TW201912184A - A radioactive labeling method for neuropeptide Y compounds and derivatives thereof - Google Patents

Abstract

The present invention relates to a method of radioactive labeling a neuropeptide Y compound and derivatives thereof. Since the neuropeptide receptor Y1 is highly expressed, it can be used as a diagnostic type radioactive medicine for breast cancer, and the neuropeptide Y is modified as a main body and labeling with the radioactive nuclei species 68Ga, 177Lu, 111In after bonding with a chelating agent to form a radiation medicine that can be used for animal model breast cancer image analysis.

Description

一種新穎神經肽Y(NPY)化合物及其衍生物與其放射線標誌方法Novel neuropeptide Y (NPY) compound and its derivative and its radiation marking method

本發明係有關一種乳癌診斷型放射線分子藥物，尤指以人類神經肽(NPY)為主體進行修飾，鍵結螯合劑後，標誌放射線核種⁶⁸ Ga、¹⁷⁷ Lu、¹¹¹ In，形成一放射線標靶藥物，進行乳癌動物模式影像分析。The invention relates to a diagnostic radioactive molecular medicine for breast cancer, in particular to a human neuropeptide (NPY) as a main body, and after binding a chelating agent, marking a radioactive nuclear species ⁶⁸ Ga, ¹⁷⁷ Lu, ¹¹¹ In to form a radioactive target drug , image analysis of breast cancer animal models.

根據衛生福利部之衛生及生命統計資料，104年臺灣十大死因以惡性腫瘤連續34年為首，占所有死亡人數的28.6%。其中，女性乳癌的死亡率在女性十大癌症死因排名第四，其癌症發生率高居女性癌症第一名，因此開發出有效的診斷方式將有助於乳癌治療，以降低台灣女性乳癌之死亡率。According to the health and vital statistics of the Ministry of Health and Welfare, the top ten causes of death in Taiwan in 104 years were led by malignant tumors for 34 consecutive years, accounting for 28.6% of all deaths. Among them, the mortality rate of female breast cancer ranks fourth among women's top ten cancer deaths, and its cancer incidence rate ranks first among female cancers. Therefore, the development of effective diagnostic methods will help breast cancer treatment to reduce the mortality rate of breast cancer in Taiwan. .

神經肽(Neuropeptide Y，NPY)是由36個胺基酸所組成的胜肽，其含有五種亞型受體主要分成Y1、Y2、Y4、Y5及Y6。NPY是一種廣泛存在於神經系統並調節體內代謝，例如:肥胖、壓力、疼痛以及血壓控制等。Neuropeptide Y (NPY) is a peptide consisting of 36 amino acids containing five subtype receptors mainly divided into Y1, Y2, Y4, Y5 and Y6. NPY is a widespread presence in the nervous system and regulates metabolism in the body, such as obesity, stress, pain, and blood pressure control.

根據2007年Ruscica的研究指出，NPY已被證實參與許多癌症之發展，包含細胞增生、血管生成(angiogenesis)與轉移。此外，有關乳腺癌的研究整理(Li, 2015)，許多學者利用NPY進行乳癌治療或診斷之相關研究(於下表)，且有相當之成就。因此，投入神經肽（NPY）診斷藥物的開發將會是未來治療惡性腫瘤疾病的新希望。According to a 2007 study by Ruscica, NPY has been shown to be involved in the development of many cancers, including cell proliferation, angiogenesis and metastasis. In addition, research on breast cancer (Li, 2015), many scholars use NPY for breast cancer treatment or diagnosis related research (in the table below), and have considerable achievements. Therefore, the development of diagnostic drugs for neuropeptide (NPY) will be a new hope for the future treatment of malignant tumor diseases.

