TW201442729A - Hypoxic tissue contrast agent precursor, its contrast agent and preparation method - Google Patents
Hypoxic tissue contrast agent precursor, its contrast agent and preparation method Download PDFInfo
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本發明係關於一種造影劑前驅物，尤指一種包含有機配位子6-(2-硝基咪唑)己基-L-L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛醯胺(6-(2-nitroimidazde)hexyl-L-3,6-diaza-4,7-dioxo
-8[(triphenylmethyl)thio]-2-[((triphenylmethyl)thio)
-methyl]octanamide，下稱為DANI)之造影劑前驅物、其造影劑及其製備方法。The invention relates to a contrast agent precursor, in particular to an organic ligand 6-(2-nitroimidazolyl)hexyl-LL-3,6-diaza-4,7-dioxo-8-[ (tritylmethyl)thio]-2-[((trityl)thio)methyl]octylamine (6-(2-nitroimidazde)hexyl-L-3,6-diaza-4,7 -dioxo
-8[(triphenylmethyl)thio]-2-[((triphenylmethyl)thio)
-methyl]octanamide, hereinafter referred to as DANI) contrast agent precursor, contrast agent thereof and preparation method thereof.
很多疾病會引起缺血症狀，以致於氧的供應量不足以滿足組織器官的需求而造成缺氧現象。以腦中風、心肌梗塞及惡性腫瘤等重大疾病而言，其組織均會有缺氧現象發生，而此時缺氧可能是因為如心肌細胞等局部的血液循環急性或短暫性地功能下降，或者是像惡性腫瘤細胞慢性地沒有充分的氧氣供應。而因為缺氧是無法預知的，因此發展用以偵測心臟、腦部以及惡性腫瘤部位的等非侵入性技術就逐漸蓬勃。Many diseases cause ischemic symptoms, so that the supply of oxygen is insufficient to meet the needs of tissues and organs, resulting in hypoxia. In the case of major diseases such as stroke, myocardial infarction, and malignant tumors, hypoxia may occur in tissues, and hypoxia may be due to acute or transient decline in local blood circulation such as cardiomyocytes, or It is like a malignant tumor cell that does not have a sufficient oxygen supply chronically. And because hypoxia is unpredictable, the development of non-invasive techniques to detect the heart, brain, and malignant tumors is growing.
所有哺乳類生物體之組織皆需要氧氣的供應方能滿足新陳代謝的需求。一般而言，經由微血管擴散至細胞之周圍的低濃度氧(約3~5 torr)，即可進行細胞內新陳代謝的反應機制。但惡性腫瘤會改變組織內氧氣之供需平衡關係，因為其所增加的細胞團需有額外氧氣供應以維持細胞的活力。故為了滿足需求，惡性腫瘤會自行調整以促進新血管在病變組織的成長。然而其對氧需求的增加量常常大於所能供應的量，當氧氣從微血管壁擴散出來即迅速被外層細胞代謝，無法擴散至腫瘤內層。較大之固形腫瘤其內部因氧氣及血液之供應不及而呈現缺氧狀況，長期缺氧之細胞則漸漸壞死，因此腫瘤依其體積及生物特性，常含有相當比例之缺氧或壞死細胞。All mammalian organisms require a supply of oxygen to meet their metabolic needs. In general, a low-concentration oxygen (about 3 to 5 torr) that spreads around the cells through the microvasculature can perform a reaction mechanism of intracellular metabolism. However, malignant tumors alter the balance of supply and demand of oxygen in the tissue because the added cell mass requires additional oxygen supply to maintain cell viability. Therefore, in order to meet the demand, the malignant tumor will adjust itself to promote the growth of new blood vessels in the diseased tissue. However, the increase in oxygen demand is often greater than the amount that can be supplied. When oxygen diffuses out of the microvascular wall, it is rapidly metabolized by the outer cells and cannot spread to the inner layer of the tumor. Larger solid tumors have hypoxic conditions due to insufficient supply of oxygen and blood, and long-term hypoxic cells gradually become necrotic. Therefore, tumors often contain a considerable proportion of hypoxic or necrotic cells depending on their volume and biological characteristics.
因此在做核醫造影之技術上，若要觀察該些惡性腫瘤以做進一步診斷、追蹤，則透過缺氧組織做為觀察之標的或媒介即存在發展潛力。Therefore, in the technique of nuclear angiography, if these malignant tumors are to be observed for further diagnosis and tracking, there is potential for development through hypoxic tissue as the target or medium of observation.
核醫造影，就是應用放射性同位素，而為病人做攝影檢查。其係將具有放射性同位素之造影劑經由靜脈注射，口服或吸入等方法而送入生物體內，待一段時間之後，這些造影劑會分佈到特定器官或組織，再利用核醫攝影儀器偵測特定器官或組織內藥物的分佈，例如是伽馬射線攝影機透過放射性同位素的伽馬射線撞擊碘化鈉晶體產生閃爍光來以產生影像；經顯像或電腦處理後，即可由醫師判讀診斷相關的生理變化。Nuclear angiography is the application of radioisotopes to the photographic examination of patients. The contrast agent having a radioisotope is sent to a living body by intravenous injection, oral or inhalation, and after a period of time, the contrast agent is distributed to a specific organ or tissue, and the specific organ is detected by a nuclear medical photographic apparatus. Or the distribution of drugs in the tissue, such as a gamma ray camera that strikes sodium iodide crystals by radioactive isotope gamma rays to produce scintillation light to produce an image; after imaging or computer processing, the physician can interpret diagnostic-related physiological changes. .
因此，如何提出一種適用之造影劑，即係攸關對惡性腫瘤做核醫造影成敗與否之關鍵。
Therefore, how to propose a suitable contrast agent is the key to the success or failure of nuclear angiography of malignant tumors.
