CN101020696A - Glucose derivative complex marked with 99mTc, 188Re or 186Rc and its prepn process - Google Patents
Glucose derivative complex marked with 99mTc, 188Re or 186Rc and its prepn process Download PDFInfo
- Publication number
- CN101020696A CN101020696A CN 200610114498 CN200610114498A CN101020696A CN 101020696 A CN101020696 A CN 101020696A CN 200610114498 CN200610114498 CN 200610114498 CN 200610114498 A CN200610114498 A CN 200610114498A CN 101020696 A CN101020696 A CN 101020696A
- Authority
- CN
- China
- Prior art keywords
- glucose
- mark
- solution
- add
- preparation
- 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
Abstract
The present invention relates to glucose derivative complex marked with 99mTc, 188Re or 186Re and its preparation process. The glucose derivative complex has nuclear intermediate of [99mTcO]3+, [188/186ReO]3+, [99mTcN]2+, [188/186ReN]2+, [99mTc(CO)3(H2O)3]1+ or [188/186Re(CO)3(H2O)3]1+, and ligand with the general expression as shown. The glucose derivative complex marked with 99mTc, 188Re or 186Re has low cost, easy preparation, proper half life and energy, SPECT developing and wide application.
Description
Technical field
The present invention relates to a kind of glucose derivative complex and preparation method thereof, particularly a kind of
99mTc,
188Re or
186Glucose derivative complex of Re mark and preparation method thereof.
Background technology
Glucose is the main energy derive of zooblast, and glucose metabolism plays an important role for keeping biological normal vital functions.
At present,
18FDG (
18F-2-deoxidation-2-fluoro-D-glucose) glucalogue of this positron radionuclide mark is widely used in the diagnosis of tumour, and is significant clinically.
18The tumor imaging mechanism of FDG is: owing to tumour cell is compared with normal cell, and active growth, cellular abnormality propagation, big to energy requirement, glycolysis-is quickened, and therefore, tumour is higher than normal cell to the picked-up of glucose and analogue thereof,
18FDG can be the same as with glucose in the mode transporte to cells of the glucose transporter GLUTs on the tumor cell membrane (glucose transporters) by the facilitation diffusion, through HK (hexokinase) phosphorylation, at endocellular metabolism is
18FDG-6-PO
4But, be phosphohexose allosteric enzyme, Hexose phosphate dehydrogenase and G-6-Pase (G6Pase) for proceeding glycometabolic enzyme,
18FDG-6-PO
4The substrate that is not best suited for, thereby
18FDG-6-PO
4Can not under the effect of above-mentioned enzyme, enter tricarboxylic acid cycle as G-6-P, can not can be detected thereby be trapped in the tumour cell through the pentose shunt metabolism.
Though
18FDG demonstrates very high specificity and susceptibility in diagnosing tumor, but the expense that exists higher, need medical cyclotron and PET video picture instrument (equipment is not popularized), transformation period short (
18The F transformation period is 108min) etc. defective.
People such as Yang Dawei 2003 the 226th phase 465-473 pages or leaves of " radiology " magazine (DavidJ.Yang, Chang-Guhn Kim, et al:Radiology, 2003,226:465-473) disclose a kind of
99mThe glucalogue of Tc mark
99mTc-EC-DG is used for the diagnosis of tumour.The structure of ligand EC-DG is:
But it is above-mentioned
99mThe shortcoming of the glucalogue of Tc mark is that the absolute picked-up value of tumour is lower, and the ratio of the picked-up of the picked-up/blood of tumour is lower simultaneously, and reason is not determined at present as yet.
Therefore develop a kind of cheap, conveniently be easy to get, target/non-target ratio that transformation period and energy are all suitable, higher, the glucose derivative complex that equipment is popularized and tumor uptake is high just becomes present technique field problem anxious to be solved as tumor developer.
Summary of the invention
One of purpose of the present invention provide a kind of cheap, conveniently be easy to get, glucose derivative complex that target/non-target ratio that transformation period and energy are all suitable, higher and equipment are popularized as tumor developer---
99mTc or
188/186The glucose derivative complex of Re mark.
The objective of the invention is to reach by the following technical programs:
Scheme one:
A kind of
99mTc,
188Re or
186The glucose derivative complex of Re mark, its core be [
99mTcO]
3+, [
188ReO]
3+, [
186ReO]
3+, [
99mTcN]
2+, [
188ReN]
2+, [
186ReN]
2+, [
99mTc (CO)
3(H
2O)
3]
1+, [
188Re (CO)
3(H
2O)
3]
1+Or [
186Re (CO)
3(H
2O)
3]
1+, its ligand is following general formula (1):
Scheme two:
A kind of
99mTc,
188Re or
186The glucose derivative complex of Re mark, its core be [
99mTcN]
2+, [
188ReN]
2+Or [
186ReN]
2+, its common part is
99mTcN-PNP,
188ReN-PNP or
186ReN-PNP, its ligand is following general formula (1):
Described PNP is one of following structure:
Another object of the present invention provides above-mentioned
99mTc,
188Re or
186The preparation method of the glucose derivative complex of Re mark.
Above-mentioned purpose of the present invention reaches by the following technical programs:
Scheme one:
A kind of
99mTc,
188Re or
186The preparation method of the glucose derivative complex of Re mark, its step is as follows:
(1) glucose-derivative is synthetic:
(2) [
99mTcN]
2+, [
188ReN]
2+, [
186ReN]
2+The preparation of nuclear intermediate:
(succinyl two hydrazides, structure is NH to add SDH in the cillin bottle
2NHCOCH
2CH
2CONHNH
2) and PDTA (1, the 2-trimethylenedinitrilo-tertraacetic acid), its structure is as follows:
Add an amount of NaOH and deionized water again and make it dissolving, transfer pH=7.4 with HCl; Add Na
99mTcO
4Or Na
188Re O
4Or Na
186Re O
4Behind the solution, add SnCl rapidly
2React under the solution, room temperature, must examine intermediate;
(3)
99mTc or
188Re or
186The preparation of the glucose derivative complex of Re mark:
The pH=8.0 of regulating step (2) gained nuclear intermediate, the water-ethanol solution of adding step (1) synthetic glucose-derivative reacts under the room temperature,
99mTc or
188Re or
186The glucose derivative complex of Re mark.
Scheme two:
A kind of
99mTc,
188Re or
186The preparation method of the glucose derivative complex of Re mark, its step is as follows:
(1) glucose-derivative is synthetic:
(2) [
99mTcO]
3+, [
188ReO]
3+, [
186ReO]
3+The preparation of the glucose derivative complex of mark:
In the aqueous solution of step (1) synthetic glucose-derivative, add Na
99mTcO
4, Na
188Re O
4Or Na
186Re O
4Solution adds SnCl rapidly
2Solution is transferred pH=8.0～8.5, respectively [
99mTcO]
3+, [
188ReO]
3+, [
186ReO]
3+The glucose derivative complex of mark.
