CN1786009A - Application of 99TcmN (CPEDTC)2 compounding agent in tumour imaging field - Google Patents

Application of 99TcmN (CPEDTC)2 compounding agent in tumour imaging field Download PDF

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CN1786009A
CN1786009A CN 200510134705 CN200510134705A CN1786009A CN 1786009 A CN1786009 A CN 1786009A CN 200510134705 CN200510134705 CN 200510134705 CN 200510134705 A CN200510134705 A CN 200510134705A CN 1786009 A CN1786009 A CN 1786009A
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cpedtc
tumour
application
99tcmn
tumor
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CN100363371C (en
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张俊波
王学斌
陆洁
唐志刚
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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 present invention discloses a 99TcmN(CPEDTC)2 coordination compound as tumor developing agent and its application in the field of nuclear medicine. Said coordination compound has an irregular tetragonal pyramid geometric configuration. It has higher chemical stability and special biological distribution property.

Description

99Tc mN (CPEDTC) 2Title complex is in the tumor imaging Application for Field
Technical field
The present invention relates to 99Tc mThe radiopharmaceutical chemistry field of mark and tumour the field of nuclear medicine relate to a kind of specifically 99Tc mN (CPEDTC) 2Title complex is in the tumor imaging Application for Field.
Background technology
In recent years, cancer has become one of healthy maximum arch-criminal of serious harm people.A large amount of facts prove that the determinative that improves cancer patients's survival rate, reduction mortality ratio not exclusively is treatment means, and should be early stage discovery and accurate location.With regard to mammary cancer, be one of women's common malignancy, its method of early diagnosis has multiple.The histology biopsy is to determine the most reliable method of lump character, but exists traumaticly, and living tissue cuts the possibility of impelling cancer metastasis is arranged in the process; Method such as X ray and MRI is highly sensitive, but specificity is lower.Nuclear medicine technology is as another big class detection means of breast cancer diagnosis, developed into various radionuclide imagings in the body from early stage external labelled immune analysis, at early diagnosing mammary cancer, by stages, aspect such as transfer, curative effect monitoring manifested the feasibility that attracts people's attention.Because 99Tc mThe ideal nulcear properties makes 99Tc mThe research of the tumour radiotherapy medicine of mark becomes one of primary study direction.At present as commodity (trade(brand)name: Miraluma) clinically as newborn mammary cancer video picture be 99Tc m-MIBI, its structural formula is as follows:
Because 99Tc mThe preparation of-MIBI needs the boiling water bath heating, and clinical application is not too convenient, and 99Tc mThe mechanism that-MIBI is used for the mammary cancer video picture also is in discussion stage, tumor uptake 99Tc m-MIBI is subjected to multiple factor affecting.In addition because 99Tc m-MIBI also is widely used as myocardial developer clinically, heart bring certain interference than the dense poly-development of high radioactivity to left part mammary cancer focus.Therefore the tumor developer of developing the New-type instant clinical application still has important practical significance.
Summary of the invention
The objective of the invention is to will 99Tc mN (CPEDTC) 2The title complex conduct has the tumor developer of medical use value in the tumor imaging Application for Field.
A kind of tumor developer of the present invention 99Tc mN (CPEDTC) 2, according to myocardial perfusion imaging agent 99Tc mN (NOET) 2Structure [Pasqualini R, et al:Bis (dithiocarbamato) nitrido technetium-99mradiopharmaceuticals:a class of neutral myocardial imaging agents.J.Nucl.Med.35:334 (1994)], can learn 99Tc mN (CPEDTC) 2Structure be:
Figure A20051013470500041
This complex compound 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 CPEDTC molecules provide are positioned at four points of bottom surface, and whole complex compound is electric neutrality.