本發明之主要目的，係提供一種造影劑前驅物，其在結構上具有硝基咪唑(nitroimidazde)之官能基，能夠滯留於生物體之缺氧組織，同時亦具備雙官能基配位子之結構，能與放射性同位素錯合，使得放射性同位素能被帶到該些缺氧組織，因此具有作為標幟用途之潛力。The main object of the present invention is to provide a contrast agent precursor having a functional group of nitroimidazolium, which is capable of retaining in an anoxic tissue of a living body and having a structure of a bifunctional ligand. It can be mismatched with radioisotopes so that radioisotopes can be carried to these anoxic tissues, thus having the potential to be used as a marker.
本發明之次要目的，係提供一種造影劑前驅物，其以三苯甲基為硫醇基之保護基，不但在化學性質穩定而有利於保存，且其在使用前可直接透過錯合反應而脫離，具有便利性。A secondary object of the present invention is to provide a contrast agent precursor which has a triphenylmethyl group as a thiol group protecting group, which is not only chemically stable but also beneficial for preservation, and can directly pass a mismatch reaction before use. And it is convenient to leave.
本發明之再一目的，係提供一種造影劑前驅物之製備方法，其可有效製備出前述具有良好保存性、便利性以及針對生物體之缺氧組織具標幟用途之造影劑前驅物。Still another object of the present invention is to provide a method for preparing a contrast agent precursor which can effectively prepare the aforementioned contrast agent precursor having good preservability, convenience, and use for anoxic tissue of a living body.
本發明之更一目的，係提供一種造影劑，其同時兼具了能滯留於生物體缺氧組織的有機官能基，而且也穩定的具有能被偵測之放射性同位素，因此能在相關儀器的檢測之下，透過觀察造影劑的分佈態樣而取得生物體缺氧組織、特別是惡性腫瘤之缺氧層的形態，提供醫生寶貴且充足的資訊以做診斷。A further object of the present invention is to provide a contrast agent which simultaneously has an organic functional group which can be retained in an anoxic tissue of a living body, and which is stable and has a radioisotope which can be detected, and thus can be used in related instruments. Under the test, by observing the distribution of the contrast agent, the morphology of the hypoxic tissue of the organism, especially the malignant tumor, is obtained, and the doctor is provided with valuable and sufficient information for diagnosis.
故為了達到上述之目的，本發明揭示了一種缺氧組織造影劑前驅物、其造影劑及其製備方法，其在雙官能基配位子接上硝基咪唑或其衍生物，再與標幟用的放射性同位素相錯合，以發展成為一種缺氧組織造影劑；藉由使用此缺氧組織造影劑，不但可以輔助醫生做診斷，還可用來做為治療後之追蹤檢查，因此這在惡性腫瘤之診斷與治療領域上，得以成為不可或缺的有力工具。Therefore, in order to achieve the above object, the present invention discloses an anoxic tissue contrast agent precursor, a contrast agent thereof and a preparation method thereof, which are provided with a nitroimidazole or a derivative thereof in a bifunctional ligand, and then The radioisotope used is misaligned to develop into an anoxic tissue contrast agent; by using this hypoxic tissue contrast agent, it can not only assist the doctor in making the diagnosis, but also can be used as a follow-up examination after treatment, so this is malignant. In the field of diagnosis and treatment of tumors, it has become an indispensable and powerful tool.
S1~S4．．．步驟流程S1~S4. . . Step flow
S51~S56．．．步驟流程S51~S56. . . Step flow
S61．．．步驟流程S61. . . Step flow
第一圖：其係為本發明之造影劑前驅物之化學結構圖；
第二圖：其係為本發明之造影劑前驅物DANI之合成流程圖；
第三圖：其係為本發明中，DANI前製之化合物之合成流程圖；
第四圖：其係為本發明中，DANI前製之化合物之合成流程圖；以及
第五圖：其係為本發明之造影劑之化學結構圖。
First: it is the chemical structure diagram of the contrast agent precursor of the present invention;
Second figure: it is a synthetic flow chart of the contrast agent precursor DANI of the present invention;
The third figure: it is a synthetic flow chart of the compound prepared by DANI in the present invention;
Figure 4 is a synthetic flow chart of the compound prepared by DANI in the present invention; and a fifth chart: it is a chemical structure diagram of the contrast agent of the present invention.
為使本發明之特徵及所達成之功效有更進一步之瞭解與認識，謹佐以較佳之實施例及配合詳細之說明，說明如後：For a better understanding and understanding of the features and advantages of the present invention, the preferred embodiments and the detailed description are described as follows:
首先，請參考第一圖，其係為本發明之造影劑前驅物之化學結構圖；如圖所示，其係為前述之DANI，結構上具有長烷基及一個硝基咪唑(nitroimidazde)，可增加其脂溶性，且此硝基咪唑或其衍生物進入細胞後會進行一系列之還原氧化反應。此時若細胞含有正常的氧量，則硝基咪唑或其衍生物將迅速逸出細胞而排出體外；而但若該細胞係處於缺氧狀態，則硝基咪唑或其衍生物將會滯留較長時間，因此其具有滯留於缺氧組織之特性，能在與放射性同位素接合後形成性能優越之缺氧組織造影劑。First, please refer to the first figure, which is a chemical structure diagram of the contrast agent precursor of the present invention; as shown in the figure, it is the aforementioned DANI, which has a long alkyl group and a nitroimidazide. It can increase its fat solubility, and this nitroimidazole or its derivative enters the cell and undergoes a series of reduction oxidation reactions. At this time, if the cells contain normal oxygen, the nitroimidazole or its derivative will quickly escape from the cells and be excreted; but if the cell line is in anoxic state, the nitroimidazole or its derivative will remain. For a long time, it has the property of being retained in an anoxic tissue, and can form a hypoxic tissue contrast agent excellent in performance after being bonded to a radioisotope.
而在具有硝基咪唑的同時，此造影劑前驅物也具有雙官能基配位子，其可以透過五配位之方式與放射性同位素進行鍵結，形成穩定的金字塔構形，進而應用為一種造影劑。While having nitroimidazole, the contrast agent precursor also has a bifunctional ligand which can be bonded to the radioisotope through a five-coordinated manner to form a stable pyramid configuration, which is then applied as an angiogram. Agent.