Scheme three:
A kind of
99mTc,
188Re or
186The preparation method of the glucose derivative complex of Re mark, its step is as follows:
(1) glucose-derivative is synthetic:
(2) [
99mTc (CO)
3(H
2O)
3]
1+, [
188Re (CO)
3(H
2O)
3]
1+Or [
186Re (CO)
3(H
2O)
3]
1+The preparation of nuclear intermediate:
Sodium-potassium tartrate and yellow soda ash are joined in the cillin bottle, add sodium borohydride more rapidly, add water, gland seal, logical carbon monoxide; Add Na
99mTcO
4Or Na
188Re O
4Or Na
186Re O
4Solution in 80 ℃ of reactions down again, must be examined intermediate;
(3)
99mTc or
188Re or
186The preparation of the glucose derivative complex of Re mark:
The pH=8.0 of regulating step (2) gained nuclear intermediate, the solution of adding step (1) synthetic glucose-derivative, 65～75 ℃ of reactions are cooled to room temperature again,
99mTc or
188Re or
186The glucose derivative complex of Re mark.
Scheme four:
A kind of
99mTc,
188Re or
186The preparation method of the glucose derivative complex of Re mark, its step is as follows:
(2) glucose-derivative is synthetic:
(2) [
99mTcN]
2+, [
188ReN]
2+Or [
186ReN]
2+The preparation of core intermediate:
(succinyl two hydrazides, structure is NH to add SDH in the cillin bottle
2NHCOCH
2CH
2CONHNH
2) and PDTA (1, the 2-trimethylenedinitrilo-tertraacetic acid), its structure is as follows:
Add an amount of NaOH and deionized water again and make it dissolving, transfer pH=7.4 with HCl; Add Na
99mTcO
4Or Na
188Re O
4Or Na
186Re O
4Behind the solution, add SnCl rapidly
2React under the solution, room temperature, get the core intermediate;
(3)
99mTc,
188Re or
186The preparation of the glucose derivative complex of Re mark:
PH=7.5～8.0 of regulating step (2) gained nuclear intermediate, water-ethanol solution (concentration 50%) and PNP5 or one of PNP6 or L6 of adding step (1) synthetic glucose-derivative, weight ratio between solution and PNP5 or PNP6 or the L6 is 1: 1, under 80 ℃ of water-baths, reacts,
99mTc or
188Re or
186The glucose derivative complex of Re mark.
Beneficial effect:
Of the present invention
99mTc,
188Re or
186The glucose derivative complex of Re mark is cheap, conveniently be easy to get, transformation period and all suitable (T of energy
1/2=6.0h; γ; 150keV), and by the SPECT video picture, equipment popularity rate height.
Synthetic of the present invention [
99mTcO]
3+/ [
188/186ReO]
3+, [
99mTcN]
2+/ [
188/186ReN]
2+,
99mTcN-PNP/
188/186ReN-PNP (3), [
99mTc (CO)
3(H
2O)
3]
1+[
188/186Re (CO)
3(H
2O)
3]
1+Glucose derivative complex have certain tumor uptake, can be used for diagnosing tumor video picture or treatment.Its mice with tumor experiment showed, than the U.S. and is in development
99mThe glucalogue of Tc mark
99mThe tumor uptake of Tc-EC-DG (6) is higher.And the picked-up of non-target organ such as liver, kidney and blood and tissue is lower, having better target/non-target ratio (is the ratio to the radiopharmaceuticals picked-up of target organ and non-target organ, for tumor developer tumour and its hetero-organization and organ ratio to the radiopharmaceuticals picked-up,), be glucose-derivative tumor developer with applications well prospect.
The present invention will be further described below by embodiment, but and do not mean that limiting the scope of the invention.
Embodiment
(1), glucose-derivative is synthetic:
Synthesizing of compound 1: R=H
3.0g glucose (0.015mol) is joined in the 12.0mL hydrazine hydrate (0.247mol), room temperature reaction 20h under the argon gas condition, the rotary evaporation that reduces pressure then is to minimum volume (decompression rotary evaporation to volume no longer reduces).Add 4mLCS under the cryosel bath condition
2(0.067mol) with the methanol solution that contains 0.6gNaOH (0.015mol), reaction is violent, emits gas, and after heat release stopped, room temperature continued reaction 24h, and the rotary evaporation that reduces pressure is removed unreacted CS
2Get the light green solid, suction filtration is used recrystallizing methanol, gets light yellow solid.
Product productive rate: 54%;
The product results of elemental analyses:
Measured value: N 9.12, C 28.43 and H 4.83%; Theoretical value: N 9.58, C 28.76 and H 4.48%; Mass spectroscopy MS (ESI): measured value: 269.0[M-Na]
-, theoretical value: 269.0;
H
1-NMR(500MHz，DMSO-d
6)：δ(ppm)7.17(d，1H，J
1,2＝6.89Hz)，6.65(s，1H)，4.26(d，1H，J＝7.72Hz)，3.73(m，1H)，3.63(m，1H)，3.56(m，1H)，3.24(m，1H)，3.16(m，1H)，2.51(broad s，5H)；
IR(KBr)：3374，2930，1635，1412，1343，1250，1081，1049cm
-1。
Synthesizing of compound 2: R=CH
3-
The preparation method of compound:
3.0g glucose (0.015mol) is joined in the 13.1mL methyl hydrazine, room temperature reaction 24h under the argon gas condition, the rotary evaporation that reduces pressure then is to minimum volume (decompression rotary evaporation to volume no longer reduces).Add 4mLCS under the cryosel bath condition
2(0.067mol) with the methanol solution that contains 0.6gNaOH (0.015mol), reaction is violent, emits gas, and after heat release stopped, room temperature continued reaction 24h, and the rotary evaporation that reduces pressure is removed unreacted CS
2Get the light green solid, suction filtration is used recrystallizing methanol, gets light yellow solid.