The present invention 99Tc mN (CPEDTC) 2The preparation method as follows:
(1) part CPEDTC's is synthetic:
Synthetic route is:
Synthesis step is: a certain amount of cyclopentamine is added in the reaction vessel, under agitation add the NaOH aqueous solution in reactor, slowly drip CS then 2, stirring 2h～3h, the entire reaction course temperature will be controlled at below 10 ℃, cyclopentamine, NaOH and CS 2Add-on add for waiting mole.Steaming desolventizes then, and residuum gets a white crystal and is part CPEDTC with Virahol/ether mixed solvent (volume ratio is 9: 1) recrystallization.
(2) 99Tc mN (CPEDTC) 2Preparation:
99Tc mN (CPEDTC) 2Preparation adopt ligand exchange reaction, reaction scheme is as follows:
[1] [ 99Tc mN] Int 2+The preparation of intermediate:
The aqueous solution, the 0.1mLSnCl that 1mL are contained 5mgSDH (succinyl two hydrazides) and 5mgPDTA (1, the 2-trimethylenedinitrilo-tertraacetic acid) 22H 2HCl solution (the SnCl among the 0.2mol/LHCl of O 22H 2The mass concentration of O is 0.5g/L) join successively in the reaction vessel, regulator solution pH value is 7.0～7.5, adds 1mL then 99Tc mO 4 -Leacheate (3.7 * 10 7Bq/mL), at room temperature react 15min, promptly obtain [ 99Tc mN] Int 2+Intermediate.
[2] 99Tc mN (CPEDTC) 2Preparation:
The CPEDTC aqueous solution of 1mL (5g/L) is joined in the above-mentioned solution, shake up, reaction 10min promptly under the room temperature 99Tc mN (CPEDTC) 2
Above-mentioned synthetic used cyclopentamine, NaOH, CS 2, SnCl 2.2H 2O, PDTA, SDH are analytical reagent; 99Tc mO 4 -Leacheate is produced by China Atomic Energy Science Research Institute 99Mo- 99Tc mProducer obtains, and its radioactive purity is greater than 99%, and radioactive concentration is 3.7 * 10 7Bq/mL-37 * 10 7Bq/mL.
By the aforesaid method synthetic 99Tc mN (CPEDTC) 2, its radiochemical purity is greater than 90%.
Of the present invention 99Tc mN (CPEDTC) 2(CPEDTC: a water .N-cyclopentyl nabam, ) be a kind of novel 99Tc mTumor developer, it with 99Tc mOne of difference of-MIBI is 99Tc m-MIBI be with [ 99Tc m] +Nuclear is centronucleus, and 99Tc mN (CPEDTC) 2Be with [ 99Tc m≡ N] 2+Nuclear is centronucleus, and [ 99Tc m≡ N] 2+Nuclear has higher chemical stability and special bio distribution character, so 99Tc mN (CPEDTC) 2For another new field has been opened up in the development of tumor developer.
The bio distribution experimental result shows in the tumor-bearing mice body 99Tc mN (CPEDTC) 2Title complex has the tumors of higher picked-up and is detained preferably in tumour, the ratio of tumour and each non-target organ is also better, especially behind injection 120min, important target/non-target ratio such as tumour/blood, tumour/muscle, tumour/bone is expected to become a kind of novel tumor developer all greater than 1.
With clinically as the mammary cancer video picture 99Tc m-MIBI bio distribution data in lotus MA-891 breast cancer model TA-2 mouse body compare, and the bio distribution of the two relatively sees Table 1.
Table 1 99Tc mN (CPEDTC) 2With 99Tc m-MIBI after injection 60min in lotus MA-891 mammary cancer
Bio distribution compares ((x ± s, n=3) %ID/g) in the model TA-2 mouse body
99Tc mN(CPEDTC) 2 99Tc m-MIBI
Tumour blood intermuscular bone tumour/hemotoncus knurl/muscle tumor/bone 3.49±0.31 2.62±0.63 4.76±1.39 2.28±1.17 1.33 0.73 1.53 0.96±0.38 0.10±0.02 3.01±1.20 1.40±0.13 9.60 0.32 0.69
Above result shows, 99Tc mN (CPEDTC) 2The picked-up of title complex in tumour will apparently higher than 99Tc m-MIBI, although 99Tc mN (CPEDTC) 2The tumour of title complex/blood ratio will be lower than 99Tc m-MIBI, but its tumour/muscle, ratios such as tumour/bone will be higher than 99Tc m-MIBI, in general, 99Tc mN (CPEDTC) 2Title complex is better than in the intravital bio distribution result of lotus MA-891 breast cancer model TA-2 mouse 99Tc m-MIBI can be used as a kind of novel tumor developer and is used for diagnosing tumor.
Description of drawings
The chromatogram of accompanying drawing 1 high pressure liquid chromatography (HPLC) evaluation gained is figure as a result.
Embodiment
1. part CPEDTC's is synthetic:
