KR100338652B1 - Radioiodination of boronophenylalanine - Google Patents
Radioiodination of boronophenylalanine Download PDFInfo
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- KR100338652B1 KR100338652B1 KR1019990013348A KR19990013348A KR100338652B1 KR 100338652 B1 KR100338652 B1 KR 100338652B1 KR 1019990013348 A KR1019990013348 A KR 1019990013348A KR 19990013348 A KR19990013348 A KR 19990013348A KR 100338652 B1 KR100338652 B1 KR 100338652B1
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- boronphenylalanine
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- NFIVJOSXJDORSP-QMMMGPOBSA-N (2s)-2-amino-3-(4-boronophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(B(O)O)C=C1 NFIVJOSXJDORSP-QMMMGPOBSA-N 0.000 title 1
- ZUXWRGYAUISHCH-QRPNPIFTSA-N (2s)-2-amino-3-phenylpropanoic acid;boron Chemical compound [B].OC(=O)[C@@H](N)CC1=CC=CC=C1 ZUXWRGYAUISHCH-QRPNPIFTSA-N 0.000 claims abstract description 27
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910052796 boron Inorganic materials 0.000 claims abstract description 15
- 238000002372 labelling Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- XMBWDFGMSWQBCA-RNFDNDRNSA-M iodine-131(1-) Chemical compound [131I-] XMBWDFGMSWQBCA-RNFDNDRNSA-M 0.000 claims abstract description 7
- 238000001727 in vivo Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 3
- 238000005259 measurement Methods 0.000 claims 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 abstract description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 abstract description 3
- 150000001639 boron compounds Chemical class 0.000 abstract description 2
- 201000001441 melanoma Diseases 0.000 description 15
- 206010028980 Neoplasm Diseases 0.000 description 10
- 206010018338 Glioma Diseases 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 208000032612 Glial tumor Diseases 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 4
- 210000000689 upper leg Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002354 inductively-coupled plasma atomic emission spectroscopy Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- -1 boron phenylalanine iodine Chemical compound 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001638 boron Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000030381 cutaneous melanoma Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000000693 radiobiological effect Effects 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
- A47J—KITCHEN EQUIPMENT; COFFEE MILLS; SPICE MILLS; APPARATUS FOR MAKING BEVERAGES
- A47J31/00—Apparatus for making beverages
- A47J31/44—Parts or details or accessories of beverage-making apparatus
- A47J31/50—Urns with devices for keeping beverages hot or cool
-
- A—HUMAN NECESSITIES
- A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
- A47J—KITCHEN EQUIPMENT; COFFEE MILLS; SPICE MILLS; APPARATUS FOR MAKING BEVERAGES
- A47J31/00—Apparatus for making beverages
- A47J31/44—Parts or details or accessories of beverage-making apparatus
- A47J31/54—Water boiling vessels in beverage making machines
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B67—OPENING, CLOSING OR CLEANING BOTTLES, JARS OR SIMILAR CONTAINERS; LIQUID HANDLING
- B67D—DISPENSING, DELIVERING OR TRANSFERRING LIQUIDS, NOT OTHERWISE PROVIDED FOR
- B67D3/00—Apparatus or devices for controlling flow of liquids under gravity from storage containers for dispensing purposes
- B67D3/0009—Apparatus or devices for controlling flow of liquids under gravity from storage containers for dispensing purposes provided with cooling arrangements
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B67—OPENING, CLOSING OR CLEANING BOTTLES, JARS OR SIMILAR CONTAINERS; LIQUID HANDLING
- B67D—DISPENSING, DELIVERING OR TRANSFERRING LIQUIDS, NOT OTHERWISE PROVIDED FOR
- B67D3/00—Apparatus or devices for controlling flow of liquids under gravity from storage containers for dispensing purposes
- B67D3/0022—Apparatus or devices for controlling flow of liquids under gravity from storage containers for dispensing purposes provided with heating arrangements
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
- F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
- F25D31/00—Other cooling or freezing apparatus
- F25D31/005—Combined cooling and heating devices
Abstract
본 발명은 붕소중성자 포획치료에 사용되는 붕소화합물인 붕소페닐알라닌의 표지에 관한 것으로, 보다 상세하게는 붕소페닐알라닌의 세포 및 체내동태를 간단히 확인하기 위하여 붕소페닐알라닌에 방사성 동위원소인123I를 표지한 붕소페닐알라닌의 방사요오드 표지화합물에 관한 것이다.The present invention relates to the labeling of boron phenylalanine, a boron compound used in the treatment of boron neutron capture, and more particularly, boron phenylalanine is labeled with 123 I, which is a radioisotope, in order to easily identify the cell and body kinetics of boron phenylalanine. A radioiodine labeling compound of phenylalanine.