Product productive rate: 51%;
The product results of elemental analyses:
Measured value: N 8.97, C 31.61 and H 4.72%; Theoretical value: N 9.14, C 31.37 and H 4.94%;
Mass spectroscopy MS (ESI): measured value: 283.0[M-Na]
-, theoretical value: 283.0;
H
1-NMR(500MHz，DMSO-d
6)：δ(ppm)7.42(d，1H，J
1.2＝6.92Hz)，4.22(d，1H，J＝7.78
Hz)，3.75(m，1H)，3.68(m，1H)，3.54(m，1H)，3.27(m，1H)，3.17(m，1H)，2.54(s，3H)，2.51(broad s，5H)；
IR(KBr)：3392，2943，1616，1427，1374，1217，1154，1061cm
-1。
Synthesizing of compound 3: R=CH
3CH
2-
The preparation method of compound:
0.25mol ethyl hydrazine oxalate is joined in an amount of methyl alcohol; under agitation add the 0.5mol triethylamine, behind the 30min, add 3.0g glucose (0.015mol); room temperature reaction 24h under the argon shield, the rotary evaporation that reduces pressure then is to minimum volume (decompression rotary evaporation to volume no longer reduces).Add 4mlLCS under the cryosel bath condition
2(0.067mol) and contain the methanol solution of 0.6gNaOH (0.015mol), react more violent, treat that heat release stops after, room temperature continues reaction 24h, the rotary evaporation that reduces pressure is removed unreacted CS
2Get the light green solid, suction filtration is used recrystallizing methanol, gets faint yellow solid.
Product productive rate: 46%;
The product results of elemental analyses:
Measured value: N 8.57, C 33.52 and H 5.72%; Theoretical value: N 8.74, C 33.74 and H 5.35%;
Mass spectroscopy MS (ESI): measured value: 297.0[M-Na]
-, theoretical value: 297.0;
H
1-NMR(500MHz，DMSO-d
6)：δ(ppm)7.50(d，1H，J＝6.78Hz)，4.27(d，1H，J＝7.75Hz)，3.77(m，1H)，3.65(m，1H)，3.51(m，1H)，3.30(m，1H)3.19(m，1H)，2.71(m，2H)，
2.51(broad s，5H)，1.32(t，3H，J＝7.14Hz)；
IR(KBr)：3390，2960，1589，1463，1375，1209，1131，1055cm
-1。
Synthesizing of compound 4: R=CH
3CH
2CH
2-
The preparation method of compound:
0.25mol propyl group hydrazine oxalate is joined in an amount of methyl alcohol; under agitation add the 0.5mol triethylamine, behind the 30min, add 3.0g glucose (0.015mol); room temperature reaction 24h under the argon shield, the rotary evaporation that reduces pressure then is to minimum volume (decompression rotary evaporation to volume no longer reduces).Add 4mlLCS under the cryosel bath condition
2(0.067mol) and contain the methanol solution of 0.6gNaOH (0.015mol), react more violent, treat that heat release stops after, room temperature continues reaction 24h, the rotary evaporation that reduces pressure is removed unreacted CS
2Get the light green solid, suction filtration is used recrystallizing methanol, gets faint yellow solid.
Product productive rate: 48%;
The product results of elemental analyses:
Measured value: N 8.43, C 36.21 and H 5.51%; Theoretical value: N 8.38, C 35.92 and H 5.73%; Mass spectroscopy MS (ESI): measured value: 311.0[M-Na]
-, theoretical value: 311.0;
H
1-NMR(500MHz，DMSO-d
6)：δ(7.58(d，1H，J＝6.88Hz)，4.19(d，1H，J＝7.70Hz)，3.81(m，1H)，3.69(m，1H)，3.55(m，1H)，3.29(m，1H)，3.13(m，1H)，2.69(t，2H，J＝7.21Hz)，2.51(broad s，5H)，1.66(m，2H)，1.03(t，3H，J＝7.32Hz)；
IR(KBr)：3387，2925，1588，1461，1375，1214，1151，1076cm
-1。
Synthesizing of compound 5: R=CH
3(CH
2)
3-
The preparation method of compound:
0.25mol butyl hydrazine hydrochloride is joined in an amount of methyl alcohol; under agitation add the 0.5mol triethylamine; behind the 30min; add 3.0g glucose (0.015mol); room temperature reaction 24h under the argon shield, 40 ℃ of decompression rotary evaporations are to minimum volume (decompression rotary evaporation to volume no longer reduces) then.Add 4mL CS under the cryosel bath condition
2(0.067mol) with the methanol solution that contains 0.6gNaOH (0.015mol), after the question response heat release stopped, room temperature continued reaction 24h, and the decompression rotary evaporation is removed unreacted CS
2. get the light green solid, suction filtration is used recrystallizing methanol, gets yellow solid.
Product productive rate: 48%;
The product results of elemental analyses:
Measured value: N 8.22, C 38.17 and H 5.81%; Theoretical value: N 8.04, C 37.92 and H 6.08%;
Mass spectroscopy MS (ESI): measured value: 325.0[M-Na]
-, theoretical value: 325.0;
H
1-NMR(500MHz，DMSO-d
6)：δ(7.61(d，1H，J＝6.93Hz)，4.24(d，1H，J＝7.71Hz)，3.87(m，1H)，3.65(m，1H)，3.56(m，1H)，3.30(m，1H)，3.19(m，1H)，2.67(t，2H，J＝7.19Hz)，2.51(broad s，5H)，1.57(m，2H)，1.38(m，2H)，0.99(t，3H，J＝7.36Hz)；
IR(KBr)：3393，2939，1582，1471，1378，1201，1124，1049cm
-1。
(2) preparation of glucose derivative complex
One of embodiment: [
99mTcN]
2+Or [
188/186ReN]
2+The preparation of glucose derivative complex
1.[
99mTcN]
2+The structure of glucose derivative complex:
1.1.[
99mTcN]
2+The preparation of nuclear intermediate:
(succinyl two hydrazides, structure is NH to add 5mgSDH in the cillin bottle
2NHCOCH
2CH
2CONHNH
2) and 5mgPDTA (1, the 2-trimethylenedinitrilo-tertraacetic acid), its structure is as follows:
Add an amount of 1N NaOH and deionized water again and make it dissolving, transfer pH=7.4 with 1N HCl.With Na
99mTcO
4(0.3～0.5mL, 1～20mCi) adds solution, adds 30 μ l SnCl rapidly
2Solution (1mg/mL, 1N HCl) reacts 15min under the room temperature.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate.Mark rate is greater than 99%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).[
99mTcN]
2+The HPLC retention time of nuclear intermediate is 3.00min.
1.2.[
99mTcN]
2+The preparation of glucose derivative complex:
Regulate above-mentioned
99mThe pH=8.0 of TcN nuclear intermediate, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL glucose-derivative.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).
Embodiment 1.1:[
99mTcN]
2+Nuclear tagged compound 1
Regulate above-mentioned
99mThe pH=8.0 of TcN nuclear intermediate, the aqueous solution (2mg/mL) of adding 1mL compound 1 reacts 15min under the room temperature.TLC (thin-layer chromatography) monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate 99.82%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in HPLC (high performance liquid chromatography) monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 16.60min, 99.82% (radiochemical purity).