如前所述，本發明之造影劑前驅物具有滯留於缺氧組織之特性之硝基咪唑，而配合惡性腫瘤之癌細胞增長迅速，因此大部分都有缺氧層之特性，在經與放射性同位素鍵結後，所形成之造影劑就能停滯留惡性腫瘤所在之處，發揮造影劑之功能。As described above, the contrast agent precursor of the present invention has nitroimidazole which is retained in the characteristics of anoxic tissue, and the cancer cells which cooperate with the malignant tumor grow rapidly, and therefore most of them have the characteristics of an oxygen-deficient layer, and undergo radioactivity. After isotope bonding, the formed contrast agent can stop where the malignant tumor is located and function as a contrast agent.
另外，本發明的化學結構中，DANI的硫醇基有CPh3保護，化學性質穩定，也可延長其儲存時間。Further, in the chemical structure of the present invention, the thiol group of DANI has CPh 3 protection, is chemically stable, and can also prolong its storage time.
而本發明所揭示之造影劑前驅物之製備方法，則請參考第二圖，其係包含步驟：
步驟S1：使用6-胺基-1-己醇(6-amino-1-hexanol)與第三丁基碳酸酯，進行胺基保護反應，生成6-羥基胺基甲酸第三丁酯(tert-butyl 6-hydroxycarbamate)；
步驟S2：使用6-羥基胺基甲酸第三丁酯與對-甲苯磺醯氯(P-toluenesulfonyl chloride)，在吡啶(Pyridine)溶液中進行取代反應，生成6-甲苯磺醯己基胺基甲酸第三丁酯(tert-butyl 6-toluenesulfonyl hexylcarbamate)；
步驟S3：使用6-甲苯磺醯己基胺基甲酸第三丁酯與2-硝基咪唑，在二甲基甲醯胺(DMF)溶液中進行取代反應，生成6-(2-硝基咪唑)己基胺基甲酸第三丁酯(tert-butyl 6-(2-nitroimidazole)hexylcarbamate)；
步驟S4：氫化6-(2-硝基咪唑)己基胺基甲酸第三丁酯，使其還原為6-(2-硝基咪唑)己胺，再與L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛酸(L-3,6-diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2
-[((triphenylmethyl)thio)methyl]octanoic acid)進行醯胺化反應，生成DANI。For the preparation method of the contrast agent precursor disclosed in the present invention, please refer to the second figure, which includes the steps:
Step S1: using 6-amino-1-hexanol and a third butyl carbonate to carry out an amine-based protection reaction to form a third butyl 3-hydroxycarbamic acid ester (tert- Butyl 6-hydroxycarbamate);
Step S2: using 6-hydroxylcarbamic acid tert-butyl ester and p-toluenesulfonyl chloride in a pyridine (Pyridine) solution to form 6-toluenesulfonylhexylaminocarboxylic acid Tert-butyl 6-toluenesulfonyl hexylcarbamate;
Step S3: using a third butyl 6-toluenesulfonylaminocarbamate and 2-nitroimidazole, and performing a substitution reaction in a solution of dimethylformamide (DMF) to form 6-(2-nitroimidazole) Tert-butyl 6-(2-nitroimidazole)hexylcarbamate;
Step S4: hydrogenating 6-(2-nitroimidazolium)hexylaminocarboxylic acid tert-butyl ester to reduce it to 6-(2-nitroimidazolium) hexylamine, and then to L-3,6-diaza- 4,7-dioxo-8-[(trityl)thio]-2-[((trityl)thio)methyl]octanoic acid (L-3,6-diaza-4,7 -dioxo-8-[(triphenylmethyl)thio]-2
-[((triphenylmethyl)thio)methyl]octanoic acid) is subjected to a guanidine reaction to form DANI.
於步驟S1中，其胺基保護反應係於無水二氯甲烷(CH2Cl2)中進行，反應溫度為室溫，反應時間24小時。而在步驟S2的吡啶溶液中進行取代反應時，反應溫度為室溫，反應時間則是1小時。In the step S1, the amine-protecting reaction is carried out in anhydrous dichloromethane (CH 2 Cl 2 ) at a reaction temperature of room temperature and a reaction time of 24 hours. On the other hand, when the substitution reaction is carried out in the pyridine solution of the step S2, the reaction temperature is room temperature, and the reaction time is 1 hour.
步驟S3的取代反應係以碳酸銫(Cs2CO3)為反應劑，搭配2-硝基咪唑(2-nitroimidazole)，於無水二甲基甲醯胺(Dimethylformamide, DMF)中進行，反應溫度為65°C，反應時間2小時。而步驟S4的醯胺化反應則是以1,3-二環己基碳二亞胺(1,3-dicyclohexylcarbodiimide, DCC)以及N-羥基丁二醯亞胺(N-hydroxysuccinimide, NHS)為反應劑，並於三氯甲烷溶液中進行，反應溫度為室溫，反應時間2.5小時。The substitution reaction in the step S3 is carried out by using cesium carbonate (Cs 2 CO 3 ) as a reactant and 2-nitroimidazole in dimethylformamide (DMF) at a reaction temperature of The reaction time was 2 hours at 65 °C. The amide amination reaction in step S4 is based on 1,3-dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS). And carried out in a chloroform solution, the reaction temperature was room temperature, and the reaction time was 2.5 hours.
