CN108570081A - The ligand compound and preparation of a kind of glucose diagnostic imaging and treatment and application - Google Patents
The ligand compound and preparation of a kind of glucose diagnostic imaging and treatment and application Download PDFInfo
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Abstract
The present invention provides a kind of glucose diagnostic imaging and the ligand compound for the treatment of, belongs to diagnosing tumor and treatment technology field.The ligand compound is served as reasons177What Lu and labelled precursor DOTA DG was chelated177Lu DOTA DG, general structure is as shown in following formula I：The present invention also provides the preparation methods of ligand compound, including：1) synthesis of labelled precursor DOTA DG：The pH for adjusting D glucosamine HCLs, is slowly dropped into DOTA NHS reagents, is stirred at room temperature to reaction and terminates, reaction solution is added to bag filter, is dialysed in distilled water after being stirred at room temperature, be lyophilized up to DOTA DG；2) ligand compound177The synthesis of Lu DOTA DG：It will177Lu and above-mentioned freshly prepared DOTA DG fully vibrates mixing, reacts in water-bath after adjusting pH and can be obtained for a period of time177Lu‑DOTA‑DG.DOTA DG are tumor-seeking agent object, with177Lu is chelated to177After Lu DOTA DG, it can be absorbed by tumor cell specific, diagnosing tumor and treatment are combined as a whole, reduce radiopharmaceutical injection number to reduce patient radiation dose.
Description
Technical field
The invention belongs to tumor imaging diagnostic techniques field, the ligand of specially a kind of glucose diagnostic imaging and treatment
Compound and preparation and application.
Background technology
In recent years, greatly developing with molecular image technology, traditional PET drugs18F-FDG and SPECT drugs99mTc-
MDP cannot meet the integrated clinical needs of diagnosis and treatment.177Lu is with its good physical property and takes into account molecular image diagnosis
The whole world attracts wide public concern with the characteristic for the treatment of.
Invention content
The purpose of the present invention is to provide a kind of glucose diagnostic imaging and the ligand compounds and preparation method for the treatment of.
Ligand compound of the present invention can be absorbed by tumor cell specific, be utilized177The biochemical property of Lu, can by diagnosing tumor with control
Treatment is combined as a whole, and can evaluate therapeutic effect, while reducing radiopharmaceutical injection number to a certain degree
Upper reduction patient radiation dose.
The object of the invention is achieved through the following technical solutions：
A kind of glucose diagnostic imaging and the ligand compound for the treatment of, the ligand compound are served as reasons177Lu and label before
Body DOTA-DG chelatings177Lu-DOTA-DG, general structure is as shown in following formula I：
The preparation method of a kind of glucose diagnostic imaging and the ligand compound for the treatment of, including labelled precursor DOTA-DG
Synthesis and ligand compound synthesis：
1) synthesis of labelled precursor DOTA-DG：The pH for adjusting D-Glucose amine hydrochlorate, is slowly dropped into after being stirred at room temperature
DOTA-NHS reagents, are stirred at room temperature to reaction and terminate, and reaction solution is added to bag filter, is dialysed in distilled water, freeze-drying is
Obtain DOTA-DG；
2) ligand compound177The synthesis of Lu-DOTA-DG：It will177Lu and above-mentioned freshly prepared DOTA-DG fully vibrate
Mixing, adjust pH after in water-bath reaction a period of time can be obtained177Lu-DOTA-DG。
One of preparation method as a kind of glucose diagnostic imaging of the present invention and the ligand compound for the treatment of
Specific embodiment, in step 1), the pH for adjusting D-Glucose amine hydrochlorate using sodium bicarbonate solution adjust pH to 8~
10；The molar ratio of the D-Glucose amine hydrochlorate and DOTA-NHS reagents is 1:1~2；The dialysis time is 24~72h.
One of preparation method as a kind of glucose diagnostic imaging of the present invention and the ligand compound for the treatment of
Specific embodiment, it is described in step 1)177The addition of Lu is 0.4mCi, and a concentration of 2.5mg/ml volumes of DOTA-DG are
50ul-100ul；It is described adjust pH using 0.1mol/L hydrochloric acid and 0.2mol/L sodium hydroxide adjust pH most 4.0~
7.5；The bath temperature is 90~100 DEG C, and the time is 30~60min.