With 0.10mol cyclopentamine (analytical pure, Fluka company produces) join in the 50mL there-necked flask, gained solution cools off with ice-water bath, under agitation adds the NaOH (analytical pure of 20mL5mol/L, the Beijing Chemical Plant produces) aqueous solution, slowly drip 0.10molCS then 2(analytical pure, Beijing gac factory are energetically produced) stirs 2h～3h, and the entire reaction course temperature will be controlled at below 10 ℃.Steaming desolventizes, and residuum is with Virahol/ether mixed solvent (volume ratio is 9: 1) recrystallization 2 times, a white crystal be part CPEDTC.The data of its infrared spectra are: v (IR)/cm -1: 3340 (OH), 3272 (NH), 2956 (CH 2), 1481 (C-N), 964 (C=S), C 6H 12NOS 2The theoretical value of each element massfraction ω is among the Na: C35.80, H6.01, N6.96; The experimental value of ω is: C36.02, H6.38, N6.75.
2. 99Tc mN (CPEDTC) 2Preparation:
(1) 1mL is contained the aqueous solution, the 0.1mLSnCl of 5mgSDH (succinyl two hydrazides) and 5mgPDTA (1, the 2-trimethylenedinitrilo-tertraacetic acid) 22H 2HCl solution (the SnCl among the 0.2mol/LHCl of O 22H 2The mass concentration of O is 0.5g/L) join successively in the reaction vessel, regulator solution pH value is 7.0～7.5, adds 1mL then 99Tc mO 4 -Leacheate (is produced by China Atomic Energy Science Research Institute 99Mo- 99Tc mProducer obtains, and radioactive purity is greater than 99%, and radioactive concentration is 3.7 * 10 7Bq/mL), at room temperature react 15min promptly obtain [ 99Tc mN] Int 2+Intermediate.
(2) the CPEDTC aqueous solution of 1mL (5g/L) is joined above-mentioned [ 99Tc mN] Int 2+In the midbody solution, shake up, reaction 10min promptly under the room temperature 99Tc mN (CPEDTC) 2
Gained 99Tc mN (CPEDTC) 2The performance of title complex is as follows:
(1) 99Tc mN (CPEDTC) 2Chromatography identify:
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)
99Tc mO 4 - 99Tc mO 2·nH 2O [ 99Tc mN] 2+ 99Tc mN(CPEDTC) 2
Physiological saline methylene dichloride: methyl alcohol=9: 1 (V/V) 0.1 0.1 0.1 0.1 0.7～1.0 0.1 0.1 0.9～1.0
Identify that by above-mentioned chromatography the radiochemical purity of measured marker is greater than 90%.
High pressure liquid chromatography (HPLC) is identified: with the reverse post of ODS-C18, Shimadzu SCL-10AVP type high pressure liquid chromatograph, the methyl alcohol of 70% (volume fraction) are as moving phase, and flow velocity is 1.0ml/min, and the retention time of each component of mensuration (Rt) is respectively: 99Tc mO 4 -: 3min; [ 99Tc mN] 2+: 2.6min; 99Tc mN (CPEDTC) 2: 17.2min, the chromatogram result of gained as shown in Figure 1, it is unimodal that what show generation is an one-component 99Tc mN (CPEDTC) 2
(2) 99Tc mN (CPEDTC) 2Bio distribution experiment in the tumor-bearing mice body
Tail vein injection 0.10mL from the TA-2 mouse of lotus MA-891 breast cancer model 99Tc mN (CPEDTC) 2Complex solution (about 7.4 * 10 5Bq), injection back 30,60,120min sacrificed by decapitation small white mouse.Get related organization and organs such as its blood, the heart, liver, lung, kidney, brain, tumour, muscle, bone, weigh after cleaning, and on FT-603 trap type γ scintillation probe, survey its radiocounting, each the time item the small white mouse number be 3.Calculate every gram percentage injected dose (%ID/g) of each tissue. 99Tc mN (CPEDTC) 2Title complex bio distribution in the TA-2 mouse body of lotus MA-891 breast cancer model the results are shown in Table 3.
Table 3 99Tc mN (CPEDTC) 2Bio distribution (x ± s, n=3) %ID/g in lotus MA-891 mammary cancer TA-2 mouse body
t/min 30 60 120
Blood brain conscience kidney lung neoplasm muscle bone tumour/hemotoncus knurl/muscle tumor/bone 2.99±0.51 4.20±0.82 11.07±5.17 32.21±6.18 10.80±2.00 10.07±2.58 5.27±1.70 6.54±2.14 2.86±1.50 1.76 0.81 1.84 2.62±0.63 3.97±1.32 6.12±1.68 23.53±3.13 7.94±2.93 6.56±0.48 3.49±0.31 4.76±1.39 2.28±1.17 1.33 0.73 1.53 2.85±0.62 3.19±0.84 4.97±0.37 28.78±6.04 7.37±1.15 5.12±1.67 3.96±1.55 3.64±1.04 1.79±0.66 1.39 1.09 2.21
As can be seen from Table 3, 99Tc mN (CPEDTC) 2Title complex has the tumors of higher picked-up and is detained preferably in tumour, the ratio of tumour and each non-target organ is also better, especially behind injection 120min, important target/non-target ratio such as tumour/blood, tumour/muscle, tumour/bone can become a class novel tumor developer all greater than 1.