Embodiment 1.2:[
99mTcN]
2+Nuclear tagged compound 2
Regulate above-mentioned
99mThe pH=8.0 of TcN nuclear intermediate, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 2.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate 99.65%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 16.60min, radiochemical purity 99.31%.
Embodiment 1.3:[
99mTcN]
2+Nuclear tagged compound 3
Regulate above-mentioned
99mThe pH=8.0 of TcN nuclear intermediate, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 3.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate is greater than 99%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 17.20min, radiochemical purity 99.43%.
Embodiment 1.4:[
99mTcN]
2+Nuclear tagged compound 5
Regulate above-mentioned
99mThe pH=8.0 of TcN nuclear intermediate, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 5.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate 99.36%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 22.10min, radiochemical purity 99.56%.
Embodiment 1.5:[
99mTcN]
2+Nuclear tagged compound 4:
Marking method is the same, and compound 5 is replaced with compound 4.Mark rate 99.57%, HPLC retention time are 18.10min, radiochemical purity 99.26%.
2.[
188/186ReN]
2+The structure of core tagged compound:
2.1.[
188/186ReN]
2+The preparation of nuclear intermediate:
(succinyl two hydrazides, structure is NH to add 5mgSDH in the cillin bottle
2NHCOCH
2CH
2CONHNH
2) and 5mgPDTA (1, the 2-trimethylenedinitrilo-tertraacetic acid), its structure is as follows:
Add an amount of 1N NaOH and deionized water again and make it dissolving, transfer pH=7.4 with 1N HCl.With Na
188/186Re O
4(0.3～0.5mL, 1～20mCi) adds solution, adds 30 μ lLSnCl rapidly
2Solution (1mg/mL, 1N HCl). react 15min under the room temperature.TLC (thin-layer chromatography) monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate.Mark rate is greater than 99%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in HPLC (high performance liquid chromatography) monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).[
188/186Re N]
2+The HPLC retention time of nuclear intermediate is 3.20min.
2.2.[
188/186ReN]
2+The preparation of nuclear tagged compound
Regulate above-mentioned [
188/186ReN]
2-The pH=8.0 of nuclear intermediate, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound.TLC (thin-layer chromatography) monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in HPLC (high performance liquid chromatography) monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).
Embodiment 2.1:[
188/186ReN]
2+Nuclear tagged compound 1
Regulate above-mentioned [
188/186ReN]
2+The pH=8.0 of nuclear intermediate, the aqueous solution (2mg/mL) of adding 1mL compound 1 reacts 15min under the room temperature.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate is greater than 99%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 16.60min, 99.56%.
Two of embodiment: [
99mTcN]
3+Or [
188/186ReN]
2+Core and PNP, compound (1～5)
Be mixed
99mThe preparation of Tc title complex
1.[
99mTcN]
3+The structure of-PNP title complex:
R1＝H，CH
3-，CH
3CH
2-，CH
3(CH
2)
2-，CH
3(CH
2)
3-
PNP＝PNP5，PNP6，L6
Embodiment 3.1:
[
99mTcN]
2+Core and PNP6, compound 1 are mixed
99mThe preparation of Tc title complex
Regulate above-mentioned
99mPH=7.5～8.0 of TcN nuclear intermediate, the aqueous solution (2mg/mL) and the 1mgPNP6 of adding 1mL compound 1 react 10min under 80 ℃ of water-baths.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate is greater than 99%.(HPLC gradient condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; The acetonitrile solution of the trifluoroacetic acid of B phase 0.1%; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 21.50min.
Embodiment 3.2:
[
99mTcN]
2+Core and PNP6, compound 2 are mixed
99mThe preparation of Tc title complex
Regulate above-mentioned
99mPH=7.5～8.0 of TcN nuclear intermediate, (1/1, V/V) solution (2mg/mL) and 2mgPNP6 react 10min to the water-ethanol of adding 1mL compound 2 under 80 ℃ of water-baths.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate 99.16%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; The acetonitrile solution of the trifluoroacetic acid of B phase 0.1%; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 22.10min.
Embodiment 3.3:
[
99mTcN]
2+Core and PNP6, compound 5 are mixed
99mThe preparation of Tc title complex
Regulate above-mentioned
99mPH=7.5～8.0 of TcN nuclear intermediate, (1/1, V/V) solution (2mg/mL) and 2mgPNP6 react 10min to the water-ethanol of adding 1mL compound 5 under 80 ℃ of water-baths.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate is greater than 98%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 23.60min.
Embodiment 3.4:
[
99mTcN]
2+Core and PNP5, compound 1 are mixed
99mThe preparation of Tc title complex
Regulate above-mentioned
99mPH=7.5～8.0 of TcN nuclear intermediate, add 1mL compound 1 the aqueous solution (2～3mg/mL) and 2mg PNP5, under 80～90 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate 98.65%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 18.60min.
Embodiment 3.5:
[
99mTcN]
2+Core and PNP5, compound 2 are mixed
99mThe preparation of Tc title complex
Regulate above-mentioned
99mPH=7.5～8.0 of TcN nuclear intermediate, (1/1, V/V) solution (2mg/mL) and 2mg PNP5 react 10min to the water-ethanol of adding 1mL compound 2 under 80～90 ℃ of water-baths.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate is greater than 98%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 19.30min.
Embodiment 3.6:
[
99mTcN]
2+Core and L6, compound 5 are mixed
99mThe preparation of Tc title complex
Regulate above-mentioned
99mThe pH=8.0 of TcN nuclear intermediate, (1/1, V/V) solution (2mg/mL) and 2mg L6 react 10min to the water-ethanol of adding 1mL compound 5 under 80～90 ℃ of water-baths.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate is greater than 97%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 21.20min.
2.[
188/186ReN]
2+-PNP complex structure:
R1＝H，CH
3-，CH
3CH
2-，CH
3(CH
2)
2-，CH
3(CH
2)
3-
PNP＝PNP5，PNP6，L6
Embodiment 3.7:
[
188ReN]
2+Core and PNP6, compound 1 are mixed
188The preparation of Re title complex
Regulate above-mentioned [
188ReN]
2+PH=7.5～8.0 of nuclear intermediate, the aqueous solution (2mg/mL) and the 1mgPNP6 of adding 1mL compound 1 react 10min under 80 ℃ of water-baths.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate is greater than 98%.(HPLC gradient condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 21.20min.