本發明對於步驟S4當中所使用的L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛酸亦有其特定之製備方法，請參考第三圖，其係包含步驟：
步驟S51：將乙硫醇酸甲基酯(thioglycolic acid methyl ester)之硫醇基以三苯甲基保護，生成三苯甲基乙硫醇酸甲基酯(triphenylmethyl thioglycolic acid methyl ester)；
步驟S52：水解三苯甲基乙硫醇酸甲基酯於鹼性甲醇溶液，生成三苯甲基乙硫醇酸(triphenylmethyl thioglycolic acid)；
步驟S53：將三苯甲基乙硫醇酸與甘胺酸乙酯(glycine ethyl ester)進行醯胺化反應，生成3-氮雜-4 -氧代-5-[(三苯甲基)硫基]戊酸乙基酯(3-aza-4-oxo-5-[(triphenylmethyl)thio]
-pentanoic acid ethyl ester)；
步驟S54：水解3-氮雜-4 -氧代-5-[(三苯甲基)硫基]戊酸乙基酯於鹼性甲醇溶液，生成3-氮雜-4 -氧代-5-[(三苯甲基)硫基]戊酸(3-aza-4-oxo-5-[(triphenylmethyl)thio]
-pentanoic acid)；
步驟S55：將3-氮雜-4 -氧代-5-[(三苯甲基)硫基]戊酸與L-三苯甲基副胱胺酸乙基酯(L-triphenylmethyl cysteine ethyl ester)進行醯胺化反應，生成L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛酸乙基酯(L-3,6-diaza-4,7-dioxo-8-[(triphenylmethyl)
-thio]-2-[((triphenyl-methyl)thio)methyl]
-octanoic acid ethyl ester)；以及
步驟S56：水解L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛酸乙基酯，生成該L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛酸(L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2- [((triphenyl-methyl)thio)methyl]octanoic acid)。The present invention relates to L-3,6-diaza-4,7-dioxo-8-[(trityl)thio]-2-[((trityl)) used in step S4 Thio)methyl]octanoic acid also has its specific preparation method, please refer to the third figure, which includes the steps:
Step S51: protecting the thiol group of the thioglycolic acid methyl ester with a trityl group to form a triphenylmethyl thioglycolic acid methyl ester;
Step S52: hydrolyzing the methyl ester of trityl ethanethiol acid in an alkaline methanol solution to form triphenylmethyl thioglycolic acid;
Step S53: subjecting trityl ethanethiol acid to glycine ethyl ester to carry out amidoximation to form 3-aza-4-oxo-5-[(trityl)sulfide Ethyl pentanoate (3-aza-4-oxo-5-[(triphenylmethyl)thio]
-pentanoic acid ethyl ester);
Step S54: Hydrolysis of ethyl 3-aza-4-oxo-5-[(trityl)thio]pentanoate in an alkaline methanol solution to form 3-aza-4-oxo-5- [(tritylmethyl)thio]pentanoic acid (3-aza-4-oxo-5-[(triphenylmethyl)thio]
-pentanoic acid);
Step S55: 3-Aza-4-oxo-5-[(trityl)thio]pentanoic acid and L-triphenylmethyl cysteine ethyl ester The guanidation reaction is carried out to form L-3,6-diaza-4,7-dioxo-8-[(trityl)thio]-2-[((trityl))thio) )methyl]octanoic acid ethyl ester (L-3,6-diaza-4,7-dioxo-8-[(triphenylmethyl)
-thio]-2-[((triphenyl-methyl)thio)methyl]
-octanoic acid ethyl ester); and step S56: hydrolysis of L-3,6-diaza-4,7-dioxo-8-[(trityl)thio]-2-[((triphenyl) Methyl)thio)methyl]octanoic acid ethyl ester to form the L-3,6-diaza-4,7-dioxo-8-[(trityl)thio]-2-[ ((tritylmethyl)thio)methyl]octanoic acid (L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2-[((triphenyl-methyl)thio)methyl) ]octanoic acid).
於步驟S51中，其於硫醇基以三苯甲基保護時，係以三氟化硼***複合物(boron trifluoride ethyl ether complex)為催化劑，以三氯甲烷為溶劑，反應溫度室溫，反應時間24小時。In step S51, when the thiol group is protected with a trityl group, a boron trifluoride ethyl ether complex is used as a catalyst, and chloroform is used as a solvent, and the reaction temperature is room temperature. Time is 24 hours.
而在步驟S52、S54、S56等過程中，其水解反應，係以氫氧化鉀或甲氧化鈉為催化劑，在甲醇溶液中進行。In the process of steps S52, S54, and S56, the hydrolysis reaction is carried out in a methanol solution using potassium hydroxide or sodium methoxide as a catalyst.
步驟S53、S55之中，是以如同前述步驟S4之方法做操作，也就是以DCC以及NHS做為反應劑，於室溫下反應24小時；惟步驟S53的醯胺化反應是在三氯甲烷溶液中進行，而步驟S55則是在四氫呋喃溶液中進行。In steps S53 and S55, the operation is carried out in the same manner as in the above step S4, that is, DCC and NHS are used as reactants, and reacted at room temperature for 24 hours; but the methanation reaction in step S53 is in chloroform. This is carried out in solution, and step S55 is carried out in a tetrahydrofuran solution.
步驟S55當中的L-三苯甲基副胱胺酸乙基酯的製備方法，則是將L-副胱胺酸乙基酯(L-cysteine methyl ester)之硫醇基以三苯甲基保護，生成該L-三苯甲基副胱胺酸乙基酯，其化學結構流程如第四圖所揭示之步驟S61。在此步驟中，係以三氟化硼***複合物為催化劑，以三氯甲烷為溶劑，反應溫度75°C，反應時間4小時。The method for preparing L-trityl paracysteine ethyl ester in step S55 is to protect the thiol group of L-cysteine methyl ester with trityl group. The L-trityl paracysteine ethyl ester is produced, and the chemical structure thereof is as shown in the fourth step of step S61. In this step, a boron trifluoride etherate complex is used as a catalyst, chloroform is used as a solvent, a reaction temperature is 75 ° C, and a reaction time is 4 hours.
透過本發明於上述所揭示之步驟，即可製備有機配位子DANI，其在結構上所具有的2-硝基咪唑得以在應用時滯留於缺氧組織，例如惡性腫瘤因癌細胞增長迅速而產生的缺氧層，因此具有應用為造影劑之優勢；而其雙官能基配位子也可錯合放射性同位素，使之藉由放射性同位素而可被相關儀器所偵測。By the steps of the present invention disclosed above, an organic ligand DANI can be prepared, and the structurally possessed 2-nitroimidazole can be retained in hypoxic tissue during application, for example, malignant tumors grow rapidly due to cancer cells. The resulting oxygen-deficient layer has the advantage of being used as a contrast agent; its bifunctional ligand can also be mismatched with a radioisotope, which can be detected by the relevant instrument by means of a radioisotope.
