KR20180001250A - A compound for PET imaging and use thereof - Google Patents
A compound for PET imaging and use thereof Download PDFInfo
- Publication number
- KR20180001250A KR20180001250A KR1020160080137A KR20160080137A KR20180001250A KR 20180001250 A KR20180001250 A KR 20180001250A KR 1020160080137 A KR1020160080137 A KR 1020160080137A KR 20160080137 A KR20160080137 A KR 20160080137A KR 20180001250 A KR20180001250 A KR 20180001250A
- Authority
- KR
- South Korea
- Prior art keywords
- phosphonium
- pyrimidin
- pyridin
- butyl
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 47
- 238000012879 PET imaging Methods 0.000 title abstract description 6
- 230000002285 radioactive effect Effects 0.000 claims abstract description 28
- 239000002872 contrast media Substances 0.000 claims abstract description 11
- -1 (tert-butoxycarbonyl) amino Chemical group 0.000 claims description 272
- 150000003839 salts Chemical class 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 235000010290 biphenyl Nutrition 0.000 claims description 13
- 239000004305 biphenyl Substances 0.000 claims description 13
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 13
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 125000006267 biphenyl group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 238000002600 positron emission tomography Methods 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 239000002738 chelating agent Substances 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 150000004696 coordination complex Chemical class 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical group ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000000732 arylene group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
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- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims 1
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- 239000007924 injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
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- 150000002823 nitrates Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012857 radioactive material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000008054 sulfonate salts Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- FIBZWZNESGFSRR-UHFFFAOYSA-N tert-butyl N-(4-phosphanylbutyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCP FIBZWZNESGFSRR-UHFFFAOYSA-N 0.000 description 1
- LIYMTLVBAVHPBU-UHFFFAOYSA-N tert-butyl n-(4-hydroxybutyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCO LIYMTLVBAVHPBU-UHFFFAOYSA-N 0.000 description 1
- KSFVNEXYCULLEJ-UHFFFAOYSA-N tert-butyl n-[2-(2-hydroxyethoxy)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCOCCO KSFVNEXYCULLEJ-UHFFFAOYSA-N 0.000 description 1
- 229960004113 tetrofosmin Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
본 발명은 심장의 효율적인 조영을 위한 방사성 화합물의 제조를 위한 전구체 화합물 및 상기 전구체 화합물을 이용하여 제조된 방사성 화합물 및 그의 PET 조영용 조영제로서의 용도를 제공한다. The present invention provides a precursor compound for the production of a radioactive compound for efficient imaging of the heart, a radioactive compound prepared using the precursor compound, and its use as contrast medium for PET imaging.
Description
본 발명은 신규 화합물 및 그의 용도에 관한 것으로서, 보다 구체적으로는 PET 조영용 신규 화합물 및 그의 용도에 관한 것이다. The present invention relates to novel compounds and uses thereof, and more particularly to novel compounds for PET imaging and uses thereof.
관상동맥질환은 현재 우리나라 사망 원인 중 3-4위를 차지할 정도로 중요한 위치를 차지하고 있다. 특히 지난 20여년간 그 유병률이 5배 가까이 빠르게 증가하고 있으며 이는 세계적인 추세에 미루어 볼 때 더욱더 가속화가 될 것이다. 관상동맥질환의 증상은 45-50세 이후에 주로 나타나지만, 최근 들어 관상동맥질환의 유병률이 증가하고, 젊은 환자에서 증상이 발생하는 경우도 늘어나고 있어 점차 조기 진단 및 예방의 중요성이 커지고 있다.Coronary artery disease accounts for 3-4 of the causes of death in Korea. In particular, the prevalence has increased nearly five times over the past two decades, and this will accelerate further in the global trend. Symptoms of coronary artery disease appear mainly after 45-50 years of age, but the prevalence of coronary artery disease has increased in recent years, and the number of cases with symptoms in younger patients has been increasing, and the importance of early diagnosis and prevention is gradually increasing.