One of preparation method as a kind of glucose diagnostic imaging of the present invention and the ligand compound for the treatment of
Specific embodiment includes the following steps：
1) synthesis of labelled precursor DOTA-DG：It takes 0.1mmol D-Glucose amine hydrochlorates to be dissolved in 5ml distilled water, uses
It is 8 that 0.01mol/L sodium bicarbonate solutions, which adjust PH, and 30min is stirred at room temperature, and 0.11mmol DOTA-NHS is taken to be dissolved in 1ml distillations
Water is slowly dropped into above-mentioned solution, is stirred at room temperature for 24 hours, reaction terminates；Reaction solution is added to bag filter, is dialysed in distilled water
48h is lyophilized up to DOTA-DG；
2) ligand compound177The synthesis of Lu-DOTA-DG：By 0.4mCi177Lu and above-mentioned freshly prepared DOTA-DG fill
Divide oscillation mixing, wherein177The pH of Lu is 6.0, DOTA-DG a concentration of 2.5mg/ml, volume 50ul, using 0.1mol/L salt
The sodium hydroxide of acid and 0.2mol/L adjust pH to 4.5, and 30min is reacted in 95 DEG C of water-baths and can be obtained177Lu-DOTA-DG。
The application of a kind of glucose diagnostic imaging and the ligand compound for the treatment of, the ligand compound is in tumor imaging
Application in antidiastole and treatment.
One of application as a kind of glucose diagnostic imaging of the present invention and the ligand compound for the treatment of is specific
Embodiment, application of the ligand compound in the antidiastole of innocent and malignant tumour image and treatment.
Compared with prior art, the invention has the advantages that：
In ligand compound of the present invention, DOTA-DG is tumor-seeking agent object, with177Lu is chelated to177It, can after Lu-DOTA-DG
To be absorbed by tumor cell specific, utilize177Diagnosing tumor and treatment can be combined as a whole by Lu biochemical properties, and can convection potential
Effect is evaluated, while reducing radiopharmaceutical injection number to reduce patient radiation dose to a certain extent.
Description of the drawings
Fig. 1 is the reaction time pair177The influence of Lu-DOTA-DG radiochemical purities.
Fig. 2 is pH value pair177The influence of Lu-DOTA-DG radiochemical purities.
Fig. 3 DOTA-DG dosages pair177The influence of Lu-DOTA-DG radiochemical purities.
Fig. 4 is injection1771h, 4h after Lu-DOTA-DG, 12h, for 24 hours, the normal rabbits SPECT/CT imaging figures of 3d, 4d.
Specific implementation mode
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
With reference to concrete principle and preparation process to the liganded of a kind of glucose diagnostic imaging of the present invention and treatment
It closes object and preparation and application is described in detail.
A kind of glucose diagnostic imaging and the ligand compound for the treatment of, the ligand compound are served as reasons177Lu and label before
Body DOTA-DG chelatings177Lu-DOTA-DG, general structure is as shown in following formula I：
177Lu receives people's favor due to its good physical property, as treatment with nucleic：It partly declines with longer
Phase (6.67d) can carry out tumor tissues the irradiation of long period to reach better therapeutic effect；Emit gamma-rays simultaneously
The moderate beta particle (0.49Mev) of (113~208Kev) and energy can be treated by Imaging Evaluation while treatment and be imitated
Fruit；Since mean range is shorter (≤670mm) in the tissue for it, when using it for treatment, it is possible to reduce to surrounding tissue
Damage.These features are based on,177Lu can be used for imaging monitoring and guiding treatment process, and patient can be reduced to be increased because of imaging
The drug dose added, so, the dose of radiation of receiving is also less.177Lu longer half-life period not only produces the quality of product for it
The selection of analysis and Control and nucleic production site provides a convenient, and can also reduce the pain that multiple injection is brought to patient.
With131I is compared,177The Beta-ray average energy that Lu discharges when decaying is lower, and the application of clinical treatment range is more extensive.