Description
본 발명은 붕소중성자 포획치료에 사용되는 붕소화합물인 붕소페닐알라닌의 표지에 관한 것으로, 보다 상세하게는 붕소페닐알라닌의 세포 및 체내동태를 간단히 확인하기 위하여 붕소페닐알라닌에 방사성 동위원소인123I를 표지한 붕소페닐알라닌의 방사요오드 표지화합물에 관한 것이다.The present invention relates to the labeling of boron phenylalanine, a boron compound used in the treatment of boron neutron capture, and more particularly, boron phenylalanine is labeled with 123 I, which is a radioisotope, in order to easily identify the cell and body kinetics of boron phenylalanine. A radioiodine labeling compound of phenylalanine.
종래에 인체의 질병에 대한 진단 및 치료에 있어서, 방사성 동위원소 자체를사용하거나, 관찰하고자 하는 장기에 특이적으로 결합내지 대사되는 화합물을 사용하였으나, 현재에는 특이 화합물에 방사성 동위원소를 표지하여 사용하는 경우가 주류를 이루고 있다.Conventionally, in the diagnosis and treatment of diseases of the human body, a radioisotope itself or a compound that specifically binds to or metabolizes an organ to be observed is used, but now a radioactive isotope is labeled on a specific compound This is the mainstream.
페닐알라닌은 아미노산중에서 소수성이 강한 방향족 단백질 구성물질이고, 그 붕소유도체인 하기의 화학식 2로 표시되는 붕소페닐알라닌은 단백질대사가 활발한 종양세포로의 집적이 높은 것으로 보고되고 있다(예컨대, 「Advances in Neutron Capture Therapy Volume II, Chemistry and Biology」(1997년, ELSEVIER)등).〔화학식 2〕상기한 화학식 2로 표시되는 붕소페닐알라닌은 악성 종양에 선택적으로 결합하며, 특히 피부암인 흑색종에 높은 집적을 보이는 것으로 알려져 있다. 현재 미국에서는 뇌암인 신경교종과 피부암인 흑색종에 대해 붕소중성자 포획치료용으로 붕소페닐알라닌과 열외중성자를 사용하여 치료를 행하고 있다. 그 치료대상은 주로 악성 뇌신경교종과 피부암인 흑색종이나, 그밖에 간암, 폐암 등에 대해서도 연구중에 있다.Phenylalanine is an aromatic protein component having a strong hydrophobicity among amino acids, and boron phenylalanine represented by the following formula (2), a boron derivative thereof, has been reported to have high accumulation in tumor cells with active protein metabolism (for example, `` Advances in Neutron Capture ''. Therapy Volume II, Chemistry and Biology ”(ELSEVIER, 1997). Boronphenylalanine represented by the above formula (2) selectively binds to malignant tumors, and is known to exhibit high accumulation, particularly in melanoma, a skin cancer. In the United States, the treatment of boron neutron capture treatment for glioma, a brain cancer, and melanoma, a skin cancer, is carried out using boron phenylalanine and an exogenous neutron. The treatment targets are mainly malignant glioma and melanoma skin cancer, and liver cancer and lung cancer.