近來羅氏、輝瑞以及默克等國際藥廠也投入神經肽Y與癌症相關研究，2001年 REUBI Jean-Claude提出新穎化合物與神經肽Y1受體結合，用以治療或診斷乳腺癌，卵巢癌和膠質母細胞瘤，，2013年Andreas等人更提出利用NPY相關胜肽作為預測未罹患癌症之女性罹患乳腺癌之風險評估方法。由學術研究與專利分析皆可觀察到NPY與癌症相關性的市場訊號。Recently, international pharmaceutical companies such as Roche, Pfizer and Merck have also invested in neuropeptide Y and cancer research. In 2001, REUBI Jean-Claude proposed a novel compound that binds to the neuropeptide Y1 receptor to treat or diagnose breast cancer, ovarian cancer and colloid. In blastoma, in 2013, Andreas et al. proposed the use of NPY-related peptides as a risk assessment method for predicting breast cancer in women who did not have cancer. Market signals related to NPY and cancer can be observed from both academic research and patent analysis.

以下是乳腺癌與神經肽Y之相關統計資料：運用國際最新發展NPY新分子技術結合本所相關核種標誌技術(例如:Ga-68、In-111以及Lu-177)，發展新穎之診斷用藥物INER-NPY系列衍生物。此外，目前亦與中研院研究團隊進行相關乳癌胜肽蛋白藥物開發之合作。以提升本所胜肽藥物開發能力。NPY- INER系列衍生物將針對乳癌病患進行診斷，早期診斷出腫瘤位置，提早讓乳癌患者能在藥物發揮作用的時間點進行治療，可以讓患者及早有效控制病情，減少後續社會成本並降低乳癌死亡率。The following are the statistics of breast cancer and neuropeptide Y: the development of novel diagnostic drugs using the latest international development of NPY molecular technology combined with the relevant nuclear marker technology (eg Ga-68, In-111 and Lu-177) INER-NPY series of derivatives. In addition, it is currently working with the research team of the Academia Sinica on the development of related breast cancer peptide protein drugs. To enhance the ability of our peptide peptide development. NPY-INER series of derivatives will be diagnosed for breast cancer patients, early diagnosis of tumor location, early breast cancer patients can be treated at the time when the drug works, allowing patients to effectively control the disease early, reduce subsequent social costs and reduce breast cancer mortality rate.

透過國內外學者、專家跨領域合作研究，成立「診斷型神經肽Y(NPY)研製團隊」計畫，發展與佈局台灣首例新穎之PET乳癌症診斷用藥物NPY-INER系列衍生物。計畫主軸為應用表徵基因學與分子影像醫學技術，開發乳癌診斷診斷技術。此研究計畫係與世界並駕齊驅，期以提昇乳癌症患者醫療品質，早期發現乳癌與早期治療，增進民生健康福祉。Through the cross-disciplinary research of scholars and experts at home and abroad, the "Diagnostic Neuropeptide Y (NPY) Development Team" project was established to develop and deploy the first novel NPY-INER series of derivatives for the diagnosis of PET breast cancer in Taiwan. The main axis of the project is the development of breast cancer diagnostic and diagnostic techniques for the application of genetic characterization and molecular imaging medical technology. This research program is in line with the world, in order to improve the medical quality of breast cancer patients, early detection of breast cancer and early treatment, and improve the health and well-being of people's livelihood.

神經肽 Y 已被證明是參與了若干機制參與癌症的進展，包括細胞增殖、血管生成和轉移。NPY 發揮其生物學功能通過五G-蛋白偶聯受體，名為 Y1、Y2-，Y4-、Y5-和 y6-R，與腫瘤的不同方面相關聯。Y1 R 似乎參與調節腫瘤細胞的增殖，而Y2-R啟動似乎促進新生血管形成。Neuropeptide Y has been shown to be involved in several mechanisms involved in the progression of cancer, including cell proliferation, angiogenesis, and metastasis. NPY exerts its biological function through five G-protein coupled receptors, named Y1, Y2-, Y4-, Y5-, and y6-R, which are associated with different aspects of the tumor. Y1 R appears to be involved in the regulation of tumor cell proliferation, whereas Y2-R initiation appears to promote neovascularization.

