CN107007843A - PET/MRI bimodal developer SPIO NOTA68Ga and preparation method thereof and purposes - Google Patents
PET/MRI bimodal developer SPIO NOTA68Ga and preparation method thereof and purposes Download PDFInfo
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
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- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
- A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
- A61K49/128—Linear polymers, e.g. dextran, inulin, PEG comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone
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- A61K51/04—Organic compounds
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Abstract
The invention discloses a kind of compound SPIO NOTA68Ga and preparation method thereof, uses polyethyleneglycol derivative (PEG2000) modification SPIO surfaces amino by bifunctional chelating agent Isosorbide-5-Nitrae, 7 three azo-cycle nonane Isosorbide-5-Nitraes, 7 triacetic acids (NOTA) are coupled into Nanosurface, obtain labelled precursor SPIO PEG2000NOTA, is then used68Ga carries out radioactive label to SPIO, obtains SPIO NOTA68Ga.In addition, the invention discloses SPIO NOTA68Ga purposes, by studying its external and part vivo biodistribution property, as a result finds SPIO NOTA68Ga has good physicochemical property and biocompatibility as PET/MRI bimodal probes, and it has higher vitro stability and a good water solubility, and mark rate it is high, without purifying, the research imaged available for follow-up PET/MRI bimodals.
Description
Technical field
The present invention relates to PET/MRI bimodal developers SPIO-NOTA-68Ga and preparation method thereof and purposes, belong to medical science
Field.
Background technology
In the clinical diagnosis of tumour, positron emission tomography (positron emission tomography,
PET more and more important effect) is played with Magnetic resonance imaging (magnetic resonance imaging, MRI), but it is single
The PET and MRI of one pattern have certain limitation in diagnosis, therefore, and PET/MRI integration technology turns into current image
The inevitable trend of technology.PET/MRI scanners in 2011 have been enter into clinic, but up to the present do not have yet for clinic
Bimodal imaging medicament comes out.So a kind of effective bimodal imaging medicament of design just becomes an important research work
Make.A kind of synthesis of new PET/MRI bimodal medicines and preliminary Quality Research are reported herein.
SPIO nano-particle (superparamagnetic iron oxide nanoparticles,
SPION the research of medical domain) is widely used in because of excellent magnetic property and good biocompatibility, it is repaiied
After decorations, it can will launch the targeted moleculars such as nucleic, the polypeptide of positive electron and be connected thereto face, reach target drug-carrying, MRIT2WI is cloudy
Property contrast agent, cell Magnetic Isolation and purify DNA effect.
The content of the invention
A kind of new PET/MRI bimodal probes are provided it is an object of the invention to overcome drawbacks described above, the spy
Needle set has good stability and biocompatibility, can be circulated in intravital blood, is provided for the imaging of PET/MRI bimodals good
Good basis.
To achieve the above object, the technical scheme taken of the present invention is:A kind of compound SPIO-NOTA-68Ga。
In addition, the invention discloses compound SPIO-NOTA-68Ga preparation method:Using68Ga is to precursor SPIO-
PEG2000- NOTA carries out radioactive label, produces compound SPIO-NOTA-68Ga。
68Ga(T1/2=68min, β+=89%, EC=11%) as excellent positron imaging nucleic, its can directly by68Ge/68Prepared by Ga generators, easy to operate, half-life period 68min, blood understands that soon, the radiation that patient is subject to is less,68Ga ions
Radius (0.062nm) size is suitable, is adapted to NOTA three azo-cycle part holes, product thermodynamics and power that the two chelating is formed
Learn stability higher, can keep complete for a long time in vivo, therefore present inventor uses68Ga carries out radioactivity mark to SPIO
Note, obtains compound SPIO-NOTA-68Ga。
It is preferred that, precursor SPIO-PEG2000- NOTA preparation method is:Use PEG2000NOTA is coupled by the SPIO of modification
Enter Nanosurface, produce precursor SPIO-PEG2000-NOTA。
Positron radionuclide and MRI contrast agent are combined to form a kind of new imaging by present inventor based on SPIO
Probe, it uses polyethyleneglycol derivative (PEG2000) modification SPIO using the amino on surface by bifunctional chelating agent 1,4,7-
Three azo-cycle nonanes-Isosorbide-5-Nitrae, 7- triacetic acids (Isosorbide-5-Nitrae, 7-triazacyclononane-1,4,7-triacetic acid, NOTA) are even
Nanosurface is connected to, labelled precursor SPIO-PEG is obtained2000-NOTA。
It is preferred that, precursor SPIO-PEG2000- NOTA preparation method comprises the following steps:(1) NOTA-NHS is dissolved in
In deionized water, stir and evenly mix, be completely dissolved to NOTA-NHS;(2) by SPIO-PEG2000-NH2It is dissolved in deionized water, adds
NaOH adjusts PH to alkalescent;(3) SPIO-PEG for adding the NOTA-NHS dissolved in step (1) in step (2)2000-
NH2In solution, heating, ultrasound, reaction end produce precursor SPIO-PEG2000-NOTA。
It is preferred that, NaOH regulations PH to 9.0-10.0 is added in step (2).