흑색종 치료에 사용되는 붕소중성자 포획치료법(Boron neutron capture therapy)은 붕소페닐알라닌(boronophenylalanine)을 환자에 주사한 후, 암조직에 열중성자선을 조사하여 열중성자선으로부터 방사되는 α입자 등에 의해 암을 선택적으로 치료하는 방법이다. 보다 상세하게 설명하면, 흑색종에 친화성을 띠는 붕소페닐알라닌을 환자에 주사한 후, 0.0035eV의 열중성자빔을 조사하면 열중성자가 붕소에 포획되면서 He(α), Li 및 γ선으로 분해되어 방사된다. 방사되는 방사선은 방사생물학적 영향이 매우 큰 MeV 단위의 강력한 에너지를 가지고 있으며, 이중 주로 α선에 의해 암조직이 죽게된다.Boron neutron capture therapy, which is used to treat melanoma, injects boronphenylalanine into a patient and then irradiates the cancer tissue with a thermal neutron beam to prevent cancer by α particles emitted from the thermal neutron beam. It is a method of selective treatment. More specifically, after injecting boronphenylalanine with affinity for melanoma into a patient and irradiating a 0.0035 eV thermal neutron beam, the thermal neutrons are trapped in boron and decomposed into He (α), Li and γ rays. And radiates. Radiated radiation has a strong energy of MeV unit with a very large radiobiological effect, of which cancer tissue is killed mainly by α rays.
즉 붕소페닐알라닌은 정상부위보다 흑색종부위에 많이 흡수되고, 전리작용이 매우 강한 α선이 암세포에 충돌되는 범위가 피부세포의 반지름밖에 되지 않는 산란에 의한 비정거리(tissue penetration range)를 가지기 때문에, 저속 중성자로 구성된 방사장에 노출된 붕소페닐알라닌을 포함하는 흑색종세포는 종양이 없는 주위의 정상 세포보다 선택적으로 많은 방사선을 조사받게 되어 죽게된다.In other words, boron phenylalanine is absorbed more in melanoma than normal, and the ionizing ray, which has a strong ionization effect, has a tissue penetration range due to scattering, in which the range of collision with cancer cells is only the radius of skin cells. Melanoma cells containing boronphenylalanine exposed to a neutron radiation field are selectively irradiated more than normal cells around the tumor and die.
그러나 종래의 붕소중성자 포획치료용으로 사용되는 붕소페닐알라닌의 경우 다음과 같은 단점이 있다. 동물실험에 있어서, 주사된 붕소페닐알라닌이 체내에서 어떻게 거동되는지 관찰하기 위해 유도결합 프라즈마 원자방출분광법을 사용하여 각 조직에서의 붕소 농도를 측정하였다. 즉 붕소페닐알라닌의 체내 흡수율은 직접 측정할 수 없는 대신 붕소농도를 측정함으로써 간접적으로 붕소페닐알라닌의 붕소투여량을 예측하는 정도였다. 또 상기 방법은 실험동물의 장기를 적출하여 강산 등에 조직을 완전히 용해시킨 후 ICP-AES(Inductively Coupled Plasma Atomic Emission Spectrometry)를 사용하여 붕소 농도를 측정하는 것이나, 이와 같은 측정장비는 고가이고 그 측정에 장기간 소요된다는 단점이 있었다.However, the conventional boron phenylalanine used for the treatment of boron neutron capture has the following disadvantages. In animal experiments, boron concentration in each tissue was measured using inductively coupled plasma atomic emission spectroscopy to observe how the injected boronphenylalanine behaves in the body. In other words, the body absorption rate of boron phenylalanine could not be measured directly, but the boron concentration of boron phenylalanine was indirectly estimated by measuring the concentration of boron. In addition, the method is to remove the organs of the experimental animal to completely dissolve the tissue in a strong acid, etc. and then to measure the boron concentration using ICP-AES (Inductively Coupled Plasma Atomic Emission Spectrometry), but such measuring equipment is expensive and There was a drawback to the long run.
