CN101020697B - Glucose derivative complex marked with 99mTc, 188 Re or 186Re and its preparation process - Google Patents

Glucose derivative complex marked with 99mTc, 188 Re or 186Re and its preparation process Download PDF

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CN101020697B
CN101020697B CN200610114499A CN200610114499A CN101020697B CN 101020697 B CN101020697 B CN 101020697B CN 200610114499 A CN200610114499 A CN 200610114499A CN 200610114499 A CN200610114499 A CN 200610114499A CN 101020697 B CN101020697 B CN 101020697B
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CN101020697A (en
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朱霖
刘锰
刘亚静
余媛
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Beijing Normal University
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Beijing Normal University
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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. R=methyl-ethyl-propyl-isopropyl-butyl-isobutyl.

Description

A kind of 99mTc, 188Re or 186Glucose derivative complex of Re mark and preparation method thereof
Technical field
The present invention relates to a kind of 99mTc, 188Re or 186Glucose derivative complex of Re mark and preparation method thereof.
Background technology
18F-FDG video picture principle:
FDG is the analogue of glucose, gets into cell offspring and thanks to the phosphoric acid into FDG-6-, and is still different with G-6-P, the former further metabolism and being trapped in the cell.Therefore, according to the FDG that is trapped in the tissue, can obtain the metabolic rate of glucose.
Tumor imaging: tumour cell has different carbohydrate metabolism mechanism with normal tissue cell; Expression owing to glucose transport mRNA in tumour cell increases; GLUT Glut1 and Glut3 level raise; The HK level raises, and multifactorial effects such as G-6-Pase horizontal down-regulation make 18FDG is the same with glucose, and the picked-up in tumour cell increases.Therefore, can accurately show tumor locus with PET 18The FDG picked-up is apparently higher than healthy tissues.
Brain metabolism video picture: multiple nutrients materials such as lipid acid, glucose can be the heart energy derives, and the metabolism of brain is different with heart, it almost all with glucose as its energy substance. 18FDG is the analogue of glucose, is widely used in aspects such as brain metabolism research and diagnosing tumor. 18The FDG/PET video picture helps the diagnosis of multiple sacred disease, and from the metabolism of molecular level evaluation cranial nerve cell, thereby the early diagnosis disease is mainly used in functional diseases such as epilepsy, AD, HD.
Because 18The FDG expense is higher, needs medical cyclotron and PET video picture instrument, equipment popularity rate not high (whole nation 60 surplus), transformation period short ( 18The F transformation period is 108min), be difficult for popularizing, and 99mTc is cheap, conveniently is easy to get all suitable (T of transformation period and energy 1/2=6.0h; γ: 150keV), picture reproducer SPECT popularity rate higher (500 in the whole nation) therefore needs development in recent years clinically 99mThe glucalogue of Tc mark.People such as Yang Dawei 2003 the 226th phase 465-473 pages or leaves of " radiology " magazine (David J.Yang, Chang-Guhn Kim, et al:Radiology, 2003,226:465-473) disclose a kind of 99mThe glucalogue of Tc mark 99mTc-EC-DG,
The structure of EC-DG is following:
Figure G061B4499420061127D000021
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.
Summary of the invention
One of the object of the invention provide the high glucose derivative complex of a kind of tumor uptake- 99mTc or 188Re or 186The glucose derivative complex of Re mark.
The objective of the invention is to reach through following technical scheme:
Scheme one:
A kind of 99mTc, 188Re or 186The glucose derivative complex of Re mark, its nuclear midbody 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 structure general formula is (1) as follows, and the quantity of ligand is 2:
Figure G061B4499420061127D000031
R＝methyl-、ethyl-、propyl-、isopropyl-、butyl-、isobutyl-
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 does 99mTcN-PNP, 188ReN-PNP or 186ReN-PNP, its ligand is formula (1):
Figure G061B4499420061127D000032
R=methyl-, ethyl-, propyl-, isopropyl-, butyl-, the said PNP of isobutyl-are one of following structure:
Another object of the present invention provides above-mentioned 99mTc or 188/186The preparation method of the glucose derivative complex of Re mark.
Above-mentioned purpose of the present invention reaches through following technical scheme:
Scheme one:
A kind of 99mTc, 188Re or 186The preparation method of the glucose derivative complex of Re mark, its step is following:
(1) glucose-derivative is synthetic:
(2) [ 99mTcN] 2+, [ 188ReN] 2+, [ 186ReN] 2+The preparation of nuclear midbody:
(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 following:
Figure G061B4499420061127D000051
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 midbody;
(3) 99mTc, 188Re or 186The preparation of the glucose derivative complex of Re mark:
The pH=8.0 of regulating step (2) gained nuclear midbody, the water-ethanol solution of adding step (1) synthetic glucose-derivative reacts under the room temperature, 99mTc or 188/186The 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 following:
(1) glucose-derivative is synthetic:
Figure G061B4499420061127D000061
(2) 99mTc, 188Re or 186The preparation of the glucose derivative complex of Re mark:
In step (1) synthetic glucose-derivative, add an amount of water and ethanol and process solution, add Na 99mTcO 4Or Na 188ReO 4Or Na 186ReO 4, add SnCl 2Solution is transferred pH=8.0～8.5, reacts 20min under the room temperature, with 0.2 μ m membrane filtration, [ 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 following:
(1) glucose-derivative is synthetic:
Figure G061B4499420061127D000071
(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 midbody:
Sodium-potassium tartrate and yellow soda ash are joined in the cillin bottle, add Peng Qinghuana 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 midbody;
(3) 99mTc or 188/186The preparation of the glucose derivative complex of Re mark:
The pH=8.0 of regulating step (2) gained nuclear midbody, the solution of adding step (1) synthetic glucose-derivative, 65～75 ℃ of reactions are cooled to room temperature again, 99mTc or 188/186The 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 following:
(2) glucose-derivative is synthetic:
Figure G061B4499420061127D000081
(2) [ 99mTcN-PNP] 2+, [ 188/186ReN-PNP] 2+The preparation of nuclear midbody:
(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 following:
Figure G061B4499420061127D000082
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 2Solution,
React under the room temperature, must examine midbody;
(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 midbody, the water-ethanol solution and the PNP of adding step (1) synthetic glucose-derivative, reaction under 80 ℃ of water-baths, 99mTc or 188/186The glucose derivative complex of Re mark.