It is preferred that, heating-up temperature is 40 DEG C in step (3), and ultrasonic time is 5min.
It is preferred that, precursor SPIO-PEG2000- NOTA preparation method also include step (4) using super filter tube purify, from
The heart, that is, obtain pure precursor SPIO-PEG2000-NOTA。
It is preferred that, the size of super filter tube is 30K, and centrifugation time is 24h.
In addition, the invention discloses compound SPIO-NOTA-68Purposes of the Ga in clinical tumor diagnosis.
It is preferred that, SPIO-NOTA-68Purposes of the Ga in the imaging of PET/MRI bimodals.
The beneficial effects of the present invention are:Compound SPIO-NOTA- of the present invention68Ga have very high radiochemicsl purity,
Good vitro stability and water solubility, is conducive to SPIO-NOTA-68Blood circulations of the Ga in mouse live body, is intravital
Biodistribution provides the foundation.SPIO-NOTA- of the present invention68Ga preparation method, by connecting big ring on SPIO surfaces
Part NOTA, successfully synthesizes labelled precursor SPIO-PEG2000- NOTA, and use positron-emitting radionuclides68Ga is carried out to it
Mark, this reaction generated time is shorter (10min), and reactions steps are simple, one-step synthesis, mild condition (70 DEG C), and mark
Rate is up to 99%, next step experiment is can be used to without being further purified, with the potential quality for being converted into clinical practice.
Brief description of the drawings
Fig. 1 is labelled precursor SPIO-PEG2000- NOTA synthetic route;
Fig. 2 is product SPIO-NOTA-68Ga synthetic route;
Fig. 3 is SPIO-PEG2000Particle diameter and pattern (TEM) figure of-NOTA nano-particles;
Fig. 4 is SPIO-PEG2000-NH2And SPIO-PEG (a)2000- NOTA (b) hydration kinetics diameter distribution profile;
Fig. 5 is SPIO-PEG2000-NH2And SPIO-PEG (a)2000- NOTA (b) Zeta potential figure;
Fig. 6 is SPIO-PEG2000-NH2(a)、SPIO-PEG2000- NOTA (b) infrared spectrogram;
Fig. 7 is SPIO-PEG2000- NOTA hysteresis curve, wherein abscissa are external magnetic field strength, and ordinate is nanoparticle
The sub- intensity of magnetization;
Fig. 8 is product SPIO-NOTA-68Ga ITLC collection of illustrative plates;
Fig. 9 is SPIO-NOTA-68Stability of the Ga in PBS and calf serum (FBS) compares figure, when wherein abscissa is
Between, ordinate is radiochemical purity;
Figure 10 is SPIO-NOTA-68Ga is in the internal distribution map (n=3) of normal kunming mice, and wherein abscissa is followed successively by
Blood, heart, lung, liver, spleen, kidney, stomach, duodenum, pancreas gland, brain, muscle, bone, skin;
Embodiment
To better illustrate the object, technical solutions and advantages of the present invention, below in conjunction with specific embodiment and accompanying drawing pair
The present invention is described further.
