N-CPFXDTC title complex after placing 6 hours radiochemical purity greater than 90%, explanation 99Tc mN-CPFXDTC title complex at room temperature vitro stability is good, is suitable for the needs of clinical application.
(4) 99Tc mThe external bacterium of N-CPFXDTC title complex is in conjunction with experiment:
Get acetum and the 0.4mL streptococcus aureus solution [1 * 10 of 0.4mL 0.01mol/L 10The PBS of/1mL 0.1mol/L (pH7.4) solution] place centrifuge tube, it is good to get mark 99Tc mN-CPFXDTC complex solution 0.2mL (3.7MBq) joins respectively in the above-mentioned mixed solution, descend centrifugal 5min (2000rpm) behind 4 ℃ of following 1h of cultivation, remove supernatant liquid, PBS (pH7.4) solution washing post precipitation recentrifuge with 1mL 0.1mol/L, merge all clear liquids after taking out supernatant liquid, measure radiocounting A1, precipitation radiocounting A2, the bacterium combination rate is [A2/ (A1+A2)] * 100%.Record 99Tc mThe bacterium combination rate of N-CPFXDTC title complex is 59.7%.
(5) 99Tc mThe bio distribution experiment of N-CPFXDTC title complex in the inflammation mouse model:
Get 0.05mL streptococcus aureus (1 * 10 10/ 1mL 0.1mol/L PBS), is expelled in the left back femoribus internus muscle of the Kunming small white mouse about 18g, gets 8 behind the 24h and infect tangible mouse, respectively through tail vein injection 0.1mL (about 7.4 * 10 5Bq) title complex, in injection back 3, the disconnected neck of 4h is put to death.Get different organs, abscess muscle and offside leg muscle, weigh after cleaning, and on FT-603 trap type γ scintillation probe, survey its radiocounting, calculate every gram percentage injected dose (%ID/g) of each tissue.The results are shown in Table 4.
Table 4 99Tc mThe bio distribution of N-CPFXDTC title complex in the inflammation mouse model (n=4, %ID/g)
Figure G200810106153901D00051
Embodiment:
Below by embodiment in detail the present invention is described in detail:
A kind of 99Tc mThe N nucleus marked ciprofloxacin dithiocarbamate complexes:
A. part CPFXDTC's is synthetic:
Get 3.625g (0.01mol) ciprofloxacin HCl and place 50mL single port flask, add the 8mL water and the 1mL tetrahydrofuran (THF) that are dissolved with 1.2g NaOH (0.03mol),, dropwise add 1mLCS in being cooled under the ice-water bath about 0 ℃ 2(being dissolved in the 2mL tetrahydrofuran (THF)), and under this temperature stirring reaction 2h, remove ice bath and under room temperature, react and spend the night.Have solid to generate, solution is yellow.Filter, drying slightly claims 4.30g, with methyl alcohol/anhydrous diethyl ether recrystallization, gets the 3.23g light yellow solid, yield 66%.
The data of the infrared spectra of part CPFXDTC are: IR (KBr)/cm -1: 3416 (vOH), 1625 (vC=O), 1009 (vC=S), 1HNMR (DMSO-d 6) δ: 8.58 (s, 1H), 7.76 (d, J=10.78,1H), 7.37 (s, 1H), 4.57 (bs, 4H), 3.58 (s, 1H), 3.16 (bs, 4H), 1.26 (bs, 2H), 0.99 (bs, 2H). 13CNMR(DMSO-d 6)δ：215.1，175.3，168.8，153.7，151.7，147.9，144.0，138.7，122.1，111.7，111.5，106.0，50.2，48.9，34.6，8.0。
B. 99Tc mThe preparation of N-CPFXDTC
Preparation SDH froze-dried kit: by with SDH, PDTA, SnCl 2.2H 2O is dissolved in an amount of secondary water by the weight ratio of 1-20: 1-20: 0.005-0.5, fully is sub-packed in the clean penicillin bottle, through freeze-dried back after the dissolving.
With 37～370MBq's 99Tc mO 4 -Leacheate 1-5mL joins in the SDH froze-dried kit, fully shakes up, and after solid dissolved fully, room temperature (20～30 ℃) reaction down obtained in 15～30 minutes 99Tc mThe N midbody solution.With 1mL concentration is that the CPFXDTC aqueous solution of 1g/L joins above-mentioned 99Tc mIn the N midbody solution, under room temperature (20～30 ℃), left standstill 15～30 minutes behind the mixing, promptly obtain described 99Tc mThe N-CPFXDTC title complex.

Claims (3)

1. one kind 99Tc mThe N nucleus marked ciprofloxacin dithiocarbamate complexes is characterized in that:
99Tc mThe structural formula of N-CPFXDTC title complex is:
Figure FSB00000216365100011
This title complex has a PYR geometric configuration of irregular pros, and wherein the N atom in the Tc ≡ N triple bond is positioned at vertex position, and four sulphur atoms that two part CPFXDTC molecules provide are positioned at four points of bottom surface.
2. one kind prepares according to claim 1 99Tc mThe method of N nucleus marked ciprofloxacin dithiocarbamate complexes is characterized in that: 99Tc mThe preparation method of N-CPFXDTC title complex is as follows:
A. part CPFXDTC's is synthetic:
Get a certain amount of ciprofloxacin HCl and place reaction flask, add the water and the tetrahydrofuran solution that are dissolved with an amount of sodium hydroxide, in being cooled under the ice-water bath about 0 ℃, dropwise add dithiocarbonic anhydride, and under this temperature stirring reaction 2 hours, remove ice bath and under room temperature, react and spend the night, have yellow solid to generate, filter, drying with methyl alcohol/anhydrous diethyl ether recrystallization, gets pale yellow crystals, be part CPFXDTC
Its synthetic route is:
Figure FSB00000216365100012
B. 99Tc mThe preparation of N-CPFXDTC:
With 37～370MBq's 99Tc mO 4 -Leacheate 1-5mL joins in the succinyl two hydrazides froze-dried kits, fully shakes up, and after solid dissolved fully, 20～30 ℃ of following reactions obtained in 15～30 minutes 99Tc mThe N midbody solution; With 1mL concentration is that the CPFXDTC aqueous solution of 1g/L joins above-mentioned 99Tc mIn the N midbody solution, under 20～30 ℃, left standstill 15～30 minutes behind the mixing, promptly obtain described 99Tc mThe N-CPFXDTC title complex;
99Tc mLigand exchange reaction is adopted in the preparation of N-CPFXDTC, and its reaction scheme is as follows:
99Tc mO 4 -+SDH+SnCl 2·2H 2O+PDTA→[ 99Tc mN] int 2+
[ 99Tc mN] int 2++CPFXDTC→ 99Tc mN-CPFXDTC。
3. as claimed in claim 1 99Tc mThe purposes of N nucleus marked ciprofloxacin dithiocarbamate complexes in preparation inflammation developer.
CN2008101061539A 2008-05-09 2008-05-09 <99>Tc<m>N nucleus marked ciprofloxacin dithiocarbamate complexes, preparation and applications Expired - Fee Related CN101289466B (en)

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CN101574531B (en) * 2009-06-18 2011-09-28 北京师范大学 <99>Tc<m>O nucleus marked ciprofloxacin dithiocarbamate complex and preparation method and applications thereof
CN101665520B (en) * 2009-10-16 2011-12-07 北京师范大学 <99>Tc<m>N(NFXDTC)2 complex and preparation method and application thereof
CN108610379B (en) * 2016-12-13 2020-09-11 北京师范大学 Technetium-99 m marked ciprofloxacin xanthate complex and preparation method and application thereof

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