Beneficial effect:
Synthetic of the present invention [ 99mTcO] 3+, [ 188ReO] 3+, [ 186ReO] 3+, [ 99mTcN] 2+, [ 188ReN] 2+, [ 186ReN] 2+, 99mTcN-PNP, 188ReN-PNP, 186ReN-PNP, [ 99mTc (CO) 3] 1+, [ 188Re (CO) 3] 1+, [ 186Re (CO) 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, ratio 99mThe glucalogue of Tc mark 99mThe tumor uptake of Tc-EC-DG is higher, is the glucose-derivative tumor developer with applications well prospect.
Through embodiment the present invention is further specified below, but and do not mean that restriction protection domain of the present invention.
Embodiment
(1), glucose-derivative is synthetic:
Synthesizing of compound 1: R=methyl
0.0547mol methylamine and 5mL methyl alcohol are joined in the single necked round bottom flask, 0.045mol glucose is added again, tipping has the cold-trap of salt ice on the single port flask, is heated to 60 ℃ under the whipped state, until producing jelly.The ethanol that adds 30mL60 ℃ of heat continues to stir until jelly dissolving formation again then.This jelly is stirred overnight at ambient temperature.The mixture of 20mL ethanol and 0.161mol dithiocarbonic anhydride is added, and heating makes system be lower than 50 ℃ of reactions 1 hour.Left standstill under the room temperature one day, refrigerator cold-storage (4 ℃) a day gets light yellow crystal.Filter, use the ethanol-water solution recrystallization, get white crystal.
Product productive rate: 46%;
Product results of elemental analyses: measured value: N 5.23, C 35.60 and H 5.77%; Theoretical value: N 5.20, C35.67 and H 5.61%;
Mass spectroscopy MS (ESI): measured value: 291.9 [M+Na] +, theoretical value: 291.9;
H 1-NMR(500MHz，DMSO-d 6)：δ(ppm)4.39(d，1H，J＝12.96Hz)，3.91(d，1H，J＝12.47Hz)，3.85(m，1H)，3.82(m，1H)，3.80(m，1H)，3.76(m，1H)，3.62(m，1H)，3.40(m，1H)，3.37(m，1H)，3.20(m，1H)，2.51(broad?s，5H)；
IR(KBr)：3363，3252，2932，1519，1399，1301，1253，1125，1096，1026cm -1。
Synthesizing of compound 4: R=isopropyl-
0.0547mol Isopropylamine and 5mL methyl alcohol are joined in the single necked round bottom flask, again 0.045mol glucose is added, connect prolong on the single port flask, be heated to 60 ℃ under the whipped state, until producing jelly.The ethanol (60 ℃) of 30mL heat is added, continue stirring and form again then until the jelly dissolving.This jelly is stirred overnight at ambient temperature.The mixture of 20mL ethanol and 0.161mol dithiocarbonic anhydride is added, and heating makes system be lower than 50 ℃ of reactions 1 hour.Left standstill under the room temperature one day, refrigerator cold-storage (4 ℃) a day gets the oyster white crystal.Filter, use the ethanol-water solution recrystallization, get white crystal.
Product productive rate: 41%;
Product results of elemental analyses: measured value: N 4.80, C 40.51 and H 6.42%; Theoretical value: N 4.71, C40.39 and H 6.44%;
Mass spectroscopy MS (ESI): measured value: 296.0 [M-H] -, theoretical value: 296.0;
H 1-NMR(500MHz，DMSO-d 6)：δ(ppm)4.24(d，1H，J＝13.27Hz)，4.15(d，1H，J＝12.68Hz)，3.93(s，1H)，3.86(s，1H)，3.78(m，1H)，3.65(d，1H，J＝8.65Hz)，3.59(d，1H，J＝10.53)，3.40(m，1H)，2.51(broad?s，5H)，1.20(m，3H)，1.14(m，3H)；
IR(KBr)：3307，2966，2943，1490，1402，1368，1288，1236，1196，1083，1068，1039cm -1。
Synthesizing of compound 6: R=isobutyl-
0.0547mol isobutylamine and 5mL methyl alcohol are joined in the single necked round bottom flask, again 0.045mol glucose is added, connect prolong on the single port flask, be heated to 60 ℃ under the whipped state, until producing jelly.The ethanol (60 ℃) of 30mL heat is added, continue stirring and form again then until the jelly dissolving.This jelly is stirred overnight at ambient temperature.The mixture of 20mL ethanol and 0.161mol dithiocarbonic anhydride is added, and heating makes system be lower than 50 ℃ of reactions 1 hour.Left standstill under the room temperature one day, refrigerator cold-storage (4 ℃) a day gets the oyster white crystal.Filter, use the ethanol-water solution recrystallization, get white crystal.
Product productive rate: 47%;
Product results of elemental analyses: measured value: N 4.46, C 42.42 and H 6.86%; Theoretical value: N 4.50, C42.42 and H 6.80%;
Mass spectroscopy MS (ESI): measured value: 310.1 [M-H] -, theoretical value: 310.09;
H 1-NMR(500MHz，DMSO-d 6)：δ(ppm)4.18(d，1H，J＝13.21Hz)，4.11(m，1H)，3.95(d，1H，J＝7.21Hz)，3.86(d，1H，J＝6.62Hz)，3.79(m，1H)，3.73(m，1H)，3.67(m，1H)，3.41(m，1H)，2.51(broad?s，5H)，1.56(m，2H)，1.12(m，3H)，0.86(m，3H)；IR(KBr)：3361，2962，2933，1488，1382，1316，1293，1236，1186，1078，1033cm -1。
Synthesizing of compound 2: R=ethyl-
0.0547mol ethamine and 5mL methyl alcohol are joined in the single necked round bottom flask, again 0.045mol glucose is added, connect prolong on the single port flask, be heated to 60 ℃ under the whipped state, until producing jelly.The ethanol (60 ℃) of 30mL heat is added, continue stirring and form again then until the jelly dissolving.This jelly is stirred overnight at ambient temperature.The mixture of 20mL ethanol and 0.161mol dithiocarbonic anhydride is added, and heating makes system be lower than 50 ℃ of reactions 1 hour.Left standstill under the room temperature one day, refrigerator cold-storage (4 ℃) a day gets white crystal.Filter, use the ethanol-water solution recrystallization, get white crystal.