1. materials and methods
1.1 reagents and instrument
SPIO-PEG2000-NH2(1mg/ml, Nanjing Xian Feng Nono-material Science & Technology Ltd.), NOTA-NHS (France
CHEMATECH companies), (the Shanghai lark waffle skill such as watery hydrochloric acid (12.5mol/L, Merck KGaA company) sodium acetate, glacial acetic acid
Art Co., Ltd), MEM nutrient solutions, hyclone, 0.25% trypsase, PBS liquid etc. (Gibco companies of the U.S.), normal Kunming
Mouse, male, 18~22g (Nanfang Medical Univ's Experimental Animal Center).
JEM-200CX transmission electron microscopes (Japanese JEOL companies), (Britain Malvern is public for NanoZS nano particle sizes potentiometer
Department), vibrating specimen magnetometer VSM 7407 (Lakeshore companies of the U.S.), IRAffinity-1 Fourier transform infrared spectroscopies
Instrument (Japanese SHIMADAZU companies), germanium-gallium generator (German ITG companies), Radio-TLC (Japanese Shimadzu Corporation), FC-
3200 radiation monitos (Bioscan companies of the U.S.), (Shanghai core institute day ring photoelectric instrument has SN-695 γ radiation immunity arithmometers
Limit company), DF-101S heat collecting types constant-temperature heating magnetic stirring apparatus (Yuhua Instrument Co., Ltd., Gongyi City), water-bath (on
The grand experimental facilities Co., Ltd DK-S22 types of Nereid);Electronic balance (Switzerland Mettlertoledo).
1.2 precursor SPIO-PEG2000- NOTA synthesis
Precursor SPIO-PEG2000- NOTA synthetic route is shown in Fig. 1.3mgNOTA-NHS is taken to be dissolved in appropriate amount of deionized water
In, stir and evenly mix, treat that NOTA-NHS is completely dissolved;Take magnetic nano particle (SPIO-PEG2000-NH2) 5mg is soluble in water, add
NaOH adjusts PH to 9.0;Logical N2, the NOTA-NHS dissolved is added in the nano particle for mixing up PH, heats 40 DEG C, ultrasound point
5min is dissipated, is stirred overnight, reacts and stops after reaction 24h;Purified using super filter tube (30K), centrifuge 24h, obtain labelled precursor
SPIO-PEG2000-NOTA。
1.3 fundamental propertys are detected
1.3.1 transmission electron microscope (TEM) is determined:Take appropriate SPIO-PEG2000- NOTA nano-particles are ground, with ethanol
Make after dispersant, ultrasonic disperse, take partial suspended liquid to be placed in copper mesh, spontaneously dry, seen using high resolution transmission electron microscopy
Survey form, the particle diameter of particle.
1.3.2 dynamic light scattering (DLS) is detected:Take 1% (ω/V) SPIO-PEG2000-NH2And SPIO-PEG2000-
The NOTA aqueous solution is added in quartz colorimetric utensil, using 633nm He/Ne laser in NanoZS nano particle size potentiometric analyzer samples
Measure is scanned in room.
1.3.3Zeta potential measurement:SPIO-PEG is measured using NanoZS nano particle sizes potentiometric analyzer2000-NH2And
SPIO-PEG2000- NOTA current potentials.
1.3.4 magnetometric analysis:Take appropriate SPIO-PEG2000-NH2And SPIO-PEG2000- NOTA loads about 7mm cotton swab pipe
In, sealing two ends are tested in vibrating specimen magnetometer (VSM 7407) sample chamber.
1.3.5 Fourier transform infrared spectroscopy (FT-IR) is determined:Take the SPIO-PEG after appropriate freeze2000-NH2And
SPIO-PEG2000After-NOTA powder is mixed with KBr respectively, tabletting is ground, is determined in IRAffinity-1 sample chambers.
1.4SPIO-NOTA-68Ga preparation
Product SPIO-NOTA-68Ga synthetic route is shown in Fig. 2.Take the SPIO- that 200 μ lFe concentration are 1mg/ml
PEG2000- NOTA adds the 68Ga (148MBq) that 500 μ l0.05N watery hydrochloric acid are eluted in the small reaction bulbs of 2ml, then adds
Enter 32.5 μ l sodium acetates (1mol/L), after being vortexed uniformly, 10min is reacted under the conditions of 70 DEG C, mark is completed.