NPY 受體亞型選擇性類似物的發展有助於澄清的生理和病理生理作用和每個受體的定位，並可能有助於更好地瞭解受體-配體相互作用。NPY系統似乎是不同程度地與特定的腫瘤，包括神經脊細胞腫瘤、乳腺癌和***癌。NPY也被證明可誘導神經細胞和平滑肌細胞增殖，受體Y1 表現與有關(Erlinge et al, 1994; Hansel et al, 2001);並經由 Y1R表現和Y2R擴散可誘導的神經脊腫瘤有關(Kitlinska et al，2005年)。增加的血漿 NPY 量可以標記神經母細胞瘤的形成。The development of NPY receptor subtype-selective analogs contributes to the clarification of physiological and pathophysiological roles and localization of each receptor and may contribute to a better understanding of receptor-ligand interactions. The NPY system appears to be varying degrees with specific tumors, including neural ridge cell tumors, breast cancer, and prostate cancer. NPY has also been shown to induce neuronal and smooth muscle cell proliferation, which is associated with receptor Y1 expression (Erlinge et al, 1994; Hansel et al, 2001); and is associated with Y1R manifestations and Y2R diffusion-induced neural vertebral tumors (Kitlinska et Al, 2005). Increased plasma NPY levels can label the formation of neuroblastoma.

Y-受體表達在人乳腺癌中。他們表明，超過90％的所有乳腺腫瘤和100％的檢查的轉移瘤表達Y1受體有關。其中值得重視的是受體的轉移亞型從健康組織中的Y2受體至Y1受體在腫瘤發現期間具有潛在相關性，研究顯示(ChemMedChem 2015, 10, 164 – 172) ，NPY衍生物標誌3個硼中子，於乳腺癌細胞中，受體Y1遠大於Y2之EC50表現。文獻(J Nucl Med May 1, 2016 vol. 57 no. supplement 2 1076)以⁶⁴ Cu標誌NPY衍生物(Pro30, Tyr32, Leu34，NPY(28-36)-NH2)，及Mengjie Liu (Int J Pept Res Ther (2013) 19:33–41 DOI 10.1007/s10989-012-9330-z) 僅選取28-36個NPY序列進行改植，提高與Y1結和性，但tumor/music並不高。Y-receptor expression is expressed in human breast cancer. They showed that more than 90% of all breast tumors and 100% of examined metastases were associated with Y1 receptor expression. Of particular note is the potential relevance of receptor transfer subtypes from Y2 receptors to Y1 receptors in healthy tissues during tumor discovery, studies have shown (ChemMedChem 2015, 10, 164 – 172) , NPY derivative markers 3 Boron neutrons, in breast cancer cells, receptor Y1 is much larger than the EC50 expression of Y2. Literature (J Nucl Med May 1, 2016 vol. 57 no. supplement 2 1076) with ⁶⁴ Cu-labeled NPY derivatives (Pro30, Tyr32, Leu34, NPY(28-36)-NH2), and Mengjie Liu (Int J Pept Res) Ther (2013) 19:33–41 DOI 10.1007/s10989-012-9330-z) Only 28-36 NPY sequences were selected for replanting to improve the knotty with Y1, but the tumor/music was not high.

先前技藝WO 2007039318 A2及US 20040076581 A1，Neuropeptide Y (NPY) and the Y₁ R-selective選擇以Re/^99m Tc進行NPY衍生物- [Phe⁷ , Pro³⁴ ]之標誌，可於患者腫瘤部位與骨轉移部位有明顯影像。然須先進行24小時反應，將其螯合物改植成N^α -histidinyl acetyl (N^α His-ac) chelator，然其反應在PH3-4下進行，其產率僅為55%。在文獻上顯示¹²³ I，⁶⁴ Cu同位素標誌過程需要在迴旋加速器現場，操作不易，⁶⁸ Ga、¹¹¹ In標誌過程不需在加速器現場，¹¹¹ In標誌輔佐藥物動學與藥物代謝觀察，¹⁷⁷ Lu含β射線可兼具診斷與提供治療用。Prior art WO 2007039318 A2 and US 20040076581 A1, Neuropeptide Y (NPY) and the Y ₁ R-selective were selected for the NPY derivative of Re/ ^99m Tc - [Phe ⁷ , Pro ³⁴ ], which can be used in patients with tumor sites and bones. There is a clear image of the transfer site. However, the reaction was first carried out for 24 hours, and the chelate was changed to N ^α -histidinyl acetyl (N ^α His-ac) chelator, and the reaction was carried out at pH 3-4, and the yield was only 55%. It is shown in the literature that the ¹²³ I, ⁶⁴ Cu isotope labeling process needs to be in the cyclotron field, and the operation is not easy. The ⁶⁸ Ga, ¹¹¹ In mark process does not need to be at the accelerator site, the ¹¹¹ In mark assists in drug kinetics and drug metabolism observation, and the ¹⁷⁷ Lu contains β. Radiation can be used for both diagnosis and treatment.