Product productive rate: 44%;
Product results of elemental analyses: measured value: N 4.76, C 38.29 and H 5.67%; Theoretical value: N 4.94, C38.15 and H 6.05%;
Mass spectroscopy MS (ESI): measured value: 306.0 [M+Na] +, theoretical value: 306.0;
H 1-NMR(500MHz，D 2O)：δ(ppm)4.69(s，1H)，4.04(s，2H)，3.78(m，1H)，3.76(m，1H)，3.72(m，1H)，3.62(m，1H)，3.56(m，1H)，3.52(m，1H)，1.15(t，3H，J＝7.18Hz)；IR(KBr)：3300，2945，2938，1509，1428，1372，1323，1276，1241，1204，1123，1088，1031cm -1。
Synthesizing of compound 3: R=propyl-
0.0547mol propylamine and 5mL methyl alcohol are joined in the single necked round bottom flask, again 0.045mol glucose is added, connect prolong on the single port flask, be heated to 60 ℃ under the whipped state, until producing jelly.The ethanol (60 ℃) of 30mL heat is added, continue stirring and form again then until the jelly dissolving.This jelly is stirred overnight at ambient temperature.The mixture of 20mL ethanol and 0.161mol dithiocarbonic anhydride is added, and heating makes system be lower than 50 ℃ of reactions 1 hour.Left standstill under the room temperature one day, refrigerator cold-storage (4 ℃) a day gets the oyster white crystal.Filter, use the ethanol-water solution recrystallization, get white crystal.
Product productive rate: 51%;
Product results of elemental analyses: measured value: N 4.85, C 40.37 and H 6.59%; Theoretical value: N 4.71, C40.39 and H 6.44%;
Mass spectroscopy MS (ESI): measured value: 320.0 [M+Na] +, theoretical value: 320.0;
H 1-NMR(500MHz，DMSO-d 6)：δ(ppm)4.44(d，1H，J＝13.39Hz)，4.34(d，1H，J＝12.77)，3.92(s，1H)，3.83(m，1H)，3.77(m，1H)，3.63(m，1H)，3.61(m，1H)，3.59(m，1H)，3.39(m，1H)，2.51(broad?s，5H)，1.61(m，2H)，0.88(t，3H，J＝7.31)；
IR(KBr)：3323，2966，2944，1505，1462，1425，1375，1324，1292，1252，1201，1129，1079，1016cm -1。
Synthesizing of compound 5: during R=butyl-:
0.0547mol butylamine and 5mL methyl alcohol are joined in the single necked round bottom flask, again 0.045mol glucose is added, connect prolong on the single port flask, be heated to 60 ℃ under the whipped state, until producing jelly.The ethanol (60 ℃) of 30mL heat is added, continue stirring and form again then until the jelly dissolving.This jelly is stirred overnight at ambient temperature.The mixture of 20mL ethanol and 0.161mol dithiocarbonic anhydride is added, and heating makes system be lower than 50 ℃ of reactions 1 hour.Left standstill under the room temperature one day, refrigerator cold-storage (4 ℃) a day gets the oyster white crystal.Filter, use the ethanol-water solution recrystallization, get white crystal.
Product productive rate: 49%;
Product results of elemental analyses: measured value: N 4.37, C 42.61 and H 6.69%; Theoretical value: N 4.50, C42.42 and H 6.80%
H 1-NMR(500MHz，DMSO-d 6)：δ(ppm)4.21(d，1H，J＝13.28Hz)，4.07(m，1H)，3.89(d，1H，J＝7.19)，3.83(m，1H)，3.76(m，1H)，3.70(m，1H)，3.63(m，1H)，3.44(m，1H)，3.09(m，1H)，2.51(broad?s，5H)，1.57(m，2H)，1.42(m，2H)，0.93(m，3H)；
IR(KBr)：3318，2957，2939，1491，1439，1375，1319，1289，1252，1197，1079，1016cm -1。
(2) preparation of glucose derivative complex
One of embodiment: [ 99mTcO] 3+Or [ 188ReO] 3+Or [ 186ReO] 3+The preparation of nuclear tagged compound
1. [ 99mTcO] 3+The structure of nuclear tagged compound:
Figure G061B4499420061127D000141
R＝methyl-、ethyl-、propyl-、isopropyl-、butyl-、isobutyl-
The corresponding compound 1,2,3,4,5,6 of difference
Embodiment 1.1: [ 99mTcO] 3+Nuclear tagged compound 1
Adding 0.5mL water and 0.5mL ethanol are processed solution in the 2mg compound 1, add the Na of the new drip washing of 0.3mL (10mCi/ml) 99mTcO 4, add 0.2mlSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.0～8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), calculate mark rate, mark rate 99.26%, (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 RT is 17.20min, 99.94%.
Embodiment 1.2: [ 99mTcO] 3+Nuclear tagged compound 3
Adding 0.5mL water and 0.5mL ethanol are processed solution in the 2mg compound 3, add the Na of the new drip washing of 0.3mL (10mCi/mL) 99mTcO 4, add 0.2mlSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.0～8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), 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 RT is 16.60min, 99.93%.
Embodiment 1.3:
[ 99mTcO] 3+Nuclear tagged compound 6
Adding 0.5mL water and 0.5mL ethanol are processed solution in 2～3mg compound 6, add the Na of the new drip washing of 0.3mL (10mCi/mL) 99mTcO 4, add 0.2mlSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.0～8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), 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 RT is 16.70min, 86.00%; 18.20min, 13.88%.
[ 99mTcO] 3+Nuclear tagged compound 2
Adding 0.5mL water and 0.5mL ethanol are processed solution in the 2mg compound 2, add the Na of the new drip washing of 0.3mL (10mCi/ml) 99mTcO 4, add 0.2mlSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.0～8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), calculate mark rate, mark rate 99.69%, (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 RT is 16.60min, 99.93%.
[ 99mTcO] 3+Nuclear tagged compound 4
Adding 0.5mL water and 0.5mL ethanol are processed solution in the 2mg compound 4, add the Na of the new drip washing of 0.3mL (10mCi/ml) 99mTcO 4, add 0.2mlSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.0～8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), calculate mark rate, mark rate is greater than 99%, and (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 RT is 16.70min, 99.51%.
[ 99mTcO] 3+Nuclear tagged compound 5
Adding 0.5mL water and 0.5mL ethanol are processed solution in the 2mg compound 5, add the Na of the new drip washing of 0.3mL (10mCi/ml) 99mTcO 4, add 0.2mlSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.0～8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), calculate mark rate, mark rate 99.54%, (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 RT is 16.60min, 99.35%.
2. [ 188ReO] 3+Or [ 186ReO] 3+The structure of nuclear tagged compound:
Figure G061B4499420061127D000171
R＝methyl-、ethyl-、propyl-、isopropyl-、butyl-、isobutyl-
The corresponding compound 1,2,3,4,5,6 of difference
Embodiment 1.4:
[ 188Re O] 3+Nuclear tagged compound 1
Adding 0.5mL water and 0.5mL ethanol are processed solution in the 2mg compound 1, add the Na of the new drip washing of 0.3mL (10mCi/ml) 188Re O 4, add 0.2mLSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.0～8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), calculate mark rate, mark rate 99.26%, (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 RT is 17.10min, 99.91%.