DOTA, that is, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid is chelate, can make with metal ion
With generation complex compound.DG is deoxyglucose.The D-Glucose amine hydrochlorate (D-Glucosamine hydrochloride) is taken to be
Raw material is reacted with DOTA-NHS reagent mixed liquors, is dialysed, that the glucose tumor metabolic imaged to get tumor metabolic is lyophilized is aobvious
As agent labelled precursor DOTA-DG.DOTA-DG is tumor-seeking agent object, with177Lu is chelated to177After Lu-DOTA-DG, tumour cell is special
Opposite sex intake, utilizes177Diagnosing tumor and treatment can be combined as a whole by Lu biochemical properties, and can evaluate curative effect, together
When reduce radiopharmaceutical injection number to reducing patient radiation dose to a certain extent.
From the ligand compound of the application,177Lu is main component, plays imaging and therapeutic effect, domestic at present to use
Developer all without therapeutic effect, tumour can be treated since it can not only be used as tumor imaging but also simultaneously, so in the whole world
Cause prodigious sensation, it is external at present to use177Lu had not only been imaged but also had been treated to prostate cancer and neuroendocrine tumor, was had been achieved with
Good effect；DOTA is an organic ligand, is for handle177Lu with DG huge legendary turtles together with, if without it, this
The two can't be a compound；DG is the drug as a cancer target, because tumor focus glucose uptake can increase
Height, when tumor uptake glucose, can by with glucose together huge legendary turtle and177Lu is absorbed together, that is, is absorbed177Lu-DOTA-
DG, at this time due to177The image displaying function of Lu, tumour will be shown at SPECT/CT；When only177Lu or177Lu-
When DOTA, it does not have targeting, although can make the light development such as skeleton, will not highlight tumor focus；Simple
Then either DOTA or the two combination will not then image only DG.
A kind of glucose diagnostic imaging and the ligand compound for the treatment of, including labelled precursor DOTA-DG synthesis and match
The synthesis of body compound, specifically includes following steps：
The synthesis of step 1) labelled precursor DOTA-DG
The pH for adjusting D-Glucose amine hydrochlorate, is slowly dropped into DOTA-NHS reagents, is stirred at room temperature to anti-after being stirred at room temperature
It should terminate, reaction solution is added to bag filter, is dialysed in distilled water, be lyophilized up to DOTA-DG.
Further, the pH for adjusting D-Glucose amine hydrochlorate adjusts pH to 8~10 using sodium bicarbonate solution；It is described
The molar ratio of D-Glucose amine hydrochlorate and DOTA-NHS reagents is 1:1~2；The dialysis time is 24~72h.
The preferred embodiment of this step is：It takes 0.1mmol D-Glucose amine hydrochlorates to be dissolved in 5ml distilled water, uses
It is 8 that 0.01mol/L sodium bicarbonate solutions, which adjust PH, and 30min is stirred at room temperature, and 0.11mmol DOTA-NHS is taken to be dissolved in 1ml distillations
Water is slowly dropped into above-mentioned solution, is stirred at room temperature for 24 hours, reaction terminates；Reaction solution is added to bag filter, is dialysed in distilled water
48h is lyophilized up to DOTA-DG.
2) ligand compound177The synthesis of Lu-DOTA-DG
It will177Lu and above-mentioned freshly prepared DOTA-DG fully vibrates mixing, when reacting one section in water-bath after adjusting pH
Between can be obtained177Lu-DOTA-DG。
Further, the addition of the 177Lu is 0.4mCi, a concentration of 2.5mg/ml of the DOTA-DG, and volume is
50ul-100ul；It is described adjust pH using 0.1mol/L hydrochloric acid and 0.2mol/L sodium hydroxide adjust pH most 4.0~
7.5；The bath temperature is 90~100 DEG C, and the time is 30~60min.
The preferred embodiment of this step is：0.4mCi 177Lu and above-mentioned freshly prepared DOTA-DG are fully vibrated
Mixing, the wherein pH of 177Lu are a concentration of 2.5mg/ml, the volume 50ul of 6.0, DOTA-DG, using 0.1mol/L hydrochloric acid and
The sodium hydroxide of 0.2mol/ adjusts pH to 4.5, and 30min is reacted in 95 DEG C of water-baths and can be obtained177Lu-DOTA-DG。
The application of a kind of glucose diagnostic imaging and the ligand compound for the treatment of, the ligand compound is in tumor imaging
Application in antidiastole and treatment.Further, the ligand compound is in the antidiastole of innocent and malignant tumour image and treatment
Application.