本發明揭露一種乳癌診斷型放射線分子藥物，其藥物為以人類神經肽(NPY)為主體進行修飾，鍵結螯合劑後標誌放射線核種⁶⁸ Ga、¹⁷⁷ Lu、¹¹¹ In，形成一放射線標靶藥物，進行乳癌動物模式影像分析。由於神經肽(Neuropeptide Y，NPY)是由36個胺基酸所組成的胜肽，是一種廣泛存在於神經系統、調節體內代謝，如:肥胖、壓力、疼痛以及血壓控制等，神經肽被證實參與許多癌症之發展，包含細胞增生、血管生成(angiogenesis)與轉移，有關許多學者利用神經肽進行乳癌之研究，發現其於神經肽受體Y1表現極高，因此，以神經肽進行開發診斷藥物的開發將會是未來治療惡性腫瘤疾病的新希望。The invention discloses a breast cancer diagnostic type radioactive molecular medicine, wherein the medicine is modified by a human neuropeptide (NPY) as a main body, and after binding a chelating agent, a radioactive nuclear species ⁶⁸ Ga, ¹⁷⁷ Lu, ¹¹¹ In is formed to form a radioactive target drug. Perform breast cancer animal model image analysis. Since neuropeptide Y (NPY) is a peptide consisting of 36 amino acids, it is a kind of neuropeptide that is widely present in the nervous system and regulates metabolism in the body, such as obesity, stress, pain and blood pressure control. Participated in the development of many cancers, including cell proliferation, angiogenesis and metastasis. Many scholars have used neuropeptides for breast cancer research and found that they are extremely high in the neuropeptide receptor Y1. Therefore, the development of diagnostic drugs with neuropeptides The development will be a new hope for the future treatment of malignant tumor diseases.

神經肽NPY衍生物 具有Y1、Y2、Y4、Y5及Y6等6種受體，其中當與Y1受體高親和性結合並且與Y2受體低親和性結果可表現在乳腺癌腫瘤上，可供作靶向性藥物用。本專利以NPY為主體，合成一種放射性標記的診斷型神經胜肽衍生物，其包含4部分(1)放射性同位素，(2)金屬螯合劑，(3)間隔物(spacer)，如胺基酸、胜肽、高分子，(4)神經胜肽衍生物。The neuropeptide NPY derivative has six receptors such as Y1, Y2, Y4, Y5 and Y6, and the high affinity binding to the Y1 receptor and the low affinity with the Y2 receptor can be expressed on breast cancer tumors. For targeted drugs. This patent uses NPY as the main body to synthesize a radiolabeled diagnostic neuropeptide derivative containing 4 parts (1) radioisotope, (2) metal chelating agent, (3) spacer, such as amino acid. , peptides, polymers, (4) neuropeptide derivatives.