Embodiment 1.5:
[ 188Re O] 3+Nuclear tagged compound 3
Adding 0.5mL water and 0.5mL ethanol are processed solution in the 2mg compound 3, add the Na of the new drip washing of 0.3mL (10mCi/mL) 188Re O 4, add 0.2mLSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.0～8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), 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 RT is 16.20min, 99.87%.
Embodiment 1.6:
[ 188Re O] 3+Nuclear tagged compound 6
Adding 0.5mL water and 0.5mL ethanol are processed solution in 2～3mg compound 6, add the Na of the new drip washing of 0.3mL (10mCi/mL) 188Re O 4, add 0.2mLSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.0～8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), 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 RT is 16.30min, 89.00%; 17.90min, 10.01%.
Two of embodiment: [[ 99mTcN] 2+Or [ 188Re N] 2+Or [ 186Re N] 2+The preparation of nuclear tagged compound
1. [ 99mTcN] 2+The structure of nuclear tagged compound
Figure G061B4499420061127D000191
R＝methyl-、ethyl-、propyl-、isopropyl-、butyl-、isobutyl-
The corresponding compound 1,2,3,4,5,6 of difference
1.1. [ 99mTcN] 2+The preparation of nuclear midbody:
(succinyl two hydrazides, structure is NH to add 5mgSDH in the cillin bottle 2NHCOCH 2CH 2CONHNH 2) and 5mgPDTA, promptly 1, the 2-trimethylenedinitrilo-tertraacetic acid, its structure is following:
Figure G061B4499420061127D000192
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 lLSnCl rapidly 2Solution (1mg/mL, 1N HCl), reaction 15min.TLC monitoring (acetonitrile/polymeric amide under the room temperature; Saline water/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 RT of nuclear midbody is 3.00min.
1.2. [ 99mTcN] 2+The preparation of nuclear tagged compound:
Regulate above-mentioned 99mThe pH=8.0 of TcN nuclear midbody, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound.TLC monitors (acetonitrile/polymeric amide; Saline water/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 2.1: [ 99mTcN] 2+Nuclear tagged compound 1
Regulate above-mentioned 99mThe pH=8.0 of TcN nuclear midbody, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 1.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate 99.15%.(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 RT is 16.60min, 99.79%.
Embodiment 2.2: [ 99mTcN] 2+Nuclear tagged compound 4
Regulate above-mentioned 99mThe pH=8.0 of TcN nuclear midbody, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 4.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate 98.49%.(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 RT is 16.60min, 14.24%; 17.40min, 85.52%.
Embodiment 2.3: [ 99mTcN] 2+Nuclear tagged compound 6
Regulate above-mentioned 99mThe pH=8.0 of TcN nuclear midbody, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 6.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate 98.67%.(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 RT is 23.60min, 99.55%.
[ 99mTcN] 2+Nuclear tagged compound 2
Regulate above-mentioned 99mThe pH=8.0 of TcN nuclear midbody, (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; Saline water/polymeric amide), calculate mark rate, mark rate 99.46%.(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 RT is 16.60min, 99.80%.
[ 99mTcN] 2+Nuclear tagged compound 3
Regulate above-mentioned 99mThe pH=8.0 of TcN nuclear midbody, (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; Saline water/polymeric amide), calculate mark rate, mark rate 99.58%.(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 RT is 17.20min, 99.34%.
[ 99mTcN] 2+Nuclear tagged compound 5
Regulate above-mentioned 99mThe pH=8.0 of TcN nuclear midbody, (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; Saline water/polymeric amide), calculate mark rate, mark rate 99.31%.(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 RT is 18.10min, 99.59%.
2. [ 188Re N] 2+The preparation of nuclear tagged compound
[ 188Re N] 2+The structure of nuclear tagged compound
Figure G061B4499420061127D000221
R＝methyl-、ethyl-、propyl-、isopropyl-、butyl-、isobutyl-
The corresponding compound 1,2,3,4,5,6 of difference
2.1. [ 188ReN] 2+The preparation of nuclear midbody:
(succinyl two hydrazides, structure is NH to add 5mgSDH in the cillin bottle 2NHCOCH 2CH 2CONHNH 2) and 5mgPDTA, promptly 1, the 2-trimethylenedinitrilo-tertraacetic acid, its structure is following:
Figure G061B4499420061127D000231
Add an amount of 1N NaOH and deionized water again and make it dissolving, transfer pH=7.4 with 1N HCl.With Na 188Re O 4(0.3～0.5mL, 1～20mCi/mL) adds solution, adds 30 μ lLSnCl rapidly 2Solution (1mg/mL, 1N HCl), reaction 15min.TLC monitoring (acetonitrile/polymeric amide under the room temperature; Saline water/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%).[ 188ReN] 2+The HPLC RT of nuclear midbody is 3.20min.
2.2. [ 188ReN] 2+The preparation of nuclear tagged compound
Regulate above-mentioned [ 188ReN] 2+The pH=8.0 of nuclear midbody, (1/1, V/V) (2mg/mL reacts 15min under the room temperature to solution to the water-ethanol of adding 1mL compound.TLC monitors (acetonitrile/polymeric amide; Saline water/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 2.4: [ 188ReN] 2+Nuclear tagged compound 1
Regulate above-mentioned [ 188Re N] 2+The pH=8.0 of nuclear midbody, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 1.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate 99.15%.(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 RT is 16.60min, 99.35%.
Embodiment 2.5: [ 188ReN] 2+Nuclear tagged compound 4
Regulate above-mentioned [ 188ReN] 2+The pH=8.0 of nuclear midbody, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 4.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate 98.49%.(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 RT is 16.60min, 12.35%; 17.10min, 86.43%.
Embodiment 2.6: [ 188ReN] 2+Nuclear tagged compound 6
Regulate above-mentioned [ 188ReN] 2+The pH=8.0 of nuclear midbody, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 6.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate 98.67%.(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 RT is 23.60min, 99.55%.
Three of embodiment: [ 99mTcN] 3+Or [ 188ReN] 2+Or [ 186ReN] 2+Core and PNP, compound (1～5) are mixed 99mThe preparation of Tc title complex
1. [ 99mTcN] 2+The structure of-PNP title complex:
Figure G061B4499420061127D000251
R1＝methyl-、ethyl-、propyl-、isopropyl-、butyl-、isobutyl-
PNP＝PNP5，PNP6，L6
Figure G061B4499420061127D000252
Wherein: R=methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-be corresponding compound 1,2,3,4,5,6 respectively.
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 midbody, add 1mL compound 1 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2mgPNP6, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/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; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 17.10min, 98.84%.
