Prostate cancer pet diagnostic reagent 68 ga-dota-ancp-psma and its preparation method and application

Abstract

The invention discloses a prostate cancer PET diagnostic reagent 68 Ga-DOTA-ANCP-PSMA and its preparation method and application. said 68 The structural formula of Ga-DOTA-ANCP-PSMA is as follows: the preparation method comprises the following steps: (S1) adopting solid phase synthesis method to synthesize precursor compound DOTA-ANCP-PSMA; (S2) using direct labeling method to carry out 68 Ga radiolabeled. said 68 Ga‑DOTA‑ANCP‑PSMA has the characteristics of fast labeling speed and high labeling rate, and also has the advantages of good stability, good hydrophilicity, high sensitivity and high specificity. in addition, 68 Ga‑DOTA‑ANCP‑PSMA clears faster in blood and has higher tumor uptake.

Description

technical field

[0001] The invention belongs to the field of medicine, in particular to a prostate cancer PET diagnostic reagent 68 Ga-DOTA-ANCP-PSMA and its preparation method and application. Background technique

[0002] Prostate cancer is the most common malignant tumor in men. As of 2018, there were 427,500 new cases worldwide every year, and the annual death toll from prostate cancer reached 361,800. It is the second most common male cancer and the fifth most fatal. high cancer. Prostate-specific antigen (PSA) screening can provide early diagnosis for most patients, but for some patients with high-risk or metastatic lesions, it cannot give an accurate diagnosis. Early and accurate diagnosis and staging are crucial for choosing effective treatment. Traditional imaging methods such as computed tomography (CT) and nuclear magnetic resonance (MRI) have certain defects, especially at low PSA levels, and the rate of missed diagnosis and misdiagnosis is high. The use of p...

Examples

Embodiment 1

[0041] This embodiment provides a prostate cancer PET diagnostic reagent 68 The preparation method of Ga-DOTA-ANCP-PSMA, described method comprises the steps:

[0042] (S1) Synthesizing the precursor compound DOTA-ANCP-PSMA by solid phase synthesis;

[0043] Preparation of compound 3

[0044] The synthetic route is shown below. Using Fmoc-Lys(Dde)-Wang Resin (compound 1) as the starting material, weigh 3g of the raw material with a substitution degree of 0.3mmol / g, add it to the reactor, add DMF, and soak for 30min. Then drain the DMF, add 3 times the volume of 20% Pip / DMF, and fill with nitrogen gas to remove Fmoc, react for 30 minutes, drain the 20% Pip / DMF, wash with DMF 5 times, and the ninhydrin detection shows dark blue. Add N,N'-succinimidyl carbonate (DSC), N,N-diisopropylethylamine (DIPEA) and 4-dimethylaminopyridine (DMAP) in proportion, and the input ratio is resin:DSC: DIPEA:DMAP=1:6:12:1, add an appropriate amount of DMF, and react for 1 h under the protection ...

Embodiment 2

[0058] In vitro stability assay:

[0059] 68 The radiochemical stability of Ga-DOTA-ANCP-PSMA was carried out in two systems of calf serum and phosphate buffer. PBS method: placed in 0.5mL phosphate buffer solution (PBS, pH=7.4), placed at 37°C, incubated for 30, 60, 90, 120, and 150min, and then measured its radiochemical purity by HPLC to determine its in vitro stability. Serum method: place in 0.5mL calf serum solution, incubate at pH=7, 37°C. When incubated for 30, 60, 90, 120, and 150 min, the radiochemical purity was determined by HPLC to determine its in vitro stability.

[0060] according to Figure 4 The results showed that from 30 minutes to 150 minutes, the radiochemical purity decreased slightly, but the stability remained above 95%. 68 Ga-DOTA-ANCP-PSMA has good stability in PBS system. In the serum system, from 30 minutes onwards, the radiochemical purity decreased to a certain extent, and the radiochemical purity was lower than 95% in 1.5 hours. 68 The st...