診斷型神經肽Y衍生物之研製與應用，所述的放射性標誌之胜肽可作為放射性藥物應用於癌症的診斷與治療。其製備方步驟包括 (1)神經肽衍生物序列設計；(2)神經肽衍生物合成與分析； (3)放射線同位素標誌神經肽衍生物，其標誌之放射性同位素如¹⁷⁷ Lu、^99m Tc、¹¹¹ In、⁶⁸ Ga、B，其標誌時間為10分鐘，標誌效率可達90%，且腫瘤動物模式(4T1)證實於腫瘤結合效果佳。The development and application of diagnostic neuropeptide Y derivatives, which can be used as radiopharmaceuticals for the diagnosis and treatment of cancer. The preparation steps include (1) neuropeptide derivative sequence design; (2) synthesis and analysis of neuropeptide derivatives; (3) radioisotope marker neuropeptide derivatives, the labeled radioisotopes such as ¹⁷⁷ Lu, ^99m Tc, ¹¹¹ In, ⁶⁸ Ga, B, the marking time is 10 minutes, the marker efficiency can reach 90%, and the tumor animal model (4T1) confirms that the tumor binding effect is good.

本發明係有關一種具放射性標記的神經肽衍生物製備方法，其特點為序列為新開發，製備方便，標緻時間縮短，標誌效率可達90%，不須於標誌反應後進行管柱純化，從動物影像上可得知其與腫瘤結合效果高，可直接給藥，並以套組形式縮減後端給藥的便利性。The invention relates to a method for preparing a radioactively labeled neuropeptide derivative, which is characterized in that the sequence is newly developed, the preparation is convenient, the Peugeot time is shortened, and the labeling efficiency is up to 90%, and the column column purification is not required after the label reaction. It is known in animal images that it has a high binding effect on tumors, can be administered directly, and reduces the convenience of back-end administration in a kit form.

放射性標誌神經肽Y衍生物胜之序列設計，其進行神經胜肽衍生物之序列設計如表一所示之DOTA-space-NPY胜肽衍生物分子量： 表一The sequence design of the radioactive marker neuropeptide Y derivative is designed, and the sequence design of the neuropeptide derivative is as shown in Table 1. The molecular weight of the DOTA-space-NPY peptide derivative is shown in Table 1: Table 1

放射性標誌神經肽Y衍生物之製備Preparation of radioactive marker neuropeptide Y derivative

合成上述表一所列之序列，以HPLC鑑定其純度皆大於90%。其製備方法係以1mg/mL 濃度配置取出200 μL溶液，加入800 μL NaOAc溶液，混和均勻後，取283 μL置入500 μl離心管中，再加入200 μL 0.1NHCl 混和均勻後，加入放射線同位素¹¹¹ In或⁶⁸ Ga共300 μL，不足量以0.1N HCl補足，其溶液pH值為6~7。取溶液置入95℃水浴槽中反應10分鐘，待冷卻後，取1μL進行ITLC分析，其標誌效率大於90%，取上述溶液20~30 μCi，進行Radio-HPLC分析，其主訊號出現滯留時間為8分鐘。The sequences listed in Table 1 above were synthesized and their purity was determined to be greater than 90% by HPLC. The preparation method is to take 200 μL of the solution at a concentration of 1 mg/mL, add 800 μL of NaOAc solution, mix well, take 283 μL into a 500 μl centrifuge tube, add 200 μL of 0.1NHCl and mix well, then add radioisotope ^111. In or ⁶⁸ Ga is 300 μL in total, and the deficiency is made up with 0.1 N HCl. The pH of the solution is 6-7. The solution was placed in a 95 ° C water bath for 10 minutes. After cooling, 1 μL was taken for ITLC analysis. The labeling efficiency was greater than 90%. The solution was taken at 20-30 μCi for Radio-HPLC analysis. The retention time of the main signal appeared. It is 8 minutes.