Embodiment 3.2:
[ 99mTcN] 2+Core and PNP6, compound 3 are mixed 99mThe preparation of Tc title complex
Regulate above-mentioned 99mPH=7.5～8.0 of TcN nuclear midbody, add 1mL compound 3 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2mgPNP6, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate is greater than 97%.(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; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 18.70min, 98.84%.
Embodiment 3.3:
[ 99mTcN] 2+Core and PNP6, compound 6 are mixed 99mThe preparation of Tc title complex
Regulate above-mentioned 99mPH=7.5～8.0 of TcN nuclear midbody, add 6mL compound 3 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 1.8mgPNP6, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate is greater than 96%.
(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; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 19.10min, 98.84%.
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 midbody, add 6mL compound 1 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2.0mgPNP5, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate is greater than 96%.(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; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 17.10min, 98.84%.
Embodiment 3.5:
[ 99mTcN] 2+Core and PNP5, compound 3 are mixed 99mThe preparation of Tc title complex
Regulate above-mentioned 99mPH=7.5～8.0 of TcN nuclear midbody, add 1mL compound 3 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2mgPNP5, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate is greater than 97%.(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; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 18.40min, 98.84%.
Embodiment 3.6:
[ 99mTcN] 2+Core and PNP5, compound 6 are mixed 99mThe preparation of Tc title complex
Regulate above-mentioned 99mPH=7.5～8.0 of TcN nuclear midbody, add 1mL compound 6 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2mgPNP5, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate is greater than 97%.(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; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 19.20min, 98.84%.
2. [ 188ReN] 2+-PNP or [ 186ReN] 2+The structure of-PNP title complex:
Figure G061B4499420061127D000281
R1＝methyl-、ethyl-、propyl-、isopropyl-、butyl-、isobutyl-
PNP＝PNP5，PNP6，L6
Figure G061B4499420061127D000282
Wherein: R=methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-be corresponding compound 1,2,3,4,5,6 respectively.
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 midbody, add 1mL compound 1 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2.0mgPNP6, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/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; B is the acetonitrile solution of 0.1% trifluoroacetic acid mutually; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 17.00min, 98.67%.
Embodiment 3.8:
[ 188ReN] 2+Core and PNP6, compound 3 are mixed 188The preparation of Re title complex
Regulate above-mentioned [ 188ReN] 2+PH=7.5～8.0 of nuclear midbody, add 1mL compound 3 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2.0mgPNP6, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate is greater than 97%.(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; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 18.60min, 98.55%.
Embodiment 3.9:
[ 188ReN] 2+Core and PNP6, compound 6 are mixed 188The preparation of Re title complex
Regulate above-mentioned [ 188ReN] 2+PH=7.5～8.0 of nuclear midbody, add 6mL compound 6 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2.0mgPNP6, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate is greater than 96%.
(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; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 19.20min, 98.74%.
Embodiment 3.10:
[ 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 midbody, add 6mL compound 1 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2.0mgPNP5, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate is greater than 96%.(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; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 17.30min, 98.17%.
Embodiment 3.11:
[ 188ReN] 2+Core and PNP5, compound 3 are mixed 188The preparation of Re title complex
Regulate above-mentioned [ 188ReN] 2+PH=7.5～8.0 of nuclear midbody, add 1mL compound 3 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2mgPNP5, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate is greater than 96%.(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; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 18.20min, 98.26%.
Embodiment 3.12:
[ 188ReN] 2+Core and PNP5, compound 6 are mixed 188The preparation of Re title complex
Regulate above-mentioned [ 188ReN] 2+PH=7.5～8.0 of nuclear midbody, add 1mL compound 6 water-ethanol (1/1, V/V) solution (2～3mg/mL) and 2mgPNP5, under 80 ℃ of water-baths, react 10min.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate is greater than 98%.(PLC 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; 0～5min:30%B; 5～25min:30%B～90%B).The HPLC RT is 19.50min, 99.16%.
Four of embodiment. [ 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 tagged compound:
1. [ 99mTc (CO) 3(H 2O) 3] 1+The structure of nuclear tagged compound:
Figure G061B4499420061127D000311
R＝methyl-、ethyl-、propyl-、isopropyl-、butyl-、isobutyl-
The corresponding compound 1,2,3,4,5,6 of difference.
[ 99mTc (CO) 3(H 2O) 3] 1+The preparation of nuclear midbody:
Sodium-potassium tartrate 20mg, yellow soda ash 4.7～4.9mg join in the 10mL cillin bottle, add 7.4～7.5mg Peng Qinghuana 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 (acetonitrile/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 RT of nuclear midbody 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+Midbody 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 4.1: [ 99mTc (CO) 3(H 2O) 3] 1+Nuclear tagged compound 1:
With the preparation [ 99mTc (CO) 3(H 2O) 3] 1+Midbody 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 90%; (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 RT is 16.70min, 12.52%; 20.10min, 87.25%.
Embodiment 4.2: [ 99mTc (CO) 3(H 2O) 3] 1+Nuclear tagged compound 4:
With the preparation [ 99mTc (CO) 3(H 2O) 3] 1+Midbody is regulated pH=8.0 with 1N HCl and 0.1N HCl, joins in the solution of 1mL compound 4 (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 90%; (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 RT is 16.70min, 86.60%; 21.90min, 13.20%.
Embodiment 4.3: [ 99mTc (CO) 3(H 2O) 3] 1+Nuclear tagged compound 6:
With the preparation [ 99mTc (CO) 3(H 2O) 3] 1+Midbody is regulated pH=8.0 with 1N HCl and 0.1N HCl, joins in the solution of 1mL compound 6 (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 90%; (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 RT is 16.70min, 93.07%; 23.80min, 6.46%.
2. [ 188Re (CO) 3(H 2O) 3] 1+Or [ 186Re (CO) 3(H 2O) 3] 1+The structure of nuclear tagged compound:
Figure G061B4499420061127D000331
R＝methyl-、ethyl-、propyl-、isopropyl-、butyl-、isobutyl-
The corresponding compound 1,2,3,4,5,6 of difference
Embodiment 4.4: [ 188Re (CO) 3(H 2O) 3] 1+Nuclear tagged compound 1 188The preparation of Re title complex (8):
5mg amino borane title complex joins in the cillin bottle, gland seal, and logical CO gas 10-15min adds 4.5 μ LH 3PO 4(85%) and Na 188Re O 4Physiological salt soln (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 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; 0～10min:A=100%, B=0; 10～20min:A=50%, B=50%; 20～30min:A=0, B=100%).The HPLC RT is 16.60min, 10.75%; 20.00min, 88.17%.