Claims (1)

1, a kind of 99Tc mN (CPEDTC) 2Title complex, its structure is
Figure A2005101347050002C1
Have a PYR geometric configuration of irregular pros, wherein the N atom in the Tc ≡ N triple bond is positioned at vertex position, and four sulphur atoms that two part CPEDTC molecules provide are positioned at four points of bottom surface, and whole complex compound is electric neutrality, should 99Tc mN (CPEDTC) 2Title complex can be used as the application of tumor developer at the field of nuclear medicine.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110183493A (en) * 2019-04-26 2019-08-30 牡丹江医学院 A kind of 99m mtc labeled complex and its application in diagnosing non-small cell lung cancer
CN117949592A (en) * 2024-03-27 2024-04-30 原子高科股份有限公司 Method for measuring residual solvent in methoxyisonitrile by headspace gas chromatography

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1234715C (en) * 2002-12-19 2006-01-04 北京师范大学 Tc N dithiocarbamate compound salts, preparation thereof and use in nuclear medicine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110183493A (en) * 2019-04-26 2019-08-30 牡丹江医学院 A kind of 99m mtc labeled complex and its application in diagnosing non-small cell lung cancer
CN110183493B (en) * 2019-04-26 2020-10-27 牡丹江医学院 99 mTechnetium labeled complex and application thereof in diagnosis of non-small cell lung cancer
CN117949592A (en) * 2024-03-27 2024-04-30 原子高科股份有限公司 Method for measuring residual solvent in methoxyisonitrile by headspace gas chromatography

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