請參考第五圖，其係為本發明使用DANI有機配位子而架構為缺氧組織造影劑之化學結構。與造影劑前驅物不同的是，此時DANI已與放射性同位素M相結合，而保護用的三苯甲基則在錯合反應時能自動脫離，不必事先移除。於此，M可選用核醫造影領域常使用的放射性同位素，例如鎝-99m(99mTc)、錸-188(188Re)、銦-115(115In)等。當此種造影劑在進入生物體體內後，將會透過DANI有機配位子結構所提供的2-硝基咪唑官能基而滯留於生物體內的缺氧組織，例如其惡性腫瘤，因此只要透過正子射出造影術或單光子射出造影術，偵測99mTc、188Re、115In等放射性同位素的分佈態樣，就可清楚地觀察到惡性腫瘤的狀態，這對於正確診斷疾病而提升醫療品質有相當大的助益。
以下為本發明於製備DANI之完整操作實施例：Please refer to the fifth figure, which is a chemical structure of the present invention using the DANI organic ligand to construct an anoxic tissue contrast agent. Unlike the contrast agent precursor, DANI has been combined with the radioisotope M at this time, and the protective trityl group is automatically detached in the case of a mismatch reaction without prior removal. Here, M may select a radioisotope commonly used in the field of nuclear medicine, such as 鎝-99m ( 99m Tc), 铼-188 ( 188 Re), indium-115 ( 115 In), and the like. When the contrast agent enters the living body, it will retain the hypoxic tissue in the living body through the 2-nitroimidazole functional group provided by the DANI organic ligand structure, such as a malignant tumor, so Ejection angiography or single-photon emission angiography to detect the distribution of radioisotopes such as 99m Tc, 188 Re, 115 In, etc., can clearly observe the state of malignant tumors, which is equivalent to the correct diagnosis of diseases and improve medical quality. Great help.
The following is a complete operational example of the invention for preparing DANI:
【合成L-Triphenylmethyl cysteine ethyl ester】
取L-cysteine ethyl ester hydrochloride (9.3g，50.0mmol) 及triethylamine (7.9mL，57.1mmol) 共溶於三氯甲烷(100mL)中，加熱迴流，加入triphenylmethanol(13.0g，50.0mmol)，再慢慢滴入boron trifluoride ethyl ether complex(17mL，135.0mmol)，繼續迴流4小時。冷卻後用飽和碳酸氫鈉水溶液(3×100mL) 清洗有機相。有機相經無水硫酸鈉乾燥後減壓濃縮，使用液相層析法(SiO2, chloroform:ethyl acetate = 4:1) 分離純化，得產物L-Triphenylmethyl cysteine ethyl ester (14.0g，72%)。
【合成Triphenylmethyl thioglycolic acid methyl ester】
取methyl thioglycolate(5.0mL，55.0mmol)及triphenylmethanol(14.3g，55.0mmol)共溶於三氯甲烷(80mL)，慢慢滴入boron trifluoride ethyl ether complex (6.9 mL，55.0mmol)在室溫攪拌，應用薄層色層分析(Thin layer chromatography, TLC)(chloroform:hexane = 1:1)追蹤反應，待起始物完全消失後，用水(2×100mL)清洗反應液。有機相經無水硫酸鈉乾燥後減壓蒸乾，獲得產物Triphenylmethyl thioglycolic acid methyl ester (18.6g，97.5%)。
【合成Triphenylmethyl thioglycolic acid】
取Triphenylmethyl thioglycolic acid methyl ester (18.6g，53.5mmol)置10%氫氧化鉀之甲醇溶液(300 mL)中，在室溫攪拌直到完全溶解。減壓濃縮後，用50%甲醇水溶液(100mL)將殘留物溶解，滴入濃鹽酸直到pH值為6，用三氯甲烷(3×100 mL)淬取，有機相經無水硫酸鈉乾燥後減壓蒸乾溶劑，得產物Triphenylmethyl thioglycolic acid (17.9 g，~100 %)。
【合成3-Aza-4-oxo-5-[(triphenylmethyl)thio]pentanoic acid ethyl ester】
取Triphenylmethyl thioglycolic acid (10.1g，30.2mmol)、glycine ethyl ester hydrochloride (4.2g，30.2mmol)、triethylamine (10.4 mL，75.4 mmol)、1,3-dicyclohexylcarbodiimide (9.3 g，45.3 mmol)以及N-hydroxysuccinimide (5.2 g，45.3 mmol)共溶於三氯甲烷(100 mL)中，室溫攪拌隔夜，過濾，濾液用水(1×100 mL)清洗，有機相經無水硫酸鈉乾燥後減壓濃縮，用乙腈(100 mL)溶解殘留物，將乙腈之溶液經濃縮後，使用液相層析法(SiO2, chloroform:hexane = 1:1) 分離純化，得產物3-Aza-4-oxo-5-[(triphenylmethyl)thio]pentanoic acid ethyl ester (9.6 g，75.5 %)。
【合成3-Aza-4-oxo-5-[(triphenylmethyl)thio]pentanoic acid】
取3-Aza-4-oxo-5-[(triphenylmethyl)thio]pentanoic acid ethyl ester (2.8 g，6.8 mmol)置10%氫氧化鉀之甲醇溶液 (80 mL)，在室溫攪拌隔夜後，在室溫下減壓濃縮，再加入四氫呋喃(50 mL)溶解，滴入濃鹽酸直到pH值為6。濃縮後，用甲醇溶解殘留物，將甲醇溶液減壓蒸乾，得產物3-Aza-4-oxo-5-[(triphenylmethyl)thio]pentanoic acid (1.5 g，60 %)。
【合成L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2- [((triphenyl-methyl)thio)methyl]octanoic acid ethyl ester】
取L-Triphenylmethyl cysteine ethyl ester (1.2 g，2.9 mmol)，3-Aza-4-oxo-5-[(triphenylmethyl)thio]pentanoic acid (1.2 g，2.9 mmol)，取1,3-dicyclohexylcarbodiimide (0.9 g，4.4 mmol)及N-hydroxy-succinimide (0.4 g，3.5 mmol)共溶於四氫呋喃(30 mL)中，室溫攪拌隔夜，過濾，將濾液減壓濃縮，用乙腈(30 mL)淬取殘留物，將乙腈溶液濃縮後用液相層析法(SiO2, ethyl acetate:hexane = 1:1) 分離純化，得L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2- [((triphenyl-methyl)thio)methyl]octanoic acid ethyl ester (1.1 g，48 %)。