Embodiment 4.5: [ 188Re (CO) 3(H 2O) 3] 1+Nuclear tagged compound 4 188The preparation of Re title complex (8):
5mg amino borane title complex joins in the cillin bottle, gland seal, and logical CO gas 10-15min adds 4.5 μ LH 3PO 4(85%) and Na 188ReO 4Physiological salt soln (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 4, 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 RT is 16.60min, 88.25%; 21.70min, 10.29%.
Embodiment 4.6: [ 188Re (CO) 3(H 2O) 3] 1+Nuclear tagged compound 6 188The preparation of Re title complex (8):
5mg amino borane title complex joins in the cillin bottle, gland seal, and logical CO gas 10-15min adds 4.5 μ LH 3PO 4(85%) and Na 188ReO 4Physiological salt soln (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 6, at 60 ℃ of reaction 15min.Surveying mark rate is 97.61%.(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 RT is 16.70min, 92.76%; 24.00min, 7.17%.
(3), 99mThe experiment of Tc tagged compound mice with tumor
[ 99mTcO] 3+Distribution experiment (n=3) 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
Adding 0.5mL water and 0.5mL ethanol are processed solution in the 2mg compound 1, add the Na of the new drip washing of 0.5mL (10mCi/mL) 99mTcO 4, add 0.3mLSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), calculate mark rate, mark rate 99.26%, (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 RT is 17.20min, 99.94%.
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 saline water, 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 mice with tumor bio distribution of nuclear tagged compound 1 title complex
ID％/g 60min 120min 240min
Tumour 2.24±0.18 1.74±0.31 1.44±0.30
Blood 4.16±0.11 3.26±0.36 2.17±0.18
The heart 1.80±0.37 1.14±0.36 0.86±0.41
Liver 9.17±0.92 9.02±2.56 6.58±1.18
Spleen 1.17±0.61 1.04±0.70 0.93±0.28
Lung 3.77±0.82 2.35±1.08 1.21±0.14
Kidney 19.42±3.67 16.33±5.23 15.84±2.92
Brain 0.15±0.03 0.13±0.05 0.11±0.03
Muscle 0.68±0.18 0.46±0.10 0.35±0.05
Tumour/blood 0.54±0.05 0.53±0.05 0.67±0.14
Tumour/muscle 3.38±0.55 3.81±0.18 4.19±1.34
[ 99mTcN] 2+Distribution experiment (n=3) 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:
1.1. [ 99mTcN] 2+The preparation of nuclear midbody:
(succinyl two hydrazides, structure is NH to add 5mgSDH in the cillin bottle 2NHCOCH 2CH 2CONHNH 2) and 5mgPDTA, 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 lLSnCl rapidly 2Solution (1mg/mL, 1N HCl), reaction 15min.TLC monitoring (acetonitrile/polymeric amide under the room temperature; Saline water/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 RT of nuclear midbody is 3.00min.
1.2.: [ 99mTcN] 2+Nuclear tagged compound 1
Regulate above-mentioned 99mThe pH=8.0 of TcN nuclear midbody, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 1.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate 99.15%.(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 RT 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 saline water, 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.
[ 99mTcN] 2+The mice with tumor bio distribution of nuclear tagged compound 1 title complex
ID％/g 30min 2h 4h
Tumour 1.02±0.05 0.75±0.08 0.61±0.13
Blood 1.70±0.05 0.73±0.11 0.61±0.13
The heart 0.77±0.02 0.48±0.13 0.24±0.19
Liver 11.00±1.709 11.14±9.96 11.41±2.48
Spleen 0.86±0.30 0.52±0.04 0.22±0.02
Lung 1.60±0.34 1.23±0.47 0.65±0.26
Kidney 6.01±0.42 3.55±0.72 3.38±0.68
Brain 0.15±0.07 0.06±0.01 0.04±0.01
Muscle 0.62±0.28 0.19±0.04 0.11±0.11
Tumour/blood 0.60±0.05 1.02±0.10 1.01±0.32
Tumour/muscle 1.65±0.18 3.97±0.69 5.61±0.76
[ 99mTcN] 2+Distribution experiment (n=3) in the lotus EMT-6 mice with tumor body of nuclear tagged compound 2
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:
1.1. [ 99mTcN] 2+The preparation of nuclear midbody:
(succinyl two hydrazides, structure is NH to add 5mgSDH in the cillin bottle 2NHCOCH 2CH 2CONHNH 2) and 5mgPDTA, 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 lLSnCl rapidly 2Solution (1mg/mL, 1N HCl), reaction 15min.TLC monitoring (acetonitrile/polymeric amide under the room temperature; Saline water/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 RT of nuclear midbody is 3.00min.
1.2.: [ 99mTcN] 2+Nuclear tagged compound 2
[ 99mTcN] 2+Nuclear tagged compound 2
Regulate above-mentioned 99mThe pH=8.0 of TcN nuclear midbody, (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; Saline water/polymeric amide), calculate mark rate, mark rate 99.46%.(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 RT is 16.60min, 99.80%.
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 saline water, 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.
[ 99mTcN] 2+The mice with tumor bio distribution of nuclear tagged compound 2 title complexs
ID％/g 30min 2h 4h
Tumour 1.26±0.39 0.40±0.03 0.45±0.02
Blood 1.25±0.08 0.62±0.02 0.46±0.05
The heart 0.76±0.20 0.52±0.44 0.24±0.01
Liver 16.20±2.31 15.59±1.87 13.37±1.21
Spleen 0.35±0.13 0.96±0.47 0.20±0.02
Lung 1.09±0.59 1.42±0.44 0.60±0.02
Kidney 5.63±0.78 2.59±0.24 2.22±0.13
Brain 0.10±0.03 0.04±0.01 0.04±0.01
Muscle 0.47±0.50 0.12±0.91 0.13±0.04
Tumour/blood 1.01±0.23 0.64±0.04 0.98±0.16
Tumour/muscle 2.71±0.79 3.26±0.91 3.46±0.91
[ 99mTc (CO) 3(H 2O) 3] 1+Distribution experiment (n=3) 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:
1.1. [ 99mTc (CO) 3(H 2O) 3] 1+The preparation of nuclear midbody:
Sodium-potassium tartrate 20mg, yellow soda ash 4.7～4.9mg join in the 10mL cillin bottle, add 7.4～7.5mg Peng Qinghuana 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 (acetonitrile/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 RT of nuclear midbody is 13.90min, two groups of broad peaks of 16.70min.