현재 붕소중성자 포획치료방법으로 흑색종치료에 사용되는 붕소페닐알라닌의 생체내 거동을 관찰하기 위한 방사성 동위원소 추적자에 대한 개발은 이루어져 있지 않다. 본 발명은 붕소페닐알라닌에 방사성 동위원소인123I를 표지하여123I로부터 방사되는 방사능을 측정하는 것만으로 붕소페닐알라닌의 세포내 섭취 및 분포를 손쉽게 알 수 있게 한 것이다.Currently, no radioisotope tracer has been developed to observe the in vivo behavior of boronphenylalanine for the treatment of melanoma as a treatment method for boron neutron capture. The invention enables one to easily know the radioisotope is 123 I for intracellular uptake and distribution of the boron-phenylalanine only by measuring the radioactivity emitted from the 123 I labeled to a boron-phenylalanine.
본 발명자는 상기와 같은 종래 기술의 단점을 극복하기 위한 것으로, 붕소중성자 치료법에 효과적인 물질인 붕소페닐알라닌의 생체 내의 거동을 용이하게 관찰하기 위한 방사성 동위원소 추적자를 개발하고 본 발명을 완성하였다.The present inventors have overcome the disadvantages of the prior art as described above, and have completed the present invention by developing a radioisotope tracer for easily observing the in vivo behavior of boronphenylalanine, which is an effective substance for treating boron neutrons.
본 발명은 붕소페닐알라닌을 인체에 적용하는 경우, 붕소페닐알라닌의 흑색종에의 붕소흡수 정도 및 거동방식을 용이하게 관찰하기 위한 것을 목적으로 한다.An object of the present invention is to easily observe the degree of boron absorption and behavior of boron phenylalanine to melanoma when boron phenylalanine is applied to the human body.
도 1은123I-붕소페닐알라닌의 고성능 액체크로마토그라피를 나타낸 그래프1 is a graph showing the high performance liquid chromatography of 123 I-boronphenylalanine
도 2는 신경교종 세포를 이식한 백서의 장기별 경시변화에 따른123I-붕소페닐알라닌 분포를 나타낸 그래프Figure 2 is a graph showing the distribution of 123 I-boronphenylalanine according to the change over time of the transplanted white graft cells of glioma cells
도 3은 흑색종 세포를 이식한 마우스의 장기별 경시변화에 따른123I-붕소페닐알라닌 분포를 나타낸 그래프Figure 3 is a graph showing the distribution of 123 I-boronphenylalanine according to the change over time of the mice transplanted with melanoma cells
본 발명은 상기의 목적을 달성하기 위하여 붕소페닐알라닌에 방사성 동위원소인123I를 표지한 하기의 화학식 1로 표시되는 방사요오드 표지화합물을 제공한다.〔화학식 1〕 The present invention provides a radioiodine labeling compound represented by the following Chemical Formula 1 in which 123 I, which is a radioisotope, is labeled on boronphenylalanine in order to achieve the above object.
붕소페닐알라닌에123I를 표지한 상기한 화학식 1로 표시되는 붕소페닐알라닌의 방사요오드 표지화합물을 인체에 투여한 후, 방사성 동위원소123I에서 나오는 방사능을 측정함으로써 붕소페닐알라닌의 체내 거동을 예상할 수 있다. 붕소페닐알라닌과 붕소페닐알라닌 요오드화합물은123I의 표지에 의한 물성변화가 없기 때문에, 체내에서 동일한 거동을 나타내게 된다. 따라서 붕소페닐알라닌을 사용하는 종래기술과 같이 방사능 측정을 위해 고가의 장비를 구비할 필요없으며,123I에서 방사되는 방사능을 감마카운터로 측정함으로써 흑색종 조직내의 붕소페닐알라닌의 함량을 알 수 있게 된다. 붕소페닐알라닌의 함량이 많은 부위가 흑색종이 발생한 부위라는 것을 알 수 있게 된다.In vivo administration of the boron phenylalanine by measuring the radioactivity from the radioisotope 123 I after administering a radioiodine labeling compound of the boron phenylalanine represented by the formula (1) labeled 123 I on the boron phenylalanine to the human body . The boron phenylalanine and boron phenylalanine iodine compound exhibit the same behavior in the body because there is no change in physical properties by the label of 123 I. Therefore, it is not necessary to have expensive equipment for measuring radioactivity as in the prior art using boron phenylalanine, and the content of boron phenylalanine in melanoma tissue can be known by measuring the radioactivity emitted from 123 I by gamma counter. It can be seen that the high content of boronphenylalanine is the site of melanoma.