Ligand compound of the present invention,177Lu is main component, plays imaging and treatment is done, domestic imaging at present
Agent all without therapeutic effect, can treat since it can not only be used as tumor imaging but also simultaneously tumour, so causing very in the whole world
Big sensation, it is external at present to use177Lu had not only been imaged but also had been treated to prostate cancer and neuroendocrine tumor, was had been achieved for very well
Effect；Tumor focus glucose metabolism can increase, and when tumor uptake glucose, will can together be chelated with glucose177Lu
It absorbs, that is, absorbs together177Lu-DOTA-DG, at this time due to177The image displaying function of Lu, tumour will be at SPECT/CT
It shows, and177Lu has therapeutic effect, can have therapeutic effect to corresponding tumour simultaneously.
With reference to specific embodiment to the ligand compound and system of a kind of glucose diagnostic imaging of the present invention and treatment
Standby and application is further described.
The preparation of 1 glucose diagnostic imaging of embodiment and the ligand compound for the treatment of
The specific preparation process of the present embodiment glucose diagnostic imaging and the ligand compound for the treatment of is as follows：
1, the synthesis of labelled precursor DOTA-DG：It takes 0.1mmol D-Glucose amine hydrochlorates to be dissolved in 5ml distilled water, uses
It is 8 that 0.01mol/L sodium bicarbonate solutions, which adjust PH, and 30min is stirred at room temperature, and 0.11mmol DOTA-NHS is taken to be dissolved in 1ml distillations
Water is slowly dropped into above-mentioned solution, is stirred at room temperature for 24 hours, reaction terminates；Reaction solution is added to bag filter, is dialysed in distilled water
48h is lyophilized up to DOTA-DG；
2, ligand compound177The synthesis of Lu-DOTA-DG：By 0.4mCi177Lu and above-mentioned freshly prepared DOTA-DG fill
Divide oscillation mixing, wherein177The pH of Lu is a concentration of 2.5mg/ml, volume 50ul, using 0.1mol/L of 6.0, DOTA-DG
The sodium hydroxide of hydrochloric acid and 0.2mol/L adjust pH to 4.5, and 30 are reacted in 95 DEG C of water-baths and can be obtained177Lu-DOTA-DG。
The radio-chemical purity for the ligand compound product that the present embodiment is prepared is 99.442%.
Influence of 2 reaction temperature of embodiment to product emissions chemical purity
By second step ligand compound in embodiment 1177Bath temperature in the building-up process of Lu-DOTA-DG adjusts separately
For room temperature (25 DEG C), 50 DEG C and 95 DEG C, other operations are identical with embodiment 1, investigate different water-bath temperatures to product
The influence of radio-chemical purity.
Reaction time is affected to radiochemical purity.When reaction temperature is room temperature and 50 DEG C, TLC separation determinations
Radiopharmaceutical is located at origin,177Lu-DOTA-DG labelling experiments are failed；When reaction temperature is 95 DEG C, RCP has reached
99.228%, meet radiopharmaceutical requirement.Therefore, best reaction temperature is 95 DEG C.
Influence of 3 reaction time of embodiment to product emissions chemical purity
By second step ligand compound in embodiment 1177Water-bath time difference in the building-up process of Lu-DOTA-DG
It is adjusted to 10min, 20min, 30min, 1h, 2h, other operations are identical with embodiment 1, investigate different water-bath times
Influence to product emissions chemical purity.
Influence of the reaction time to radiochemical purity is as shown in Figure 1.It is not difficult to find out by Fig. 1, the reaction time is to activation
The influence for learning purity is relatively small.RCP has reached 95% or more when reaction time is 20min, meets wanting for radiopharmaceutical
Ask, when reacted between when being 30min RCP be more than 99%, as the time further extends, RCP is without obviously increasing.Therefore, most
Good water-bath time is 30min.