【合成L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2
-[((triphenyl-methyl) thio)methyl]octanoic acid】
取L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2- [((triphenyl-methyl)thio)methyl]octanoic acid ethyl ester (1.1 g，1.4 mmol)置於10% 氫氧化鉀之甲醇溶液(30 mL)中，在室溫攪拌3小時後，減壓濃縮，加入四氫呋喃(30 mL)，溶解殘留物，滴入濃鹽酸直到pH值為6。再減壓濃縮，用甲醇(30 mL)淬取殘留物，有機相經濃縮後以液相層析法(SiO2, chloroform: methanol = 9 : 1) 分離純化，得L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2
-[((triphenyl-methyl) thio)methyl]octanoic acid (0.16 g，15.6 %)。
【合成tert-butyl 6-hydroxycarbamate】
取化合物6-aminohexanol (5.05 g，43.1 mmol)溶於無水二氯甲烷(50 mL)中。加入di-tert-butyl dicarbonate (12.3 mL，51.7 mmol)在室溫下攪拌隔夜。加入Hexane(100 mL)清洗，取不溶Hexane者，再以水(100 mL)清洗。取有機相層，用Na2SO4除水，減壓濃縮得產物tert-butyl 6-hydroxycarbamate ( 9.06g, 97 %)。
【合成tert-butyl 6-toluenesulfonylhexylcarbamate】
取tert-butyl 6-hydroxycarbamate (4.56 g，21.0 mmol) 溶於無水Pyride (25 mL)，在冰浴狀態下緩慢加入P-toluenesulfonyl chloride (4.00 g，21.0 mmol)並在室溫下攪拌1小時，再加入水(25 mL)並加入濃鹽酸調pH值為酸性。以二氯甲烷 (100 mL)萃取二次，取其有機層，再以2N鹽酸水溶液清洗，取其有機層加入經無水硫酸鈉除水後，減壓蒸乾，使用液相層析法(SiO2, EA : CHCl3=1 : 2) 分離純化，得產物tert-butyl 6-toluenesulfonylhexylcarbamate (4.82 g，62 %)。
【合成tert-butyl 6-(2-nitroimidazole)hexylcarbamate】
取tert-butyl 6-toluenesulfonylhexylcarbamate ( 1.64 g，4.42 mmol)、2-nitroimidazole(0.5 g，4.42mmol)、Cs2CO3( 1.44 g，4.42 mmol)加入無水DMF(20 mL)，並加熱至65℃攪拌2小時。上真空加熱至50℃抽乾，再加入氯仿溶解，取溶者減壓濃縮，使用液相層析法（EA : CHCl3=1 : 4 )分離純化，得產物tert-butyl 6-(2-nitroimidazole)hexylcarbamate (0.68 g，47%)。
【合成DANI】
取tert-butyl 6-(2-nitroimidazole)hexylcarbamate經由氫化反應所得產物6-(2-nitroimidazole)hexylamine (0.24 g，0.71mmol)、N-hydroxysuccinimide (0.12 g，1.04mmol)、1,3-dicyclohexylcarbodiimide (0.22 g，1.07 mmol)、L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2
-[((triphenylmethyl) thio)methyl]octanoic acid (0.59 g，0.71mmol)加入氯仿 (100 mL)，並在室溫下攪拌2.5小時。真空濃縮後加入丙酮溶解，抽氣過濾取濾液濃縮，使用液相層析法(SiO2, CHCl3: CH3OH = 100 : 10) 分離純化，得產物DANI (0.48g, 65 %)。
【Synthesis of L-Triphenylmethyl cysteine ethyl ester】
L-cysteine ethyl ester hydrochloride (9.3g, 50.0mmol) and triethylamine (7.9mL, 57.1mmol) were dissolved in chloroform (100mL), heated under reflux, and added triphenylmethanol (13.0g, 50.0mmol), then slowly Boron trifluoride ethyl ether complex (17 mL, 135.0 mmol) was added dropwise and reflux was continued for 4 hr. After cooling, the organic phase was washed with saturated aqueous sodium bicarbonate (3×100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then purified and purified using liquid chromatography (SiO 2 , chloroform: ethyl acetate = 4:1) to give the product L-triphenylmethyl cysteine ethyl ester (14.0 g, 72%).
【Synthesis of Triphenylmethyl thioglycolic acid methyl ester】
Methyl thioglycolate (5.0 mL, 55.0 mmol) and triphenylmethanol (14.3 g, 55.0 mmol) were dissolved in chloroform (80 mL), and slowly added dropwise to boron trifluoride ethyl ether complex (6.9 mL, 55.0 mmol). The reaction was followed by thin layer chromatography (TLC) (chloroform: hexane = 1:1). After the starting material completely disappeared, the reaction mixture was washed with water (2×100 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to dryness to give the product triphenylmethyl thioglycolic acid methyl ester (18.6 g, 97.5%).
【Synthesis of Triphenylmethyl thioglycolic acid】
Triphenylmethyl thioglycolic acid methyl ester (18.6 g, 53.5 mmol) was placed in 10% potassium hydroxide in methanol (300 mL) and stirred at room temperature until completely dissolved. After concentration under reduced pressure, the residue was dissolved in 50% aqueous methanol (100 mL), and concentrated hydrochloric acid was added dropwise until pH 6 was taken, and extracted with trichloromethane (3×100 mL). The solvent was evaporated to give the product triphenylmethyl thioglycolic acid (17.9 g, ~100%).