Embodiment 3.8:
[
188ReN]
2+Core and PNP5, compound 1 are mixed
188The preparation of Re title complex
Regulate above-mentioned [
188ReN]
2+PH=7.5～8.0 of nuclear intermediate, add 1mL compound 1 the aqueous solution (2～3mg/mL) and 2mg PNP5, under 80～90 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate 98.65%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 18.30min.
Three .[of embodiment
99mTcO]
3+Or [
188/186ReO]
3+The preparation of nuclear tagged compound
[
99mTcO]
3+The structure of nuclear tagged compound:
Embodiment 4.1:
[
99mTcO]
3+Nuclear tagged compound 1
The aqueous solution (Na that adds new drip washing in 2～3mg/mL) at 1mL compound 1
99mTcO
4(5～10mCi/mL) 0.5mL add 0.4～0.5mLSnCl rapidly to solution
2Solution (adds 10～12mg SnCl among the 0.1MHCl
2), transferring pH=8.0～8.5, room temperature reaction 30min surveys mark rate, mark rate 99.37%; (HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is: 2.60min, 9%; 16.60min, 90%.(known under this HPLC condition, Na
99mTcO
4Retention time be 4.1min).
Embodiment 4.2:
[
99mTcO]
3+Nuclear tagged compound 2
The water-ethanol of 1mL compound 2 (1/1, V/V) add the Na of new drip washing in the solution (2mg/mL)
99mTcO
4(5～10mCi/mL) 0.5ml add 0.4～0.5mLSnCl rapidly to solution
2Solution (adds 10～12mg SnCl among the 0.1MHCl
2), transferring pH=8.0～8.5, room temperature reaction 30min surveys mark rate, mark rate 99.24%; (HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is: 2.70min, 10%; 18.10min, 89%.(known under this HPLC condition, Na
99mTcO
4Retention time be 4.1min).
Embodiment 4.3:
[
99mTcO]
3+Nuclear tagged compound 5
The water-ethanol of 1mL compound 5 (1/1, V/V) add the Na of new drip washing in the solution (2mg/mL)
99mTcO
4(5～10mCi/mL) 0.5mL add 0.4～0.5mLSnCl rapidly to solution
2Solution (adds 10～12mg SnCl among the 0.1MHCl
2), transferring pH=8.0～8.5, room temperature reaction 30min surveys mark rate, mark rate 99.16%; (HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is: 2.70min, 8%; 23.20min, 90%.(known under this HPLC condition, Na
99mTcO
4Retention time be 4.1min).[
188/186ReO]
3+The structure of nuclear tagged compound:
Embodiment 4.4:
[
188ReO]
3+Nuclear tagged compound 1
The aqueous solution (Na that adds new drip washing in 2～3mg/mL) at 1mL compound 1
188ReO
4(5～10mCi/mL) 0.5mL add 0.4～0.5mLSnCl rapidly to solution
2Solution (adds 10～12mg SnCl among the 0.1MHCl
2), transferring pH=8.0～8.5, room temperature reaction 30min surveys mark rate, and mark rate is greater than 99%; (HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is: 2.70min, 7.62%; 16.60min, 91.87%.(known under this HPLC condition, Na
99mTcO
4Retention time be 4.1min).
Four .[of embodiment
99mTc (CO)
3(H
2O)
3]
1+The preparation of nuclear tagged compound:
1.[
99mTc (CO)
3(H
2O)
3]
1+The structure of nuclear tagged compound:
[
99mTc (CO)
3(H
2O)
3]
1+The preparation of nuclear intermediate:
Sodium-potassium tartrate 20mg, yellow soda ash 4.7～4.9mg join in the 10ml cillin bottle, add 7.4～7.5mg sodium borohydride more rapidly, add 1mL water, gland seal, logical carbon monoxide 30～40min.Add Na
99mTcO
4Solution (0.3～0.6mL, 20mCi/mL), 80 ℃ of reaction 40min.TLC monitorings (second eyeball/polymeric amide system) again; (HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).
99mTc (CO)
3The HPLC retention time of nuclear intermediate is 13.90min, two groups of broad peaks of 16.70min.
[
99mTc (CO)
3(H
2O)
3]
1+The preparation of nuclear tagged compound:
With the preparation [
99mTc (CO)
3(H
2O)
3]
1+Intermediate is regulated pH=8.0 with 1N HCl and 0.1N HCl, joins (2mg/mL) in the ligand solution, and 65～75 ℃ of reaction 10min. are cooled to room temperature.TLC monitors (chloroform/methanol=9/1, polymeric amide), calculates mark rate; (HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).
Embodiment 5.1:[
99mTc (CO)
3(H
2O)
3]
1+Nuclear tagged compound 1:
With the preparation [
99mTc (CO)
3(H
2O)
3]
1+Intermediate is regulated pH=8.0 with 1N HCl and 0.1N HCl, joins in the solution of 1mL compound 1 (2mg/mL), and 65～75 ℃ of reaction 10min. are cooled to room temperature.TLC monitors (chloroform/methanol=9/1, polymeric amide), calculates mark rate, and mark rate is greater than 95%; (HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 3.00min, 99.90%.
Embodiment 5.2:[
99mTc (CO)
3(H
2O)
3]
1+Nuclear tagged compound 3:
With the preparation [
99mTc (CO)
3(H
2O)
3]
1+Intermediate is regulated pH=8.0 with 1N HCl and 0.1N HCl, and (1/1, V/V) in the solution (2mg/mL), 65～75 ℃ of reaction 10min. are cooled to room temperature to join the water-ethanol of 1mL compound 3.TLC monitors (chloroform/methanol=9/1, polymeric amide), calculates mark rate, and mark rate is greater than 94%; (HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 3.40min, 99.56%.
Embodiment 5.3:[
99mTc (CO)
3(H
2O)
3]
1+Nuclear tagged compound 5:
With the preparation [
99mTc (CO)
3(H
2O)
3]
1+Intermediate is regulated pH=8.0 with 1N HCl and 0.1N HCl, and (1/1, V/V) in the solution (2mg/mL), 65～75 ℃ of reaction 10min. are cooled to room temperature to join the water-ethanol of 1mL compound 5.TLC monitors (chloroform/methanol=9/1, polymeric amide), calculates mark rate, and mark rate is greater than 95%; (HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 3.70min, 99.34%.
2.[
188/186Re (CO)
3(H
2O)
3]
1+The structure of nuclear tagged compound:
Embodiment 5.4:[
188/186Re (CO)
3(H
2O)
3]
1+Nuclear tagged compound 1
188The preparation of Re title complex (5):
5mg amino borane title complex joins in the cillin bottle, gland seal, and logical CO (carbon monoxide converter) gas 10-15min adds 4.5 μ LH
3PO
4(85%) and Na
188/186ReO
4Normal saline solution (0.3～0.5mL, 1～10mCi/mL), bottle cap is inserted a syringe with the complemental air volumetric expansion, is heated to 60 ℃ of reaction 15min, transfers pH=8.0, gets in the aqueous solution (2mg/mL) that 0.2mL joins compound 1, at 60 ℃ of reaction 15min.Survey mark rate, greater than 95%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 3.2min, 98.25%.