Influence of 4 pH value of embodiment to product emissions chemical purity
By second step ligand compound in embodiment 1177PH value in the building-up process of Lu-DOTA-DG is according to pH value of human body
It is 2.5,3.0,3.5,4.0,4.5,5.0,5.5,6.0,6.5,7.0,7.5,8.0 (totally 12 that (7.40 ± 0.05), which adjust separately,
Point), other operations are identical with embodiment 1, investigate influence of the different pH value to product emissions chemical purity.
PH value pair177The influence for putting chemical purity of Lu-DOTA-DG is as shown in Figure 2.As seen from Figure 2, with reaction
System pH value increases,177The RCP of Lu-DOTA-DG constantly increases.When PH is greater than or equal to 4.0,177The RCP of Lu-DOTA-DG
Have been above 90%；When PH is 4.5,177The RCP of Lu-DOTA-DG is maximum, maximum value 98.428%；But with PH
Value continues to increase, and RCP starts to reduce, and when pH value increases to 8.0, RCP is less than 95%.When pH value is within the scope of 4.0-7.5,177The RCP of Lu-DOTA-DG is all higher than 95%, meets the requirement of radiopharmaceutical.Therefore, best ph value of reaction is 4.5.
5 DOTA-DG dosages of embodiment are to the influence to product emissions chemical purity
By second step ligand compound in embodiment 1177The addition body of DOTA-DG in the building-up process of Lu-DOTA-DG
Integral is not changed to 20ul, 30ul, 40ul, 50ul, 60ul, 70ul, 80ul, 90ul, 100ul, 110ul, 120ul, 130ul, examines
Examine influence of the different DOTA-DG dosages to product emissions chemical purity.
DOTA-DG dosages pair177The influence that Lu-DOTA-DG puts chemical purity is as shown in Figure 3.As seen from Figure 3, when
When DOTA-DG dosages >=20ul, RCP has been above 90%, and when DOTA-DG dosages are 50ul,177Lu-DOTA-DG reaches
To 98%, hereafter as DOTA-DG dosages further increase,177The RCP of Lu-DOTA-DG is maintained at 98% or so, is in then small
Amplitude downward trend.As DOTA-DG dosage ＞ 100ul,177The RCP of Lu-DOTA-DG is less than 95%.When DOTA-DG dosage mistakes
RCP is relatively low when big, it may be possible to which due to dissociating in reaction system at this time, colloid proportion is relatively large.Therefore, DOTA-DG dosages
50ul(177Lu 0.4mCi) the effect that can reach effect and cost and take into account.
6 ligand compound of embodiment177Lu-DOTA-DG vitro stabilities
Embodiment 1 is freshly prepared177Lu-DOTA-DG placed under room temperature (25 ± 2 DEG C) 1h, 4h, for 24 hours, 48h carry out
Point sample, TLC measure top coal drawing.Each time point detects 3 batches.The result shows that ligand compound prepared by embodiment 1177Lu-
The best stabilized phase at room temperature of DOTA-DG is 1~2 day.
7 ligand compound of embodiment177Lu-DOTA-DG is distributed in normal mouse body
18-22 grams of kunming mice of weight is grouped for experimental animal, by 0.2mCi/ dosage through tail vein injection embodiment
1 preparation177Lu-DOTA-DG ligand-complexes, 1 after injection, 4,24,48,72 hours and 6 days sacrificed by decapitation mouse, take blood and
Organ is weighed, and measures its radiocounting, calculates the percentage injection measurement rate (%ID/g) of per gram of tissue.Per gram of tissue is injected
Percentage dose (%ID/g)=(tissue CPM-B)/(T-B) × liver mass (g) { T:Gross activity counts, n=4；B：Background
Pipe radiocounting；CPM：Often pipe radiocounting }.The results are shown in Table 1.