본 발명은 붕소페닐알라닌의 방사요오드 표지화합물에 관한 것으로, 하기의 실시예에서는 백서(fisher rat)의 뇌에 신경교종을 이식한 실험과 마우스의 우측대퇴부에 흑색종을 이식한 실험을 행하였다.The present invention relates to a radioiodine labeling compound of boron phenylalanine. In the following examples, an experiment was performed in which gliomas were transplanted into the brain of a fisher rat, and melanoma was implanted into the right thigh of a mouse.
도 1은123I를 붕소페닐알라닌에 표지한 후의 표지화합물인123I-붕소페닐알라닌의 고속 액체크로마토그라피(HPLC)를 나타낸 그래프이다. 표지정도는 방사능검출기를 사용하여123I에서 방사되는 방사능을 측정함으로써 알 수 있다.Figure 1 is a graph showing the labeling compound is a high performance liquid 123 of I- boron phenylalanine chromatography (HPLC) after being labeled with 123 I to a boron-phenylalanine. Labeling can be determined by measuring radioactivity emitted at 123 I using a radioactivity detector.
본 실시예에서 사용된 붕소페닐알라닌의 방사요오드 표지화합물은 다음과 같이 합성하였다. 붕소페닐알라닌 5mg을 50㎕의 트리플로오르아세틴산으로 용해시킨 후, 0.2몰 칼륨버퍼 1㎖를 넣고 수산화나트륨을 이용하여 pH 7∼8로 조정한다. 이후 반응용기에 이오도비드(pharmacia Co.사 제조) 1개와 붕소페닐알라닌 용액 200㎕를 넣고, 포타슘아이오다이드 15㎕/5㎕를 첨가한다. 약 2mCi/20㎕의 Na123I를 넣고 교반하에 실온에서 30분 동안 반응시킨다.The radioiodine labeling compound of boronphenylalanine used in this Example was synthesized as follows. After dissolving 5 mg of boronphenylalanine with 50 µl of trifluoroacetinic acid, 1 ml of 0.2 mol potassium buffer was added and adjusted to pH 7-8 using sodium hydroxide. Thereafter, one iodobide (manufactured by Pharmacia Co.) and 200 µl of boronphenylalanine solution were added to the reaction vessel, and 15 µl / 5 µl of potassium iodide was added thereto. Add about 2mCi / 20ul Na 123 I and react for 30 minutes at room temperature under stirring.
고속 액체크로마토그라피 C18μ 본드어팩(bondapak) 컬럼을 사용하여 반응 종료 후의 반응혼합물의 표지수율을 측정한다. 반응혼합물의 전개제로서 증류수:에틸알코올:아세트산 = 87.5:10:2.5인 이동상을 사용하고, 이동속도는 1㎖/분이다. 반응혼합물은 전개개시 후 약 17분경에 요오드 붕소페닐알라닌이 분리된다. 표지수율은 80∼90% 이상인 것으로 확인할 수 있다. 그 결과를 도 1에 나타낸다.The label yield of the reaction mixture after the completion of the reaction was measured using a high performance liquid chromatography C18μ bondapak column. As a developing agent of the reaction mixture, a mobile phase of distilled water: ethyl alcohol: acetic acid = 87.5: 10: 2.5 was used, and the moving speed was 1 ml / min. The reaction mixture is separated from iodine boron phenylalanine about 17 minutes after the start of development. It is confirmed that the label yield is 80 to 90% or more. The result is shown in FIG.