(3), mice with tumor experiment
One, [
99mTcN]
2+Experiment (n=3) distributes in the lotus EMT-6 mice with tumor body of nuclear tagged compound 1
Lotus EMT-6 mice with tumor: left oxter implants 2 * 10 before female BACB/C mouse
6Tumour cell, diameter of tumor is 13～15mm after growing about 10 days;
1. mark
Regulate
99mThe pH=8.0 of TcN nuclear intermediate, the aqueous solution (2mg/mL) of adding 1mL compound 1 reacts 15min under the room temperature.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate 99.92%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the second eyeball solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 16.60min, 99.79%.
2. experimentation on animals
Marked product solution is diluted to 0.3mCi/mL with pure water.Take out 0.1mL dilution after product solution, add 9.9mL physiological saline, take out 0.1mL behind the mixing, as standardized solution.Lotus EMT-6 mice with tumor tail vein injection 0.1mL product solution (about 30 μ Ci), put to death respectively at injection back 1,2, the disconnected neck of 4h, get tissues such as tumour, blood, the heart, liver, spleen, lung, kidney, brain, muscle, bone, weigh and measure radiocounting, calculate ID%/g.
99mThe lotus EMT-6 mice with tumor bio distribution of TcN-compound 1 title complex
| ID％/g | 30min | 2h | 4h |
| Tumour | 1.86±0.27 | 1.38±0.25 | 1.26±0.16 |
| Blood | 2.92±0.26 | 1.02±0.39 | 0.84±0.23 |
| The heart | 2.23±0.25 | 1.19±0.54 | 1.07±0.40 |
| Liver | 3.41±0.36 | 2.55±0.63 | 2.78±0.73 |
| Spleen | 1.68±0.44 | 1.44±0.79 | 1.05±0.27 |
| Lung | 5.75±0.49 | 3.93±1.26 | 3.50±0.79 |
| Kidney | 7.56±1.36 | 3.78±1.14 | 3.96±0.26 |
| Brain | 1.37±0.06 | 0.64±0.23 | 0.94±0.14 |
| Muscle | 1.52±0.27 | 0.77±0.32 | 1.25±0.21 |
| Bone | 0.17±0.01 | 0.08±0.04 | 0.09±0.03 |
| Tumour/blood | 0.64±0.05 | 1.43±0.32 | 1.53±0.23 |
Contrast:
99mThe lung cancer mice with tumor bio distribution of Tc-EC-DG
| ID％/g | 30min | 2h | 4h |
| Tumour | 0.787±0.163 | 0.415±0.123 | 0.414±0.161 |
| Blood | 1.607±0.389 | 0.977±0.267 | 0.787±0.152 |
| The heart | 0.61 1±0.193 | 0.336±0.080 | 0.318±0.071 |
| Liver | 5.674±2.089 | 5.807±1.708 | 6.656±1.786 |
| Spleen | 3.240±1.709 | 4.205±1.374 | 5.933±3.194 |
| Lung | 1.048±0.259 | 0.72 1±0.210 | 0.606±0.128 |
| Kidney | 6.726±1.842 | 5.687±1.540 | 4.318±0.890 |
| Brain | 0.058±0.008 | 0.042±0.006 | 0.042±0.006 |
| Muscle | 0.264±0.072 | 0.148±0.039 | 0.147±0.022 |
| Tumour/blood | 0.499±0.022 | 0.424±0.022 | 0.502±0.120 |
Two, [
99mTcO]
3+Experiment (n=3) lotus EMT-6 mice with tumor distributes in the lotus EMT-6 mice with tumor body of nuclear tagged compound 2: left oxter implants 2 * 10 before female BACB/C mouse
6Tumour cell, diameter of tumor is 13～15mm after growing about 10 days;
1. mark
[
99mTcO]
3+Nuclear tagged compound 2
The aqueous solution (Na that adds new drip washing in 2～3mg/mL) at 1mL compound 2
99mTcO
4(5～10mCi/mL) 0.5mL add 0.4～0.5mLSnCl rapidly to solution
2Solution (adds 10～12mg SnCl among the 0.1MHCl
2), transferring pH=8.0～8.5, room temperature reaction 30min surveys mark rate, mark rate 99.37%; (HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is: 2.60min, 9%; 16.60min, 90%.(known under this HPLC condition, Na
99mTcO
4Retention time be 4.1min).
2. experimentation on animals
Marked product solution is diluted to 0.3mCi/mL with pure water.Take out 0.1mL dilution after product solution, add 9.9mL physiological saline, take out 0.1mL behind the mixing, as standardized solution.Lotus EMT-6 mice with tumor tail vein injection 0.1mL product solution (about 30 μ Ci), put to death respectively at injection back 1,2, the disconnected neck of 4h, get tissues such as tumour, blood, the heart, liver, spleen, lung, kidney, brain, muscle, bone, weigh and measure radiocounting, calculate ID%/g.
[
99mTcO]
3+The lotus EMT-6 mice with tumor bio distribution of-compound 2 title complexs
| ID％/g | 30min | 2h | 4h |
| Tumour | 1.75±0.18 | 1.57±0.14 | 1.12±0.03 |
| Blood | 3.13±0.37 | 1.23±0.29 | 0.67±0.15 |
| The heart | 1.97±0.22 | 0.98±0.31 | 0.76±0.12 |
| Liver | 4.14±0.39 | 3.52±0.47 | 3.27±0.54 |
| Spleen | 1.57±0.44 | 1.62±0.79 | 1.22±0.31 |
| Lung | 4.38±0.49 | 3.39±0.46 | 3.42±0.87 |
| Kidney | 6.85±1.36 | 2.93±0.31 | 2.78±0.47 |
| Brain | 1.88±0.15 | 0.80±0.08 | 1.17±0.54 |
| Muscle | 1.76±0.19 | 0.83±0.44 | 0.76±0.39 |
| Bone | 0.09±0.03 | 0.05±0.01 | 0.07±0.06 |
| Tumour/blood | 0.56±0.08 | 1.28±0.41 | 1.67±0.27 |
Three, [
188Re N]
2+Experiment (n=3) distributes in the lotus EMT-6 mice with tumor body of nuclear tagged compound 4
Lotus EMT-6 mice with tumor: left oxter implants 2 * 10 before female BACB/C mouse
6Tumour cell, diameter of tumor is 12～15mm after growing about 10 days;
1. mark
[
188ReN]
2+Nuclear tagged compound 4
Regulate above-mentioned [
188ReN]
2+The pH=8.0 of nuclear intermediate, the aqueous solution (2mg/mL) of adding 1mL compound 4 reacts 15min under the room temperature.TLC monitors (acetonitrile/polymeric amide; Physiological saline/polymeric amide), calculate mark rate, mark rate is greater than 99%.(HPLC condition: A is 0.1% trifluoroacetic acid aqueous solution mutually in the HPLC monitoring; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; Gradient: 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC retention time is 18.50min, 99.36%.