Table 1177Organio biodistribution (X ± S) (%ID/g) in Lu-DOTA-DG normal mouse bodies
| 1h | 4h | 24h | 48h | 72h | 6d | |
| The heart | 0.75±0.28 | 0.07±0.01 | 0.16±0.05 | 0.06±0.01 | 0.93±0.02 | 0.04±0.03 |
| Liver | 0.96±0.18 | 0.61±0.39 | 0.29±0.10 | 0.08±0.04 | 0.06±0.02 | 0.22±0.28 |
| Spleen | 0.48±0.21 | 0.08±0.05 | 0.21±0.05 | 0.14±0.07 | 0.18±0.03 | 0.06±0.01 |
| Lung | 1.75±0.51 | 0.13±0.07 | 0.30±0.16 | 0.06±0.02 | 0.06±0.01 | 0.05±0.03 |
| Kidney | 10.89±3.10 | 2.32±1.88 | 1.73±0.85 | 1.38±0.64 | 1.02±0.24 | 0.20±0.02 |
| Intestines | 0.59±0.20 | 0.10±0.05 | 0.77±0.80 | 0.04±0.02 | 0.16±0.124 | 0.52±0.78 |
| Stomach | 1.01±0.33 | 0.47±0.22 | 0.24±0.16 | 0.83±0.47 | 0.55±0.35 | 0.91±0.50 |
| Muscle | 0.59±0.21 | 0.06±0.03 | 1.05±0.20 | 0.11±0.04 | 0.13±0.09 | 0.05±0.03 |
| Bone | 0.66±0.24 | 0.12±0.14 | 1.04±0.59 | 0.14±0.03 | 0.32±0.15 | 0.18±0.05 |
| Blood | 1.64±0.69 | 0.03±0.01 | 0.02±0.01 | 0.07±0.05 | 0.05±0.03 | 0.08±0.08 |
As can be seen from Table 1, normal kunming mice is through tail vein injection177Kidney uptake ratio is obviously high after Lu-DOTA-DG
In its hetero-organization, organ, kidney, blood lung increased radioactivity decline comparatively fast, and enteron aisle increased radioactivity is relatively low.
8 ligand compound of embodiment177Lu-DOTA-DG is imaged and is distributed in normal rabbits body
It is prepared to the auricular vein of normal rabbits injection embodiment 1177Lu-DOTA-DG ligand-complexes 4mCi/
Only, different time ligand compound is distributed in normal rabbit body after observation injection.Fig. 4 is injection1771h, 4h after Lu-DOTA-DG,
12h, for 24 hours, the normal rabbit SPECT/CT of 3d, 4d imaging figures.From the graph as can be seen that177Lu-DOTA-DG injects the rabbit after 1h
Imaging, it can be seen that kidney increased radioactivity increases, and is discharged into bladder radiation and increases, and appendicular skeleton and backbone can see that slightly
Increased radioactivity increases, and brain, lung, small intestine and muscle etc. have no that increased radioactivity increases；When to injection 4h, kidney, bladder, cranium
Bone, backbone and four limbs increased radioactivity further increase；To injection 12h, rabbit kidney, bladder, backbone and four limbs radioactivity part
It is reduced when distribution is compared with 4h；When to injection for 24 hours, further decreased when the imaging results of rabbit are compared with 12h；When to injection 3d, rabbit whole body is aobvious
As that can not see that apparent increased radioactivity increases part；To injection 4d when, when 3d compared with without significant change.It is entire aobvious
As process, brain, lung, small intestine, muscle etc. increase without apparent increased radioactivity.
Embodiment interpretation of result
Above-described embodiment the results show that177Lu-DOTA-DG marking operations are simple, and the time is short, need not be purified after label,
Mark rate measures simplicity, and label yield is high, and vitro stability is high, and plasma protein binding rate is low, in normal mouse organism
Distribution is consistent with normal rabbits image results.
The per gram of tissue percentage injection dose rate of major organs decreased significantly in 4 hours, the percentage injection of blood
Dosage rate declines rapidly in 4 hours, this177After patient may being needed to inject when the clinical imaging of Lu-DOTA-DG as early as possible into
Row SPECT/CT imagings.
Experiment is found177Lu-DOTA-DG is removed soon in vivo, and the percentage injection dose rate of kidney is apparently higher than other groups
It knits, organ, enteron aisle increased radioactivity is relatively low, illustrates that it is mainly drained through kidney with urine, but the high radioactivity of kidney may
The diagnosis compared with small lesion around kidney can be interfered.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
All any modification, equivalent and improvement etc., should all be included in the protection scope of the present invention made by within refreshing and principle.