1.2. [ 99mTc (CO) 3(H 2O) 3] 1+Nuclear tagged compound 6:
With the preparation [ 99mTc (CO) 3(H 2O) 3] 1+Midbody is regulated pH=8.0 with 1N HCl and 0.1N HCl, joins in the solution of 1mL compound 6 (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 90%; (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 RT is 16.70min, 93.07%; 23.80min, 6.46%.
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 saline water, 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.
[ 99mTc (CO) 3(H 2O) 3] 1+The mice with tumor bio distribution of nuclear tagged compound 6 title complexs
ID％/g 30min 2h 4h
Tumour 1.83±0.62 2.53±1.18 1.52±0.20
Blood 1.52±0.11 1.79±0.09 1.07±0.29
The heart 1.26±0.42 0.81±0.07 0.68±0.28
Liver 5.19±0.30 3.47±0.69 2.54±0.15
Spleen 0.81±0.26 0.60±0.21 0.42±0.02
Lung 2.90±0.88 2.41±1.34 1.62±0.20
Kidney 10.79±2.65 8.68±1.56 9.40±2.42
Brain 0.15±0.03 0.12±0.06 0.07±0.02
Muscle 0.41±0.06 1.98±1.68 0.83±0.88
Tumour/blood 1.20±2.76 1.41±0.59 1.41±0.23
Tumour/muscle 4.43±9.86 1.28±2.02 1.84±2.94
(4) 188The experiment of Re tagged compound mice with tumor
[ 188Re O] 3+Distribution experiment (n=3) 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
[ 188Re O] 3+Nuclear tagged compound 1
Adding 0.5mL water and 0.5mL ethanol are processed solution in the 2mg compound 1, add the Na of the new drip washing of 0.3mL (10mCi/ml) 188Re O 4, add 0.2mLSnCl rapidly 2(1mg/mL 0.1NHCl), transfers pH=8.0～8.5 to solution, reacts 20min under the room temperature, and with 0.2 μ m membrane filtration, TLC monitors (acetonitrile/polymeric amide; Saline water/silica gel), calculate mark rate, mark rate 99.26%, (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 RT is 17.10min, 99.91%.
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 saline water, 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.
[ 188Re O] 3+The mice with tumor bio distribution of nuclear tagged compound 1 title complex
ID％/g 60min 120min 240min
Tumour 2.19±0.12 1.83±0.42 1.57±0.27
Blood 3.95±0.08 3.17±0.12 1.85±0.24
The heart 1.57±0.33 1.22±0.17 0.68±0.28
Liver 9.03±1.54 8.67±1.89 5.88±1.46
Spleen 1.21±0.49 0.84±0.58 0.71±0.33
Lung 3.36±1.35 2.43±1.23 1.08±0.26
Kidney 18.67±2.87 15.93±3.89 15.24±3.12
Brain 0.23±0.05 0.18±0.08 0.14±0.03
Muscle 0.75±0.21 0.38±0.26 0.36±0.09
Tumour/blood 0.55±0.11 0.57±0.21 0.85±0.08
Tumour/muscle 2.92±0.33 4.82±0.27 4.36±1.06
[ 188Re N] 2+Distribution experiment (n=3) 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
1.1. [ 188ReN] 2+The preparation of nuclear midbody:
Add 5mgSDH and 5mgPDTA in the cillin bottle, add an amount of 1N NaOH and deionized water again and make it dissolving, transfer pH=7.4 with 1N HCl.With Na 188Re O 4(0.3～0.5mL, 1～20mCi/mL) adds solution, adds 30 μ lLSnCl rapidly 2Solution (1mg/mL, 1N HCl), reaction 15min.TLC monitoring (acetonitrile/polymeric amide under the room temperature; Saline water/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; 1～20min:A=50%, B=50%; 20～30min:A=0, B=100%).[ 188Re N] 2+The HPLC RT of nuclear midbody is 3.20min.
1.2. [ 188ReN] 2+Nuclear tagged compound 1
Regulate above-mentioned [ 188Re N] 2+The pH=8.0 of nuclear midbody, (1/1, V/V) solution (2mg/mL) reacts 15min under the room temperature to the water-ethanol of adding 1mL compound 1.TLC monitors (acetonitrile/polymeric amide; Saline water/polymeric amide), calculate mark rate, mark rate 99.15%.(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 RT is 16.60min, 99.35%.
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 saline water, 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 mice with tumor bio distribution of nuclear tagged compound 1 title complex
ID％/g 30min 2h 4h
Tumour 1.17±0.06 0.81±0.09 0.77±0.18
Blood 1.66±0.04 0.71±0.13 0.55±0.18
The heart 0.86±0.11 0.51±0.11 0.20±0.17
Liver 11.67±1.22 10.99±8.95 10.38±1.65
Spleen 0.77±0.42 0.67±0.06 0.18±0.01
Lung 1.54±0.60 1.07±0.33 0.57±0.34
Kidney 6.62±0.33 3.26±0.54 3.49±0.55
Brain 0.18±0.05 0.05±0.01 0.04±0.01
Muscle 0.57±0.23 0.13±0.06 0.15±0.18
Tumour/blood 0.70±0.04 1.14±0.09 1.40±0.28
Tumour/muscle 2.05±0.11 6.23±1.35 5.13±0.56
[ 188Re (CO) 3(H 2O) 3] 1+Distribution experiment (n=3) 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;
[ 188Re (CO) 3(H 2O) 3] 1+Nuclear tagged compound 6 188The preparation of Re title complex (8):
5mg amino borane title complex joins in the cillin bottle, gland seal, and logical CO gas 10-15min adds 4.5 μ LH 3PO 4(85%) and Na 188ReO 4Physiological salt soln (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 6, at 60 ℃ of reaction 15min.Surveying mark rate is 97.61%.(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 RT is 16.70min, 92.76%; 24.00min, 7.17%.
[ 188Re (CO) 3(H 2O) 3] 1+The mice with tumor bio distribution of nuclear tagged compound 6 title complexs
ID％/g 30min 2h 4h
Tumour 1.79±0.55 2.62±1.23 1.57±0.29
Blood 1.44±0.25 1.56±0.17 0.98±0.32
The heart 1.12±0.12 0.90±0.11 0.71±0.23
Liver 5.32±0.27 3.55±0.36 2.16±0.25
Spleen 0.88±0.14 0.71±0.37 0.46±0.15
Lung 2.67±0.48 2.26±0.57 1.31±0.23
Kidney 10.51±1.88 8.23±1.11 7.40±2.14
Brain 0.23±0.08 0.16±0.03 0.09±0.05
Muscle 0.56±0.02 1.28±1.16 0.77±0.47
Tumour/blood 1.24±2.45 1.67±0.40 1.60±0.18
Tumour/muscle 3.19±5.72 2.04±1.71 2.04±2.16
Contrast: 99mTc-EC-DG:
99mThe 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 0.611±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 0.721±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
Tumour/muscle 3.352±0.749 2.754±0.120 2.795±0.982
Contrast can be known:
[ 99mTcO] 3+The tumor uptake of nuclear tagged compound 1 title complex is higher than 99mTc-EC-DG is that one type of potential is good 99mThe glucose-derivative tumor developer of Tc mark.