2. experimentation on animals
Marked product solution is diluted to 0.3mCi/mL with pure water.Take out 0.1mL dilution after product solution, add 9.9mL physiological saline, take out 0.1mL behind the mixing, as standardized solution.Lotus EMT-6 mice with tumor tail vein injection 0.1mL product solution (about 30 μ Ci), put to death respectively at injection back 1,2, the disconnected neck of 4h, get tissues such as tumour, blood, the heart, liver, spleen, lung, kidney, brain, muscle, bone, weigh and measure radiocounting, calculate ID%/g.
[
188ReN]
2+The lotus EMT-6 mice with tumor bio distribution of nuclear tagged compound 4 title complexs
| ID％/g | 30min | 2h | 4h |
| Tumour | 1.48±0.11 | 1.02±0.06 | 1.01±0.04 |
| Blood | 3.13±0.37 | 0.93±0.17 | 0.74±0.08 |
| The heart | 1.85±0.41 | 1.59±0.22 | 1.46±0.12 |
| Liver | 5.67±1.43 | 325±0.58 | 3.38±0.31 |
| Spleen | 1.57±0.44 | 1.15±0.53 | 1.21±0.29 |
| Lung | 4.89±0.72 | 4.71±1.32 | 3.12±2.35 |
| Kidney | 6.37±2.11 | 3.99±1.52 | 3.64±1.13 |
| Brain | 0.27±0.15 | 0.08±0.03 | 0.07±0.01 |
| Muscle | 1.53±0.26 | 1.10±0.17 | 0.67±0.08 |
| Bone | 0.8 1±0.03 | 0.76±0.03 | 0.89±0.02 |
| Tumour/blood | 0.47±0.15 | 1.10±0.32 | 1.36±0.29 |
Contrast as can be known:
99mTcN-compound 1 title complex and [
99mTcO]
3+-compound 2 title complexs and [
188ReN]
2+The tumor uptake of-compound 4 title complexs all is higher than
99mTc-EC-DG; And
99mTcN-compound 1 title complex and [
99mTcO]
3+-compound 2 title complexs and [
188ReN]
2+The non-target tissue of-compound 4 title complexs and organ as: the picked-up of blood, liver, kidney then is lower than
99mTc-EC-DG has better target/non-target ratio, is that a class potential is good
99mThe glucose-derivative tumor developer of Tc mark.
With respect to
18FDG is owing to be used for preparation
18FDG's
18F is made by accelerator, and price is higher, and the PET (positron emission tomography) scanner (PET) that is used for video picture is very expensive, popularity rate not high (surplus the whole nation 60).In addition,
18Short (T of F transformation period
1/2=109 minutes), more to the preparation and the video picture restriction of medicine.In contrast,
99mTc by
99Mo/
99mThe preparation of Tc producer conveniently is easy to get, and is cheap; SPECT picture reproducer price is relatively low, the popularity rate height; Simultaneously
99mThe transformation period T of Tc
1/2=6.0h, this for radiopharmaceutic preparation and in vivo concentrating of target organ adequate time is provided, simultaneously can reduce the suffered radiation dose of patient as far as possible; The emission gamma-rays; Ray energy is 150keV, and energy is suitable.)
Claims (6)
1, a kind of
99mTc,
188Re or
186The glucose derivative complex of Re mark, its core be [
99mTcO]
3+, [
188ReO]
3+, [
186ReO]
3+, [
99mTcN]
2+, [
188ReN]
2+, [
186ReN]
2+, [
99mTc (CO)
3(H
2O)
3]
1+, [
188Re (CO)
3(H
2O)
3]
1+Or [
186Re (CO)
3(H
2O)
3]
1+, its ligand is following general formula (1):
R＝H，CH
3-，CH
3CH
2-，CH
3(CH
2)
2-，CH
3(CH
2)
3-
(1)
2, a kind of
99mTc,
188Re or
186The glucose derivative complex of Re mark, its core be [
99mTcN]
2+, [
188ReN]
2+Or [
186ReN]
2+, its common part is
99mTcN-PNP,
188ReN-PNP or
186ReN-PNP, its ligand is following general formula (1):
R＝H，CH
3-，CH
3CH
2-，CH
3(CH
2)
2-，CH
3(CH
2)
3-
(1)
Wherein said PNP is one of following structure:
3, a kind of
99mTc,
188Re or
186The preparation method of the glucose derivative complex of Re mark, its step is as follows:
(3) glucose-derivative is synthetic:
R＝H，CH
3-，CH
3CH
2-，CH
3(CH
2)
2-，CH
3(CH
2)
3-
(2) [
99mTcN]
2+, [
188ReN]
2+, [
186ReN]
2+The preparation of nuclear intermediate:
Add succinyl two hydrazides in the cillin bottle, add an amount of NaOH and deionized water again and make it dissolving, transfer pH=7.4 with HCl; Add Na
99mTcO
4Or Na
188Re O
4Or Na
186Re O
4Behind the solution, add SnCl rapidly
2React under the solution, room temperature, must examine intermediate;
(3)
99mTc or
188Re or
186The preparation of the glucose derivative complex of Re mark:
The pH=8.0 of regulating step (2) gained nuclear intermediate, the water-ethanol solution of adding step (1) synthetic glucose-derivative reacts under the room temperature,
99mTc or
188Re or
186The glucose derivative complex of Re mark.
4, a kind of
99mTc,
188Re or
186The preparation method of the glucose derivative complex of Re mark, its step is as follows:
(1) glucose-derivative is synthetic:
R＝H，CH
3-，CH
3CH
2-，CH
3(CH
2)
2-，CH
3(CH
2)
3-
(2) [
99mTcO]
3+, [
188ReO]
3+, [
186ReO]
3+The preparation of the glucose derivative complex of mark:
In the aqueous solution of step (1) synthetic glucose-derivative, add Na
99mTcO
4, Na
188ReO
4Or Na
186Re O
4Solution adds SnCl rapidly
2Solution is transferred pH=8.0～8.5, respectively [
99mTcO]
3+, [
188ReO]
3+, [
186ReO]
3+The glucose derivative complex of mark.