Embodiment 3

[0062] Measurement of lipid-water partition coefficient:

[0063] Mark 68Ga-DOTA-ANCP-PSMA was separated and purified by Sep-Pak C18 Cartridge, and eluted with 95% ethanol. The obtained marker was blown dry by dry nitrogen, and the obtained marker was dissolved in a 1.5mL EP tube (about 3.7MBq) using the same volume (0.5mL: 0.5mL) of n-octanol and phosphate buffer solution (pH=7.4) middle. Fully shake for 5 minutes, and centrifuge the layers in a centrifuge for 5 minutes at a speed of 2000 rpm. Take 100uL each of the organic phase and the aqueous phase in 1mL EP tubes, measure their radioactive counts in the well-type γ detector, and calculate the lipid-water partition coefficient P from the ratio of the radioactive counts of the organic phase and the aqueous phase. P=log (N O / N W )(N O and N W are the counts of the organic and aqueous phase samples, respectively). The operation was repeated 3 times, and the average value was taken as the lipid-water partition coeffic...

technical field

[0001] The invention belongs to the field of medicine, in particular to a prostate cancer PET diagnostic reagent 68 Ga-DOTA-ANCP-PSMA and its preparation method and application. Background technique

[0002] Prostate cancer is the most common malignant tumor in men. As of 2018, there were 427,500 new cases worldwide every year, and the annual death toll from prostate cancer reached 361,800. It is the second most common male cancer and the fifth most fatal. high cancer. Prostate-specific antigen (PSA) screening can provide early diagnosis for most patients, but for some patients with high-risk or metastatic lesions, it cannot give an accurate diagnosis. Early and accurate diagnosis and staging are crucial for choosing effective treatment. Traditional imaging methods such as computed tomography (CT) and nuclear magnetic resonance (MRI) have certain defects, especially at low PSA levels, and the rate of missed diagnosis and misdiagnosis is high. The use of p...

Examples

Embodiment 1

[0041] This embodiment provides a prostate cancer PET diagnostic reagent 68 The preparation method of Ga-DOTA-ANCP-PSMA, described method comprises the steps:

[0042] (S1) Synthesizing the precursor compound DOTA-ANCP-PSMA by solid phase synthesis;

[0043] Preparation of compound 3

[0044] The synthetic route is shown below. Using Fmoc-Lys(Dde)-Wang Resin (compound 1) as the starting material, weigh 3g of the raw material with a substitution degree of 0.3mmol / g, add it to the reactor, add DMF, and soak for 30min. Then drain the DMF, add 3 times the volume of 20% Pip / DMF, and fill with nitrogen gas to remove Fmoc, react for 30 minutes, drain the 20% Pip / DMF, wash with DMF 5 times, and the ninhydrin detection shows dark blue. Add N,N'-succinimidyl carbonate (DSC), N,N-diisopropylethylamine (DIPEA) and 4-dimethylaminopyridine (DMAP) in proportion, and the input ratio is resin:DSC: DIPEA:DMAP=1:6:12:1, add an appropriate amount of DMF, and react for 1 h under the protection ...

Embodiment 2

[0058] In vitro stability assay:

[0059] 68 The radiochemical stability of Ga-DOTA-ANCP-PSMA was carried out in two systems of calf serum and phosphate buffer. PBS method: placed in 0.5mL phosphate buffer solution (PBS, pH=7.4), placed at 37°C, incubated for 30, 60, 90, 120, and 150min, and then measured its radiochemical purity by HPLC to determine its in vitro stability. Serum method: place in 0.5mL calf serum solution, incubate at pH=7, 37°C. When incubated for 30, 60, 90, 120, and 150 min, the radiochemical purity was determined by HPLC to determine its in vitro stability.

[0060] according to Figure 4 The results showed that from 30 minutes to 150 minutes, the radiochemical purity decreased slightly, but the stability remained above 95%. 68 Ga-DOTA-ANCP-PSMA has good stability in PBS system. In the serum system, from 30 minutes onwards, the radiochemical purity decreased to a certain extent, and the radiochemical purity was lower than 95% in 1.5 hours. 68 The st...

Embodiment 3

[0062] Measurement of lipid-water partition coefficient:

[0063] Mark 68Ga-DOTA-ANCP-PSMA was separated and purified by Sep-Pak C18 Cartridge, and eluted with 95% ethanol. The obtained marker was blown dry by dry nitrogen, and the obtained marker was dissolved in a 1.5mL EP tube (about 3.7MBq) using the same volume (0.5mL: 0.5mL) of n-octanol and phosphate buffer solution (pH=7.4) middle. Fully shake for 5 minutes, and centrifuge the layers in a centrifuge for 5 minutes at a speed of 2000 rpm. Take 100uL each of the organic phase and the aqueous phase in 1mL EP tubes, measure their radioactive counts in the well-type γ detector, and calculate the lipid-water partition coefficient P from the ratio of the radioactive counts of the organic phase and the aqueous phase. P=log (N O / N W )(N O and N W are the counts of the organic and aqueous phase samples, respectively). The operation was repeated 3 times, and the average value was taken as the lipid-water partition coeffic...

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