Owing to be used for 18The PET video picture instrument of FDG video picture costs an arm and a leg, equipment popularity rate not high (whole nation 60 surplus), and 18F needs the medical cyclotron preparation, and expense is higher, simultaneously 18The F transformation period short ( 18The F transformation period is 108min), its use is very limited; And 99mTc by 99Mo/ 99mThe Tc producer makes, and is cheap, conveniently is easy to get all suitable (T of transformation period and energy 1/2=6.0h, this provides adequate time for radiopharmaceutic preparation and concentrating of target organ in vivo, and the while can reduce the suffered radiation dose of patient as far as possible; The emission gamma-rays; Ray energy is 150keV, and energy is suitable), picture reproducer SPECT popularity rate higher (500 in the whole nation) therefore needs development in recent years clinically 99mThe glucalogue of Tc mark.

Claims (4)

1. one kind 99mTc, 188Re or 186The preparation method of the glucose derivative complex of Re mark, its step is following:
(1) glucose-derivative is synthetic:
Figure FSB00000810500500011
Wherein, R is a methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-;
(2) [ 99mTcN] 2+, [ 188ReN] 2+Or [ 186ReN] 2+The preparation of nuclear midbody:
Add succinyl two hydrazides and 1 in the cillin bottle, the 2-trimethylenedinitrilo-tertraacetic acid adds an amount of NaOH and deionized water and makes it dissolving, transfers pH=7.4 with HCl; Add Na 99mTcO 4Or Na 188ReO 4Or Na 186Re O 4Behind the solution, add SnCl rapidly 2React under the solution, room temperature, must examine midbody;
(3) 99mTc, 188Re or 186The preparation of the glucose derivative complex of Re mark:
The pH=8.0 of regulating step (2) gained nuclear midbody, the water-ethanol solution of adding step (1) synthetic glucose-derivative reacts under the room temperature, 99mTc, 188Re or 186The glucose derivative complex of Re mark.
2. one kind 99mTc, 188Re or 186The preparation method of the glucose derivative complex of Re mark, its step is following:
(1) glucose-derivative is synthetic:
Figure FSB00000810500500021
Wherein, R is a methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-;
(2) 99mTc, 188Re or 186The preparation of the glucose derivative complex of Re mark:
In step (1) synthetic glucose-derivative, add an amount of water and ethanol and process solution, add Na 99mTcO 4Or Na 188ReO 4Or Na 186ReO 4, add SnCl 2Solution is transferred pH=8.0～8.5, reacts 20min under the room temperature, with 0.2 μ m membrane filtration, [ 99mTcO] 3+, [ 188ReO] 3+, [ 186ReO] 3+The glucose derivative complex of mark.
3. one kind 99mTc, 188Re or 186The preparation method of the glucose derivative complex of Re mark, its step is following:
(1) glucose-derivative is synthetic:
Figure FSB00000810500500031
Wherein, R is a methyl, ethyl, propyl group, different interior base, butyl, isobutyl-;
(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 midbody:
Sodium-potassium tartrate and yellow soda ash are joined in the cillin bottle, add Peng Qinghuana more rapidly, add water, gland seal, logical carbon monoxide; Add Na 99mTcO 4Or Na 188Re O 4Or Na 186ReO 4Solution 80 ℃ of reactions down, must be examined midbody again;
(3) 99mTc, 188Re or 186The preparation of the glucose derivative complex of Re mark:
The pH=8.0 of regulating step (2) gained nuclear midbody, the solution of adding step (1) synthetic glucose-derivative, 65～75 ℃ of reactions are cooled to room temperature again, 99mTc, 188Re or 186The glucose derivative complex of Re mark.
4. one kind 99mTc, 188Re or 186The preparation method of the glucose derivative complex of Re mark, its step is following:
(1) glucose-derivative is synthetic:
Wherein, R is a methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-;
(2) [ 99mTcN-PNP] 2+, [ 188ReN-PNP] 2+Or [ 186ReN-PNP] 2+The preparation of nuclear midbody:
Add succinyl two hydrazides and 1 in the cillin bottle, the 2-trimethylenedinitrilo-tertraacetic acid adds an amount of NaOH and deionized water and makes it dissolving, transfers pH=7.4 with HCl; Add Na 99mTcO 4Or Na 188ReO 4Or Na 186ReO 4Behind the solution, add SnCl rapidly 2React under the solution, room temperature, must examine midbody;
(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 midbody, the water-ethanol solution and the PNP of adding step (1) synthetic glucose-derivative, reaction under 80 ℃ of water-baths, 99mTc, 188Re or 186The glucose derivative complex of Re mark,
Said PNP is one of following structure:
Figure FSB00000810500500042
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2568888C1 (en) * 2014-06-26 2015-11-20 Федеральное государственное бюджетное учреждение "Научно-исследовательский институт онкологии" Сибирского отделения Российской академии медицинских наук (ФГБУ "НИИ онкологии" СО РАМН) METHOD AND FORMULATION FOR PRODUCING 99m TC LABELLED 5-THIO-D-GLUCOSE AGENT FOR RADIONUCLIDE DIAGNOSIS

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1286122A (en) * 1999-08-26 2001-03-07 马远鸣 Radioactive Re labelled glucosan medicines and preparing process thereof
WO2002009771A1 (en) * 2000-07-28 2002-02-07 Nihon Medi-Physics Co., Ltd. Radiopharmaceutical for diagnostic imaging containing a technetium-99m nitride heterocomplex

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1286122A (en) * 1999-08-26 2001-03-07 马远鸣 Radioactive Re labelled glucosan medicines and preparing process thereof
WO2002009771A1 (en) * 2000-07-28 2002-02-07 Nihon Medi-Physics Co., Ltd. Radiopharmaceutical for diagnostic imaging containing a technetium-99m nitride heterocomplex

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2568888C1 (en) * 2014-06-26 2015-11-20 Федеральное государственное бюджетное учреждение "Научно-исследовательский институт онкологии" Сибирского отделения Российской академии медицинских наук (ФГБУ "НИИ онкологии" СО РАМН) METHOD AND FORMULATION FOR PRODUCING 99m TC LABELLED 5-THIO-D-GLUCOSE AGENT FOR RADIONUCLIDE DIAGNOSIS

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