Radio-HPLC分析條件為C18管柱，設定如下：　　 A: ACN+0.1%TFA (0% to100%, A in 20min) B: ddH₂ O+0.1%TFA Flow rate: 0.8mL/min, : 220nmRadio-HPLC analysis conditions were C18 column, set as follows: A: ACN + 0.1% TFA (0% to 100%, A in 20 min) B: ddH ₂ O + 0.1% TFA Flow rate: 0.8 mL / min, : 220 nm

其相關DOTA-NPY胜肽衍生物標誌效率整理如下表二所示之¹¹¹ In-DOTA-GSG-NPY4_ITLC分析結果。以¹¹¹ In-DOTA-GSG-NPY4為例，其Radio-HPLC-HPLC滯留時間為7.36分鐘，純放射化學純度為94.77%，如圖一所示。ITLC/SG 分析條件為檸檬酸(citric acid) (0.1M)/檸檬酸鈉(sodium citrate) (0.1 M)=2.1/7.9 ,自2cm 至10cm，標誌效率結果如圖二。表二The efficiency of the related DOTA-NPY peptide derivative was as follows: ¹¹¹ In-DOTA-GSG-NPY4_ITLC analysis results shown in Table 2. Taking ¹¹¹ In-DOTA-GSG-NPY4 as an example, the Radio-HPLC-HPLC retention time was 7.36 minutes, and the pure radiochemical purity was 94.77%, as shown in Figure 1. The ITLC/SG analysis conditions were citric acid (0.1 M)/sodium citrate (0.1 M)=2.1/7.9, from 2 cm to 10 cm, and the results of the labeling efficiency are shown in Fig. 2. Table II

放射性標誌神經肽Y衍生物動物影像實驗結果Radiographic marker neuropeptide Y derivative animal imaging experiment results

選擇以4T1乳癌腫瘤動物模式，以靜脈注射方式¹¹¹ In-DOTA-space-NPY ，藥物濃度為4.85 μg / 583 μL，並以0.5、2、4、24小時後進行Nano-SPECT/CT造影影像分析結果以注射劑量百分比/重量( %ID/g)呈現，結果如圖三之(f)至(h)所示，可得知圖三之(h)¹¹¹ In-DOTA-GSG-(2B)NPY4所示之結果最佳，於24小時達到最高4.41%ID/g。The 4T1 breast cancer tumor animal model was selected by intravenous injection of ¹¹¹ In-DOTA-space-NPY at a drug concentration of 4.85 μg / 583 μL, and subjected to Nano-SPECT/CT imaging analysis at 0.5, 2, 4, and 24 hours later. The results are presented as the injection dose percentage/weight (%ID/g). The results are shown in (f) to (h) of Fig. 3. It can be seen that (h) ¹¹¹ In-DOTA-GSG-(2B)NPY4 The results shown are the best and reached a maximum of 4.41% ID/g in 24 hours.

第一圖(A)係Free¹¹¹ In之RP-HPLC分析圖譜。 第一圖(B)係¹¹¹ In-DOTA-GSG-NPY4之RP-HPLC分析圖譜，保持時間(retention time)為7.366分鐘，放化純度為94.77%。 第二圖係¹¹¹ In-DOTA-GSG-NPY4_ITLC分析結果，其標誌效率可達94.85%。 第三圖係¹¹¹ In-DOTA-GSG-(2B)NPY4與¹¹¹ In-DOTA-GSG-(B)NPY4藥物於4T1乳癌腫瘤動物模式Nano-SPECT/CT造影結果，以0.5、2、4、24小時之時間，分別注射劑量百分比/重量( %ID/g)呈現觀察結果。The first panel (A) is an RP-HPLC analysis map of Free ¹¹¹ In. The first panel (B) is an RP-HPLC analysis pattern of ¹¹¹ In-DOTA-GSG-NPY4 with a retention time of 7.366 minutes and a radiochemical purity of 94.77%. The second graph is the result of ¹¹¹ In-DOTA-GSG-NPY4_ITLC analysis, and its marking efficiency can reach 94.85%. The third panel is the results of Nano-SPECT/CT angiography of ¹¹¹ In-DOTA-GSG-(2B)NPY4 and ¹¹¹ In-DOTA-GSG-(B)NPY4 drugs in 4T1 breast cancer tumors, with 0.5, 2, 4, 24 At the time of the hour, the observed dose percentage/weight (%ID/g) was observed.