The measure of 1.5 mark rates
Mark rate is determined using instant thin-layer chromatography method (ITLC).Take 2 μ l react liquid spotting in ITLC-SG paper (10mm ×
On 150mm), the ascending development in ultra-pure water dries in air naturally.It is scanned with Bioscan radio thin layer's scanners,
Calculate mark rate (%).
1.6 estimation of stability
100ul reaction solutions are taken, 500 μ l calf serum and 500 μ l PBS (pH=7.24,0.02mol/ is added separately to
L in).Incubation 0.5,1,1.5,2h in 37 DEG C of water bath are placed in, takes about 2ul sample ITLC methods to survey respectively at different time points
Its fixed radiochemicsl purity, in triplicate, averages.
1.7 lipids are determined
10 μ l reaction solutions are taken, (containing 500 μ l n-octyl alcohols and 500 μ l PBS), to be sealed in 1.5ml centrifuge tubes with glued membrane respectively,
After abundant vortex 2min, high speed centrifugation 3min (10000rpm/min), to biphase equilibrium.It is each from organic phase and aqueous phase with liquid-transfering gun
Sample 10 μ l to be placed in two V counter tubes, measure its radiocounting.Lipid (logP) is calculated as follows.Weight
It is measured by sampling 3 times, averages again.
LogP=log (cts n-octyl alcohols/cts PBS), wherein, cts n-octyl alcohols and cts PBS are respectively n-octyl alcohol and PBS
In γ count.
Bio distribution in 1.8 normal mouse bodies
100 μ l reaction solutions (7.4MBq) are taken respectively, are entered through tail vein injection in 12 Kunming mouse bodies, respectively at after injection
After 5min, 30min, 60min, 120min eyeball venous blood sampling, disconnected neck is put to death and dissected, take respectively blood, heart, lung, liver,
The organ or tissues such as spleen, kidney, stomach, small intestine, pancreas, brain, muscle, bone, skin, are weighed, and γ is counted, after correction for attenuation
Determine the percentage injection dose rate (%ID/g) of its per gram of tissue.
1.9 interpretations of result and processing statistical analysis application SPSS13.0 software kits, continuous data mean ± standard deviationRepresent, figure is made using GraphPad Prism 5.0 and obtained.
2. conclusion
2.1 precursor SPIO-PEG2000- NOTA synthesized reference JarrettBR report, by the SPIO- of design
PEG2000-NH2A large amount of amino are contained in end, and it enters with the carbonyl (dissociateing free carboxy under alkalescence condition) on NOTA-NHS esters
Row reaction, as shown in Fig. 1 red lines, obtains precursor SPIO-PEG2000-NOTA.This reactions steps is simple, mild condition, quick, high
Effect.
2.2 basic characterize are detected
2.2.1 precursor SPIO-PEG2000- NOTA is dissolved in ultra-pure water, is light brown clear solution.
2.2.2 precursor SPIO-PEG2000- NOTA transmission electron microscopes (TEM) image be shown under Fig. 3, Electronic Speculum nanometer particle size be 8~
12nm or so, it is spherical in shape, it is uniform in size, disperse homogeneous.
2.2.3DLS before analysis result such as Fig. 4, connection NOTA the DLS figures of (a) and (b) afterwards be illustrated as it is unimodal, before connection
Darwin's particle diameter of nanometer about 34nm and 89nm respectively, is connected into after NOTA, Darwin's particle diameter is significantly increased afterwards, and distribution compared with
It is narrow.
2.2.4Zeta current potential result such as Fig. 5, is connected (a) and rear (b) before NOTA, because a large amount of amino of Nanosurface are carboxylic
Base is replaced, and current potential forms upset (11.6mV~-29mV).
2.2.5 infrared spectrum (curve b) 1632.2cm after infrared detections such as Fig. 6, NOTA modification-1Place is (red in Fig. 6 b
Line) occur in that new absworption peak, it is considered to it is by newly forming the N-H flexural vibrations in amido link in NH-CO and C-N stretching vibration
Interact and produce.
2.2.6 magnetometric analysis result such as Fig. 7, magnetic hysteresis loop shows, increases with external magnetic field strength, the nano-particle intensity of magnetization
Increase, when additional magnetic intensity reaches certain value (2000Oe), magnetic intensity speedup tends to be slow, gradually up to magnetic saturation state.SPIO-
PEG2000- NOTA specific saturation magnetizations are 56.04emu/g, with good superparamagnetism, point out this precursor can be as MRI
The potentiality of developer.