5, a kind of
99mTc,
188Re or
186The preparation method of the glucose derivative complex of Re mark, its step is as follows:
(1) glucose-derivative is synthetic:
R＝H，CH
3-，CH
3CH
2-，CH
3(CH
2)
2-，CH
3(CH
2)
3-
(2) [
99mTc (CO)
3(H
2O)
3]
1+, [
188Re (CO)
3(H
2O)
3]
1+Or [
186Re (CO)
3(H
2O)
3]
1+The preparation of nuclear intermediate:
Sodium-potassium tartrate and yellow soda ash are joined in the cillin bottle, add sodium borohydride more rapidly, add water, gland seal, logical carbon monoxide; Add Na
99mTcO
4Or Na
188Re O
4Or Na
186ReO
4Solution in 80 ℃ of reactions down again, must be examined intermediate;
(3)
99mTc or
188Re or
186The preparation of the glucose derivative complex of Re mark:
The pH=8.0 of regulating step (2) gained nuclear intermediate, the solution of adding step (1) synthetic glucose-derivative, 65～75 ℃ of reactions are cooled to room temperature again,
99mTc or
188Re or
186The glucose derivative complex of Re mark.
6, a kind of
99mTc,
188Re or
186The preparation method of the glucose derivative complex of Re mark, its step is as follows:
(4) glucose-derivative is synthetic:
R＝H，CH
3-CH
3CH
2-，CH
3(CH
2)
2-，CH
3(CH
2)
3-
(2) [
99mTcN]
2+, [
188ReN]
2+Or [
186ReN]
2+The preparation of core intermediate:
Add succinyl two hydrazides in the cillin bottle, add an amount of NaOH and deionized water again and make it dissolving, transfer pH=7.4 with HCl; Add Na
99mTcO
4Or Na
188Re O
4Or Na
186ReO
4Behind the solution, add SnCl rapidly
2React under the solution, room temperature, get the core intermediate;
(3)
99mTc,
188Re or
186The preparation of the glucose derivative complex of Re mark:
PH=7.5～8.0 of regulating step (2) gained nuclear intermediate, the water-ethanol solution (concentration is 50%) and PNP5 or PNP6 or the L6 that add step (1) synthetic glucose-derivative, weight ratio between described water-ethanol solution and described PNP5, PNP6 or the L6 is 1: 1, under 80 ℃ of water-baths, react,
99mTc or
188Re or
186The glucose derivative complex of Re mark.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610114498 CN101020696A (en) | 2006-11-10 | 2006-11-10 | Glucose derivative complex marked with 99mTc, 188Re or 186Rc and its prepn process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610114498 CN101020696A (en) | 2006-11-10 | 2006-11-10 | Glucose derivative complex marked with 99mTc, 188Re or 186Rc and its prepn process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101020696A true CN101020696A (en) | 2007-08-22 |
Family
ID=38708583
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200610114498 Pending CN101020696A (en) | 2006-11-10 | 2006-11-10 | Glucose derivative complex marked with 99mTc, 188Re or 186Rc and its prepn process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101020696A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993243A (en) * | 2012-12-19 | 2013-03-27 | 北京师范大学 | 99mTc marked glucose derivative and preparation method and application thereof |
| CN106008636B (en) * | 2016-06-23 | 2018-03-09 | 北京师范大学 | Tc 99m labelled glucose dithiocarbamate complexes and preparation method and application |
-
2006
- 2006-11-10 CN CN 200610114498 patent/CN101020696A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993243A (en) * | 2012-12-19 | 2013-03-27 | 北京师范大学 | 99mTc marked glucose derivative and preparation method and application thereof |
| CN106008636B (en) * | 2016-06-23 | 2018-03-09 | 北京师范大学 | Tc 99m labelled glucose dithiocarbamate complexes and preparation method and application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0200492B1 (en) | Radiodiagnostic agents | |
| CN112079900B (en) | Cyclic NGR polypeptide, radionuclide labeled molecular probe and application thereof | |
| KR20190121824A (en) | 99m-Tc labeled isonitrile-containing glucose derivative and its preparation method and use | |
| WO2005087275A2 (en) | Metal radiolabeled pet imaging agents | |
| US20230263914A1 (en) | Benzene ring-containing glucose derivative and use thereof | |
| CN103333079B (en) | Imino group acids PET developer and preparation method and application | |
| Storr et al. | A glucosamine–dipicolylamine conjugate of 99m Tc (i) and 186 Re (i) for use in imaging and therapy | |
| CN101020696A (en) | Glucose derivative complex marked with 99mTc, 188Re or 186Rc and its prepn process | |
| US20240109929A1 (en) | Mannose derivative and application thereof | |
| CN103435684B (en) | 18f-fluorine mark pentapeptide title complex and synthetic method | |
| CN112933253A (en) | Compound with radioactive nuclide labeled FAPI and synthesis process method thereof | |
| CN108570081B (en) | Ligand compound for glucose image diagnosis and treatment, preparation and application | |
| KR100430061B1 (en) | Radioisotope labeled complex of glucose derivatives and kit for preparation thereof | |
| CN113861254B (en) | Tumor PET imaging agent 68 Ga-NOTAN-aDG, and preparation method and application thereof | |
| EP1148878A1 (en) | 1,4,8,11-tetraazacyclotetradecane derivatives as radiodiganostic agents and their use in determining hypoxia and radioresistance of tumors | |
| CN101020697B (en) | Glucose derivative complex marked with 99mTc, 188 Re or 186Re and its preparation process | |
| CN101486707B (en) | 2-methyl-5-nitro glyoxaline compound, preparation and use thereof | |
| JP5179811B2 (en) | Uracil compounds or salts thereof, imaging agents containing these as active ingredients, and imaging agents for diagnosing tumors containing these as active ingredients | |
| CN101486708B (en) | 4-nitro glyoxaline compound, preparation and use thereof | |
| JPH09176179A (en) | Glucose or mannose derivative and radiodiagnostic agent containing the same | |
| EP3747874B1 (en) | Sodium saccharin having conjugated ligand, derivatives thereof and process for the preparation thereof | |
| CN102311460B (en) | Carbonyl-technetium-labeled chlorambucil complex as well as preparation method and application thereof | |
| CN100363371C (en) | Application of 99TcmN (CPEDTC)2 compounding agent in tumour imaging field | |
| US20200376147A1 (en) | Sodium saccharin having conjugated ligand, derivatives thereof and process for the preparation thereof | |
| US9024035B2 (en) | Radiotracer precursor BANI for imaging of hypoxic tissue, radiotracer, and method for preparing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20070822 |