[Synthesis of 3-Aza-4-oxo-5-[(triphenylmethyl)thio]pentanoic acid ethyl ester]
Take Triphenylmethyl thioglycolic acid (10.1 g, 30.2 mmol), glycine ethyl ester hydrochloride (4.2 g, 30.2 mmol), triethylamine (10.4 mL, 75.4 mmol), 1,3-dicyclohexylcarbodiimide (9.3 g, 45.3 mmol) and N-hydroxysuccinimide ( 5.2 g, 45.3 mmol) was dissolved in chloroform (100 mL), EtOAc (EtOAc) (EtOAc) The residue was dissolved in 100 mL), and the solution of acetonitrile was concentrated and purified by liquid chromatography (SiO 2 , chloroform:hexane = 1:1) to give the product 3-Aza-4-oxo-5-[( Triphenylmethyl)thio]pentanoic acid ethyl ester (9.6 g, 75.5 %).
[Synthesis of 3-Aza-4-oxo-5-[(triphenylmethyl)thio]pentanoic acid]
3-Aza-4-oxo-5-[(triphenylmethyl)thio]pentanoic acid ethyl ester (2.8 g, 6.8 mmol) was placed in 10% potassium hydroxide in methanol (80 mL) and stirred at room temperature overnight. It was concentrated under reduced pressure at room temperature, then added to tetrahydrofuran (50 mL), and concentrated hydrochloric acid was dropped to pH 6. After concentrating, the residue was dissolved in methanol, and then evaporated to dryness, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
[Synthesis L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2-[((triphenyl-methyl)thio)methyl]octanoic acid ethyl ester]
Take L-Triphenylmethyl cysteine ethyl ester (1.2 g, 2.9 mmol), 3-Aza-4-oxo-5-[(triphenylmethyl)thio]pentanoic acid (1.2 g, 2.9 mmol), and take 1,3-dicyclohexylcarbodiimide (0.9 g) , 4.4 mmol) and N-hydroxy-succinimide (0.4 g, 3.5 mmol) were dissolved in tetrahydrofuran (30 mL), stirred at room temperature overnight, filtered, and the filtrate was concentrated under reduced pressure. The acetonitrile solution was concentrated and purified by liquid chromatography (SiO 2 , ethyl acetate:hexane = 1:1) to obtain L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio ]-2-[((triphenyl-methyl)thio)methyl]octanoic acid ethyl ester (1.1 g, 48%).
[Synthesis of L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2
-[((triphenyl-methyl) thio)methyl]octanoic acid]
L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2-[((triphenyl-methyl)thio)methyl]octanoic acid ethyl ester (1.1 g, 1.4 mmol) was placed After stirring at room temperature for 3 hours, a solution of EtOAc (3 mL), EtOAc (EtOAc) The mixture was concentrated under reduced pressure. The residue was purified eluting with methanol (30mL). The organic phase was concentrated and purified by liquid chromatography (SiO 2 , chloroform: methanol = 9 : 1 ) to give L-3,6-Diaza -4,7-dioxo-8-[(triphenylmethyl)thio]-2
-[((triphenyl-methyl) thio)methyl]octanoic acid (0.16 g, 15.6%).
[Synthetic tert-butyl 6-hydroxycarbamate]
The compound 6-aminohexanol (5.05 g, 43.1 mmol) was dissolved in anhydrous dichloromethane (50 mL). Di-tert-butyl dicarbonate (12.3 mL, 51.7 mmol) was added and stirred at room temperature overnight. Wash with Hexane (100 mL), insoluble Hexane, and rinse with water (100 mL). The organic layer was taken, and water was evaporated with Na2SO?
[Synthetic tert-butyl 6-toluenesulfonylhexylcarbamate]
The tert-butyl 6-hydroxycarbamate (4.56 g, 21.0 mmol) was dissolved in anhydrous Pyry (25 mL). P-toluenesulfonyl chloride (4.00 g, 21.0 mmol) was slowly added in an ice bath and stirred at room temperature for 1 hour. Further water (25 mL) was added and concentrated hydrochloric acid was added to adjust the pH to be acidic. The organic layer was extracted with dichloromethane (100 mL), and then washed with 2N aqueous hydrochloric acid. , EA : CHCl3 = 1: 2) Separation and purification gave the product tert-butyl 6-toluenesulfonylhexylcarbamate (4.82 g, 62%).
[Synthesis of tert-butyl 6-(2-nitroimidazole)hexylcarbamate]
Add tert-butyl 6-toluenesulfonylhexylcarbamate ( 1.64 g, 4.42 mmol), 2-nitroimidazole (0.5 g, 4.42 mmol), Cs 2 CO 3 ( 1.44 g, 4.42 mmol) to dry DMF (20 mL) and warm to 65 ° C Stir for 2 hours. The mixture was heated to 50 ° C under vacuum, and then dissolved in chloroform. The solvent was concentrated under reduced pressure and purified by liquid chromatography (EA: CHCl3 = 1: 4) to give the product tert-butyl 6-(2-nitroimidazole )hexylcarbamate (0.68 g, 47%).
[synthetic DANI]
The product obtained by hydrogenation of tert-butyl 6-(2-nitroimidazole)hexylcarbamate 6-(2-nitroimidazole)hexylamine (0.24 g, 0.71 mmol), N-hydroxysuccinimide (0.12 g, 1.04 mmol), 1,3-dicyclohexylcarbodiimide ( 0.22 g, 1.07 mmol), L-3,6-Diaza-4,7-dioxo-8-[(triphenylmethyl)thio]-2
-[((triphenylmethyl) thio)methyl]octanoic acid (0.59 g, 0.71 mmol) was added to chloroform (100 mL) and stirred at room temperature for 2.5 hr. After concentration in vacuo, acetone was added to dissolve, and the filtrate was concentrated by suction filtration, and purified by liquid chromatography (SiO 2 , CHCl 3 : CH 3 OH = 100 : 10) to give product DANI (0.48 g, 65 %).