2.3 mark rates are determined
Marked product SPIO-NOTA-68After Ga is separated through ITLC, detected, as a result such as Fig. 8, shown with thin layer radioactive scanning instrument
Show in this expansion system, SPIO-NOTA-68Ga is retained in origin nearby (Rf is 0~0.1), free68Ga ions are with solvent
Chromatographic paper forward position is moved to, its Rf is 0.8~1.0, and it is about 99% that system automatic integration, which measures its mark rate,.
2.4 estimation of stability
In the environment of 37 DEG C, product SPIO-NOTA-68Ga is incubated 0.5 respectively in PBS and FBS, 1,1.5, after 2h, use
Radio-TLC determines its radiochemical purity, as a result sees Fig. 9.Known by figure, until 120min, SPIO-NOTA-68Ga no matter
Good stability is respectively provided with PBS or FBS, radiochemicsl purity shows that it has good stabilization in vitro more than 95%
Property
2.5 lipid
SPIO-NOTA-68Ga lipid log P=-2.60 ± 0.13 (n=3), shows as hydrophily.This with
Its surface modification has a large amount of PEG relevant, and its water-wet behavior can improve the distribution operating of nanometer in vivo, during extension body-internal-circulation
Between.
Biodistribution in 2.6 normal mouse bodies
SPIO-NOTA-68Ga is shown in Figure 10 and table 1 in normal kunming mice vivo biodistribution distributed data, as a result shows SPIO-
NOTA-68Ga is mainly liver and spleen intake, and with time lengthening, intake is increased, and 120min reaches highest.Rarely seen a small amount of radiation in kidney
Property accumulation, with time lengthening, radioactivity substantially lowers.Probe in blood clean up speed quickly, with time lengthening, in blood
Radioactivity substantially lower.Obvious intake is showed no in other organs.
The SPIO-NOTA- of table 168Internal distribution results of the Ga in normal kunming mice
3. Analysis of conclusion
This experiment is prepared for the labelled precursor SPIO-PEG of excellent aqueous solubility2000-NOTA.Pass through the means table such as TEM, DLS
Levy, show the precursor pattern prepared preferably, good dispersion, particle diameter is small and homogeneous, the SPIO-PEG that this experiment is measured2000-NOTA
TEM particle diameters for 10nm or so, DLS particle diameters reach 89nm, and it is consistent with document description, and what is measured mainly due to Electronic Speculum is granular core
Heart particle diameter, and the measurement of nano particle size instrument is hydration particle diameter, contains the water-soluble coating of nanometer outer layer.Relaxation rate test shows
The nano particle of gained has higher r2 relaxation rates, can be used as the good platform for building PET/MRI bimodal developers.Shi Xudong
Etc. using64Cu is marked to SPIO-DOPA-PEG-DOTA/RGD, has obtained PET/MRI bimodal probe, but it is marked
Note rate is relatively low, and only 71%, it is necessary to which DTPA is further purified;Madru R are used99TcmSPIO is marked, is obtained
SPECT/MRI bimodals probes is used for lymph node imaging;It is rare to use68Ga marks SPIO report, and this research is used68Ga marks SPIO obtains SPIO-NOTA-68Ga, this reaction generated time is shorter (10min), and reactions steps are simple, and a step is closed
Into, mild condition (70 DEG C), and mark rate is up to 99%, next step experiment is can be used to without being further purified, with conversion
For the potential quality of clinical practice.
SPIO-NOTA-68Ga is demonstrated by very high radiochemicsl purity in PBS and FBS, shows that it has well external
Stability, is that further vivo biodistribution evaluation is had laid a good foundation.PEG is modified with because this receives detecting probe surface, its
Surface hydrophilic, kernel lipophilic, good water solubility and biocompatibility are conducive to blood circulation of the nanometer in mouse live body, are
Intravital biodistribution provides the foundation.