도 2는 신경교종을 마우스의 뇌에 이식한 다음 분리 정제된123I-BPA를 주사한 후의 경시변화에 따른 장기별123I-BPA 분포를 나타낸 그래프이다. 도 2에 나타난 바와 같이,123I-BPA는 정상적인 뇌부위보다 뇌종양에 다량으로 집적되는 것을알 수 있다. 또123I-BPA는 대사상의 특성때문에 다른 정상적인 장기에도 접적되나, 붕소중성자 포획치료는 수술시 원하는 부위에만 중성자를 조사하기 때문에 다른 부위에의 집적은 고려대상이 아니다. 한편 도 2는 최적 집적시간이123I-BPA 주사후 1시간대임을 알 수 있다.Figure 2 is a graph showing the distribution of 123 I-BPA by organ according to the change over time after glioma transplanted to the brain of the mouse and injected with purified purified 123 I-BPA. As shown in Figure 2, it can be seen that 123 I-BPA is accumulated in a greater amount of brain tumor than normal brain region. In addition, 123 I-BPA is incorporated into other normal organs because of its metabolic properties. However, boron neutron capture therapy only examines neutrons at desired sites during surgery, so accumulation at other sites is not considered. 2 shows that the optimal integration time is 1 hour after the 123 I-BPA injection.
도 3은 흑색종을 마우스의 허벅지에 이식한 다음123I-BPA를 주사한 후의 경시변화에 따른 장기별123I-BPA 분포를 나타낸 그래프이다. 도 3에 나타난 바와 같이,123I-BPA는 정상 근육부위보다 허벅지종양에 다량으로 집적되는 것을 알 수 있다.Figure 3 is a graph showing the long-term specific 123 I-BPA distribution according to change with time after the injection of 123 I-BPA then transplanted melanoma in the thigh of the mouse. As shown in Figure 3, it can be seen that 123 I-BPA is accumulated in a greater amount of thigh tumor than normal muscle area.
(실시예 1)(Example 1)
신경교종을 이식한 백서와 흑색종을 이식한 마우스에 요오드 붕소페닐알라닌을 주입한 후의 경시변화에 따른 생체내 분포실험을 하였다.In vivo distribution experiments were performed according to the change over time after injection of iodine boronphenylalanine into glioma-transplanted rats and melanoma-grafted mice.
9L 신경교종 배양세포(9L glioma: ATCC; American Type Culture Collection) 1×107개를 백서의 좌측뇌에 이식하였고, B16 흑색종을 마우스의 우측대퇴부에 이식하였다. 이식한지 14일이 경과한 후에123I-붕소페닐알라닌 100μCi를 백서 및 마우스의 꼬리정맥에 각각 주사하고 30분, 1시간 및 24시간이 경과한 다음 각 장기 및 종양을 적출하였다. 적출된 장기들을 감마카운터로 방사능을 측정하여 단위 조직당 방사능을 측정하였다. 시간이 경과함에 따라 장기에서의 분포가 달라지는 것을 확인하였다. 그 결과를 도 2 및 도 3에 나타낸다. 상기 도로부터 알 수 있는 바와 같이, 정상부위보다는 종양에123I-BPA가 많이 집적되는 것으로 나타났다.1 × 10 9 L glioma culture cells (9 L glioma: ATCC; American Type Culture Collection) were transplanted into the left brain of the white paper, and B16 melanoma was implanted into the right thigh of the mouse. After 14 days of implantation, 100 μCi of 123 I-boronphenylalanine was injected into the tail vein of white paper and mouse, respectively, and after 30 minutes, 1 hour and 24 hours, each organ and tumor were extracted. The extracted organs were measured for radioactivity with a gamma counter to measure radioactivity per unit tissue. It was confirmed that the distribution in organs changed over time. The results are shown in FIGS. 2 and 3. As can be seen from the figure, it was shown that more 123 I-BPA was accumulated in the tumor than in the normal region.
본 발명에 의한123I-붕소페닐알라닌은 고가의 측정장비없이 암종치료에 사용되는 붕소페닐알라닌의 체내동태 및 암종 내의 붕소페닐알라닌의 함량을123I로부터 방사되는 방사능을 감마카운터로 측정함으로써 용이하게 관찰 또는 진단할 수 있다. 123 I- boron-phenylalanine according to the present invention is easily observed or diagnosed by measuring the radiation emitted, the content of boron-phenylalanine in the pharmacokinetics and carcinoma of the boron-phenylalanine for use in cancer treatment without expensive measuring equipment from the 123 I in a gamma counter can do.
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