Claims (6)

一種神經肽Y衍生物衍生物放射性標誌之製備方法，包含螯合物（cheater）、間隔物（Spacer）及神經肽Y衍生物，在一定反應溫度時間下與放射性同位素作用，形成放射性標記的神經肽衍生物，其中神經肽Y衍生物序列係以NPY為主體之胜肽，以YNLITRPRY序列進行修飾，以Y與C₄ H₁₂ B₁₀ O₄ 鍵結，其製備方法係以30μg~60μg，¹¹¹ In-DOTA-space-NPY4衍生物溶於0.2~1M NaOAc 中，並加入放射性同位素，使總體積為40~600μL，溶液pH值為4~8；取溶液置入加熱反應器中，高溫反應10分鐘，反應後，取1μL以進行ITLC分析其標誌效率並以Radio-HPLC進行放化純度分析，其主訊號出現滯留時間為7~12分鐘，其標誌效率與放化純度大於90%，不須經過管柱純化分離，其中¹¹¹ In-DOTA-GSG-(2B)-NPY4於4T1腫瘤動物模式中，經24小時有腫瘤/肌肉(T/M)蓄積為4.42 (ID%/g)。A method for preparing a radioactive marker of a neuropeptide Y derivative derivative, comprising a chelate, a spacer and a neuropeptide Y derivative, which react with a radioisotope at a certain reaction temperature to form a radiolabeled nerve Peptide derivative, wherein the neuropeptide Y derivative sequence is a peptide which is mainly composed of NPY, modified by YNLITRPRY sequence, and Y is bonded with C ₄ H ₁₂ B ₁₀ O ₄ , and the preparation method thereof is 30 μg~60 μg, ¹¹¹ The In-DOTA-space-NPY4 derivative is dissolved in 0.2~1M NaOAc, and the radioisotope is added to make the total volume 40~600μL, the pH value of the solution is 4~8; the solution is placed in the heating reactor, and the high temperature reaction is 10 After the reaction, 1 μL was taken for ITLC analysis and its labeling efficiency was analyzed by Radio-HPLC. The retention time of the main signal was 7~12 minutes, and the labeling efficiency and radiochemical purity were greater than 90%. Purified by column purification, in which ¹¹¹ In-DOTA-GSG-(2B)-NPY4 had tumor/muscle (T/M) accumulation of 4.42 (ID%/g) in the 4T1 tumor animal model over 24 hours. 如請求項1所述，螯合物部分包括可用以標誌放射性同位素之金屬螯合物，如DOTA、NOTA、DTPA。As described in claim 1, the chelate moiety includes a metal chelate that can be used to label the radioisotope, such as DOTA, NOTA, DTPA. 如請求項1所述，間隔物包括胺基酸、胜肽、PEG聚合物、或醣類衍生物。As described in claim 1, the spacer includes an amino acid, a peptide, a PEG polymer, or a saccharide derivative. 如請求項1所述，放射性同位素包含⁶⁸ Ga、⁶⁷ Ga、¹¹¹ In、¹⁷⁷ Lu或Ｂ，適用於診斷之放射性同位素與硼中子治療(BNCT)。As described in claim 1, the radioisotope comprises ⁶⁸ Ga, ⁶⁷ Ga, ¹¹¹ In, ¹⁷⁷ Lu or B, which is suitable for diagnostic radioisotopes and boron neutron therapy (BNCT). 如請求項1所述，其在一定反應溫度下進行標誌反應，其加熱反應器溫度為80~100℃，反應時間為1至30分鐘，PH值為4-8。As described in claim 1, it performs a labeling reaction at a certain reaction temperature, and the temperature of the heated reactor is 80 to 100 ° C, the reaction time is 1 to 30 minutes, and the pH is 4-8. 如請求項1所述，其放射性標記的神經肽Y衍生物適用於乳腺癌細胞株(4T1、MDA-MB-231，MCF-7)與人類神經母細胞瘤。As described in claim 1, the radiolabeled neuropeptide Y derivative is suitable for use in breast cancer cell lines (4T1, MDA-MB-231, MCF-7) and human neuroblastoma.