Distribution is shown in normal mouse body, radioactive uptake highest ((31.87 ± 2.89) %ID/g) in 5min in blood,
Decline rapidly with time lengthening, during 30min reach ((2.85 ± 0.82) %ID/g), 120min be down to ((1.83 ±
0.72) %ID/g) show that it is cleaned up rapidly in blood;Radioactively labelled substance is mainly gathered in liver and spleen, and prolongs with the time
Long, radioactive uptake is further raised, and 120min reaches highest, and liver is ((68.00 ± 7.78) %ID/g), and spleen is
((52.24 ± 8.32) %ID/g);And the intake of other organs is relatively low, show that the label is mainly metabolized by liver, spleen.
Bio distribution and metabolic pathway are basically identical in this nanometer body with particle diameter < 100nm.Reticuloendothelial system (RES, including liver
Dirty, spleen, lung and myeloid tissue) containing abundant macrophage, the nanometer of particular size can be swallowed as foreign matter, be retained in liver and spleen
Deng in internal organs.100~200nm of LaurentS report particle diameters particle is clear by the macrophage phagocytosis of reticuloendothelial system quickly
Remove, in the lysosome for reaching Kupffer Schwann Cells;50~100nm of particle diameter particles can enter liver parenchyma, then main point of < 50nm
It is distributed in spleen and marrow, SPIO-NOTA- in the present invention68Ga particle diameter is about 89nm, therefore mainly by liver, splenic uptake.
4. conclusion
By connecting macrocyclic ligand NOTA on SPIO surfaces, labelled precursor SPIO-PEG is successfully synthesized2000- NOTA, and
Use positron-emitting radionuclides68Ga is marked to it, reaction time 10min, 70 DEG C of reaction temperature, and mark rate is reachable
99%.The label has higher vitro stability and with good water solubility.Biodistribution in normal mouse body
Disclose it to be mainly metabolized by liver and spleen, imaged available for follow-up PET/MRI bimodals.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than the present invention is protected
The limitation of scope is protected, although being explained in detail with reference to preferred embodiment to the present invention, one of ordinary skill in the art should
Understand, technical scheme can be modified or equivalent substitution, without departing from the essence of technical solution of the present invention.
Claims (10)
1. a kind of compound SPIO-NOTA-68Ga。
2. a kind of preparation method of compound as claimed in claim 1, it is characterised in that use68Ga is to precursor SPIO-
PEG2000- NOTA carries out radioactive label, produces compound SPIO-NOTA-68Ga。
3. the preparation method of compound as claimed in claim 2, it is characterised in that the precursor SPIO-PEG2000- NOTA system
Preparation Method is:Use PEG2000NOTA is coupled into Nanosurface by the SPIO of modification, produces precursor SPIO-PEG2000-NOTA。
4. the preparation method of compound as described in Claims 2 or 3, it is characterised in that the precursor SPIO-PEG2000- NOTA's
Preparation method comprises the following steps:(1) NOTA-NHS is dissolved in deionized water, stirred and evenly mixed, it is completely molten to NOTA-NHS
Solution;(2) by SPIO-PEG2000-NH2It is dissolved in deionized water, adds NaOH and adjust PH to alkalescent;(3) will be molten in step (1)
The SPIO-PEG that the NOTA-NHS solved is added in step (2)2000-NH2In solution, heating, ultrasound, reaction end produce precursor
SPIO-PEG2000-NOTA。
5. the preparation method of compound as claimed in claim 4, it is characterised in that NaOH regulations PH is added in the step (2)
To 9.0-10.0.
6. the preparation method of compound as claimed in claim 4, it is characterised in that heating-up temperature is 40 DEG C in the step (3),
Ultrasonic time is 5min.
7. the preparation method of compound as claimed in claim 4, it is characterised in that the precursor SPIO-PEG2000- NOTA system
Preparation Method is also included step (4) and is purified, centrifuged using super filter tube, that is, obtains pure precursor SPIO-PEG2000-NOTA。
8. the preparation method of compound as claimed in claim 7, it is characterised in that the size of the super filter tube is 30K, during centrifugation
Between be 24h.
9. purposes of the compound as claimed in claim 1 in clinical tumor diagnosis.
10. purposes as claimed in claim 9, it is characterised in that the SPIO-NOTA-68Ga is imaged in PET/MRI bimodals
In purposes.
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