Claims (7)
1. a kind of glucose diagnostic imaging and the ligand compound for the treatment of, which is characterized in that the ligand compound is served as reasons177What Lu and labelled precursor DOTA-DG was chelated177Lu-DOTA-DG, general structure is as shown in following formula I：
2. the preparation method of a kind of glucose diagnostic imaging and the ligand compound for the treatment of as described in claim 1, feature
It is, including the synthesis of labelled precursor DOTA-DG and the synthesis of ligand compound：
1) synthesis of labelled precursor DOTA-DG：The pH for adjusting D-Glucose amine hydrochlorate, DOTA- is slowly dropped into after being stirred at room temperature
NHS reagents, are stirred at room temperature to reaction and terminate, and reaction solution is added to bag filter, dialyses, is lyophilized in distilled water to obtain the final product
DOTA-DG；
2) ligand compound177The synthesis of Lu-DOTA-DG：It will177Lu and above-mentioned freshly prepared DOTA-DG fully vibrate mixing,
Reaction a period of time can be obtained in water-bath after adjusting pH177Lu-DOTA-DG。
3. the preparation method of a kind of glucose diagnostic imaging and the ligand compound for the treatment of as claimed in claim 2, feature
It is, in step 1), the pH for adjusting D-Glucose amine hydrochlorate adjusts pH to 8~10 using sodium bicarbonate solution；It is described
The molar ratio of D-Glucose amine hydrochlorate and DOTA-NHS reagents is 1:1~2；The dialysis time is 24~72h.
4. the preparation method of a kind of glucose diagnostic imaging and the ligand compound for the treatment of as claimed in claim 2, feature
It is, it is described in step 2)177The addition of Lu is 0.4mCi, and a concentration of 2.5mg/ml volumes of DOTA-DG are 50ul-
100ul；The pH that adjusts adjusts pH most 4.0~7.5 using the hydrochloric acid of 0.1mol/L and the sodium hydroxide of 0.2mol/L；It is described
Bath temperature is 90~100 DEG C, and the time is 30~60min.
5. the preparation method of a kind of glucose diagnostic imaging and the ligand compound for the treatment of as claimed in claim 2, feature
It is, includes the following steps：
1) synthesis of labelled precursor DOTA-DG：It takes 0.1mmol D-Glucose amine hydrochlorates to be dissolved in 5ml distilled water, uses
It is 8 that 0.01mol/L sodium bicarbonate solutions, which adjust PH, and 30min is stirred at room temperature, and 0.11mmol DOTA-NHS is taken to be dissolved in 1ml distillations
Water is slowly dropped into above-mentioned solution, is stirred at room temperature for 24 hours, reaction terminates；Reaction solution is added to bag filter, is dialysed in distilled water
48h is lyophilized up to DOTA-DG；
2) ligand compound177The synthesis of Lu-DOTA-DG：By 0.4mCi177Lu and above-mentioned freshly prepared DOTA-DG fully shake
Mixing is swung, wherein177The pH of Lu is a concentration of 2.5mg/ml, the volume 50ul of 6.0, DOTA-DG, using 0.1mol/L hydrochloric acid
PH to 4.5 is adjusted with the sodium hydroxide of 0.2mol/L, 30min is reacted in 95 DEG C of water-baths and can be obtained177Lu-DOTA-DG。
6. the application of a kind of glucose diagnostic imaging and the ligand compound for the treatment of as described in claim 1, which is characterized in that
Application of the ligand compound in tumor imaging antidiastole and treatment.
7. the application of a kind of glucose diagnostic imaging and the ligand compound for the treatment of as described in claim 1, which is characterized in that
Application of the ligand compound in the antidiastole of innocent and malignant tumour image and treatment.
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| CN116655715A (en) * | 2023-07-27 | 2023-08-29 | 北京炫景瑞医药科技有限公司 | GalNAc derivative, conjugate, composition and application thereof |
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| CN116655715A (en) * | 2023-07-27 | 2023-08-29 | 北京炫景瑞医药科技有限公司 | GalNAc derivative, conjugate, composition and application thereof |
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