관상동맥질환은 운동부하 검사, 심장 초음파 검사, 관상동맥 조영술, 핵의학 검사의 방법들을 통해서 조기진단을 시행한다. 하지만 운동부하 검사는 협심증의 경우 증상이 없는 안정 상태에서 검사할 경우 이상 소견이 나타나지 않을 수 있으며 심장 초음파 검사는 심장을 완전히 포함하지 못하는 경우 그 크기나 기능을 확실히 계산하지 못하며 화상의 입수에서부터 결과를 보는데 까지 시간이 많이 걸리는 단점이 있다. 또한 관상동맥 조영술은 0.1% 미만에서 사망이나 급성심근경색증 등의 합병증을 일으킬 수 있어 협심증을 의심하는 모든 환자에게 시행할 수는 없다. 그에 비해 극소량의 방사성 의약품을 팔의 정맥에 주입하고 이것이 심장 근육에 흡수되는 양상을 촬영해 확인하는 핵의학적 방법은 심장에서 방사성물질의 흡수가 적은 부위가 혈류가 부족한 부분을 의미하므로 운동부하 검사에 비해 이상 부위를 빠르게 구분할 수 있으며 극소량의 방사성의약품을 사용하기 때문에 안전성 역시 높다고 할 수 있다.Coronary artery disease is diagnosed early by methods of exercise testing, echocardiography, coronary angiography, and nuclear medicine. However, exercise testing may not reveal any abnormality when examined in a stable state with no symptoms in angina pectoris. Echocardiography can not reliably calculate the size or function of heart if it does not completely contain the heart. There is a drawback that it takes much time to see. In addition, coronary angiography can cause complications such as death or acute myocardial infarction at less than 0.1%, so it can not be applied to all patients suspected of angina. In contrast, a nuclear medicine method that injects a very small amount of radiopharmaceuticals into the veins of the arm and captures the patterns of absorption into the heart muscle is a part of the heart where there is less absorption of radioactive material, And the use of a very small amount of radiopharmaceuticals makes it safer.
현재 사용되는 핵의학적 방법은 단일광자방출 전산화 단층촬영(Single photon emission computed tomography, SPECT)를 이용하는 것이며, 대표적으로 심장 영상을 확인하기 위해 사용되는 방사성 의약품은 201Tl 착화합물이나 99mTc-sestamibi, 99mTc-tetrofosmin이 사용된다. 하지만 조직의 감쇄현상을 보정할 수 있는 정형화된 방법이 없으며, 특히 심장 밑에 바로 위치한 간에 의한 광자의 산란 현상 때문에 정확한 진단의 어려움이 있다. 따라서 이러한 단점을 극복하여 핵의학적 진단 방법의 효과를 극대화하기 위해서는 SPECT가 아닌 양전자 방출 단층촬영(Positron Emission Tomography, PET)을 이용할 수 있어야 하며 이를 위해서는 양전자 방출 핵종이 표지된 방사성의약품이 필요하다.Currently, the nuclear medicine method used is single photon emission computed tomography (SPECT). Typically, the radiopharmaceutical used to identify the heart image is 201 Tl complex, 99m Tc-sestamibi, 99m Tc -tetrofosmin is used. However, there is no formalized method for correcting the attenuation of tissue, and there is a difficulty in accurate diagnosis due to scattering phenomenon of photons due to the liver located directly under the heart. Therefore, in order to overcome these shortcomings and maximize the effect of nuclear medicine diagnosis, Positron Emission Tomography (PET), not SPECT, should be used. For this, radiopharmaceuticals labeled with positron emission nuclei are needed.
이와 관련하여, 다른 심장 영상 확인을 위해 양전자 방출 핵종인 11C을 표지한 구조가 다른 지방 친화성 양이온 물질을 합성하여, 이 화합물로 개의 dynamic PET 연구를 시행하여 심근에서의 오랜 머무름 시간을 보이는 것과 혈액과 폐에서 소량의 방사성 물질을 확인할 수 있었음이 보고된 바 있다(Rimoldi et al., Eur. J. Nucl. Med. Mol. Imaging 34(2): 197-205, 2007. 그러나 11C의 반감기가 20분이기 때문에 임상에서의 응용을 하기 위해서는 많은 제약이 있다.In this regard, for the purpose of identifying other cardiac images, we have synthesized a lipophilic cationic material with a structure that has a positron emission nucleus, 11 C, which has a structure that shows long retention time in the myocardium (Rimoldi et al ., Eur., J. Nucl. Med., Imaging 34 (2): 197-205, 2007) . However, the half-life of 11 C Is 20 minutes, there are many limitations to apply in clinical applications.
이에 본 발명자들은 Tetraphenylphosphonium(TPP) 염 기반의 18F를 포함하는 PET용 조영제를 개발한 바 있다(특허 제1172157호). Accordingly, the present inventors have developed a contrast agent for PET containing 18 F based on tetraphenylphosphonium (TPP) salt (Patent No. 1172157).
그러나 상기 TPP 염 기반의 PET용 조영제의 경우, 심장선택성이 다소 떨어지고 뼈에서의 섭취율이 높은 편일 뿐만 아니라, 심장에 인접한 간에서의 높은 섭취율로 인해서 심장 영상 분석 시 문제를 일으킬 가능성이 존재한다. However, the TPP salt-based contrast agent for PET has a problem in that it has a low cardiac selectivity and a high uptake rate in bones, as well as a problem in heart image analysis due to a high uptake rate in the liver adjacent to the heart.
본 발명은 상기와 같은 문제점을 포함하여 여러 문제점들을 해결하기 위한 것으로서, 심장섭취도가 향상되고 뼈흡수율이 낮으며, 간에서의 제거율이 향상된 개선된 신규 PET 조영용 화합물을 제공하는 것을 목적으로 한다. It is an object of the present invention to provide an improved novel PET imaging compound having improved cardiac uptake, lowered bone uptake rate, and improved liver removal rate.