配合透過上述之步驟，所製備之DANI即具有良好的保存性質，待使用前與放射性同位素錯合後，所形成之造影劑即可透過DANI的官能基作用而滯留於生物體的缺氧組織，並同時致使放射性同位素能夠確實抵達該些缺氧組織於生物體內的位置，發揮造影劑之功效，故本發明無疑提供了一種具實用價值之缺氧組織造影劑前驅物、其造影劑及其製備方法。In combination with the above steps, the prepared DANI has good storage properties, and the contrast agent formed after being mismatched with the radioisotope before use can be retained in the anoxic tissue of the organism through the functional group of DANI. At the same time, the radioactive isotope can surely reach the position of the hypoxic tissue in the living body and exert the effect of the contrast agent, so the invention undoubtedly provides a practical hypoxic tissue contrast agent precursor, the contrast agent and the preparation thereof. method.
惟以上所述者，僅為本發明之較佳實施例而已，並非用來限定本發明實施之範圍，舉凡依本發明申請專利範圍所述之形狀、構造、特徵及精神所為之均等變化與修飾，均應包括於本發明之申請專利範圍內。The above is only the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and the variations, modifications, and modifications of the shapes, structures, features, and spirits described in the claims of the present invention. All should be included in the scope of the patent application of the present invention.
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Claims (16)
。A contrast agent precursor comprising a structure:
.
使用6-胺基-1-己醇與第三丁基碳酸酯，進行胺基保護反應，生成6-羥基胺基甲酸第三丁酯；
使用6-羥基胺基甲酸第三丁酯與對-甲苯磺醯氯，在吡啶溶液中進行取代反應，生成6-甲苯磺醯己基胺基甲酸第三丁酯；
使用6-甲苯磺醯己基胺基甲酸第三丁酯與2-硝基咪唑，在二甲基甲醯胺溶液中進行取代反應，生成6-(2-硝基咪唑)己基胺基甲酸第三丁酯；以及
氫化6-(2-硝基咪唑)己基胺基甲酸第三丁酯，使其還原為6-(2-硝基咪唑)己胺，再與L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛酸進行醯胺化反應，生成6-(2-硝基咪唑)己基-L-L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛醯胺。A method for preparing a contrast agent precursor, comprising the steps of:
6-amino-1-hexanol and a third butyl carbonate are subjected to an amine group protection reaction to form a 6-hydroxyaminocarbamic acid tert-butyl ester;
Using 6-hydroxyaminocarbamic acid tert-butyl ester and p-toluenesulfonium chloride, a substitution reaction in a pyridine solution to form a third butyl 6-toluenesulfonylhexylcarbamate;
The third substitution of 6-toluenesulfonylhexylaminocarbamate and 2-nitroimidazole is carried out in a dimethylformamide solution to form 6-(2-nitroimidazolyl)hexylaminocarboxylic acid. Butyl ester; and hydrogenated 6-(2-nitroimidazolium) hexylaminocarboxylic acid tert-butyl ester, which is reduced to 6-(2-nitroimidazolium) hexylamine, and then with L-3,6-diaza -4,7-dioxo-8-[(trityl)thio]-2-[((trityl)thio)methyl]octanoic acid is subjected to amidoximation to give 6-(2 -nitroimidazolium)hexyl-LL-3,6-diaza-4,7-dioxo-8-[(trityl)thio]-2-[((trityl)thio) )methyl]octylamine.
將乙硫醇酸甲基酯之硫醇基以三苯甲基保護，生成三苯甲基乙硫醇酸甲基酯；
水解三苯甲基乙硫醇酸甲基酯於鹼性甲醇溶液，生成三苯甲基乙硫醇酸；
將三苯甲基乙硫醇酸與甘胺酸乙酯進行醯胺化反應，生成3-氮雜-4 -氧代-5-[(三苯甲基)硫基]戊酸乙基酯；
水解3-氮雜-4 -氧代-5-[(三苯甲基)硫基]戊酸乙基酯於鹼性甲醇溶液，生成3-氮雜-4 -氧代-5-[(三苯甲基)硫基]戊酸；
將3-氮雜-4 -氧代-5-[(三苯甲基)硫基]戊酸與L-三苯甲基副胱胺酸乙基酯進行醯胺化反應，生成L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛酸乙基酯；以及
水解L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛酸乙基酯，生成該L-3,6-二氮雜-4,7-二氧代-8-[(三苯甲基)硫基]-2-[((三苯甲基)硫基)甲基]辛酸。The preparation method according to claim 3, wherein the L-3,6-diaza-4,7-dioxo-8-[(trityl)thio]-2-[( The preparation method of (tritylmethyl)thio)methyl]octanoic acid comprises the steps of:
The thiol group of methyl ethanesulfonate is protected with trityl group to form methyl ester of trityl ethanethiol acid;
Hydrolyzing a methyl ester of trityl ethane thiolate in an alkaline methanol solution to form trityl ethanethiol acid;
The mercaptoylation reaction of trityl ethanethiol acid with ethyl glycinate to form ethyl 3-aza-4-oxo-5-[(trityl)thio]pentanoate;
Hydrolysis of 3-azet-4-oxo-5-[(trityl)thio]pentanoic acid ethyl ester in an alkaline methanol solution to form 3-aza-4-oxo-5-[(three Benzyl)thio]pentanoic acid;
3-Aza-4-oxo-5-[(trityl)thio]pentanoic acid is subjected to amidoximation with L-trityl paracysteine to form L-3. 6-diaza-4,7-dioxo-8-[(trityl)thio]-2-[((trityl)thio)methyl]octanoic acid ethyl ester; and hydrolysis L-3,6-diaza-4,7-dioxo-8-[(trityl)thio]-2-[((trityl)thio)methyl]octanoic acid ethyl Ester to form L-3,6-diaza-4,7-dioxo-8-[(trityl)thio]-2-[((trityl)thio)methyl ] bitter.
其中，M係選自鎝-99m、錸-188以及銦-115所組成之群組其中之一者。A contrast agent comprising a structure:
Among them, the M system is selected from the group consisting of 鎝-99m, 铼-188, and indium-115.
The contrast agent of claim 15 wherein the contrast agent comprising the structure is for use in nuclear diagnostic imaging of hypoxic tissue.
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| TWI633099B (en) * | 2016-10-04 | 2018-08-21 | 行政院原子能委員會核能研究所 | Contrast agent precursor and method for preparing the same |
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