또한 본 발명은 상기 화합물를 포함하는 PET 조영제 등 상기 화합물의 다양한 용도를 제공하는 것을 제공하는 것을 목적으로 한다.It is another object of the present invention to provide various uses of the above-mentioned compounds such as a PET contrast agent containing the compound.
그러나 이러한 과제는 예시적인 것으로, 이에 의해 본 발명의 범위가 한정되는 것은 아니다. However, these problems are exemplary and do not limit the scope of the present invention.
본 발명의 다른 일 관점에 따르면, 하기 화학식 I을 갖는 신규 화합물 또는 그의 허용가능한 염이 제공된다:According to another aspect of the present invention there is provided a novel compound having the formula (I): < EMI ID =
(상기 식에서 X1은 O, S, N, 또는 C이고, X2 내지 X10은 각각 독립적으로 C 또는 N으로, 상기 X2 내지 X10 중 적어도 하나 이상은 N이고, 상기 L1 및 L2는 각각 독립적으로 탄소수 1 내지 6인 포화 또는 불포화 알킬렌기, 탄소수 6 또는 10의 아릴렌기, 또는
본 발명의 다른 일 관점에 따르면, 상기 화합물 또는 그의 허용가능한 염의 R1이 118F, 76Br, 123I, 124I 및 131I로 구성되는 군으로부터 선택되는 하나 이상의 방사성 동위원소로 치환된, 방사성 화합물 또는 그의 허용가능한 염이 제공된다.According to another aspect of the invention, the compound or a acceptable salt thereof R 1 118 F, 76 Br, 123 I, substituted with one or more radioisotopes selected from the group consisting of 124 I and 131 I, radioactive A compound or an acceptable salt thereof is provided.
본 발명의 다른 일 관점에 따르면, 하기 화학식 II의 구조를 갖는 화합물 및 방사성 동위 금속원소를 포함하는 방사성 금속 착물이 제공된다:According to another aspect of the present invention there is provided a radial metal complex comprising a compound having a structure of formula II and a radioisotope element:
(상기 식에서 X1은 O, S, N, 또는 C이고, X2 내지 X10은 각각 독립적으로 C 또는 N으로, 상기 X2 내지 X10 중 적어도 하나 이상은 N이며, 상기 L1 및 L2는 각각 독립적으로 탄소수 1 내지 6인 포화 또는 불포화 알킬렌기, 탄소수 6 또는 10의 아릴렌기, 또는
본 발명의 다른 일 관점에 따르면, 상기 화학식 1의 화합물 또는 그의 허용가능한 염의 R1을 118F, 76Br, 123I, 124I 및 131I로 구성되는 군으로부터 선택되는 하나 이상의 방사성 동위원소로 치환하는 단계를 포함하는 방사성 화합물 또는 그의 허용가능한 염의 제조방법이 제공된다.According to another aspect of the present invention, replacing the compound or a acceptable salt thereof, R 1 of formula (I) with one or more radioisotopes selected from the group consisting of 118 F, 76 Br, 123 I , 124 I and 131 I ≪ / RTI > or a pharmaceutically acceptable salt thereof, is provided.
본 발명의 다른 일 관점에 따르면, 상기 방사성 화합물 또는 그의 허용가능한 염 또는 상기 방사성 금속 착물을 유효성분으로 포함하는 양전자 방출 단층촬영(PET)용 조영제가 제공된다.According to another aspect of the present invention, there is provided a contrast agent for positron emission tomography (PET) comprising the radioactive compound or an acceptable salt thereof or the radioactive metal complex as an active ingredient.
본 발명의 일 실시예에 따른 신규 화합물 및 그의 허용가능한 염은 PET 조영용 방사성 화합물의 제조를 위한 전구체로 사용가능하며, 상기 전구체를 이용하여 제조된 방사성 화합물은 심장 표적능이 향상되고, 뼈 흡수능이 약화되어 보다 양전자 단층 촬영시 선명한 심장영상을 얻을 수 있게 해준다. 그러나, 본 발명의 범위는 상기 효과에 의해 제한되는 것은 아니다.The novel compounds and their acceptable salts according to one embodiment of the present invention can be used as precursors for the production of radiological compounds for PET imaging and the radioactive compounds prepared using the precursors have improved cardiac targeting capacity and reduced bone resorption capacity This allows us to obtain clear cardiac images during positron tomography. However, the scope of the present invention is not limited by the above effects.
도 1은 종래 특허 제1172157호에 기재된 트리포스포니움염([18F]FPTP)을 이용하여 수득한 실험동물의 양전자 단층 촬영 영상이다.
도 2는 본 발명의 일 실시예에 따른 [18F]FEPP를 이용하여 수득한 실험동물의 양전자 단층 촬영 영상이다.
도 3은 본 발명의 일 실시예에 따른 [18F]FDPP를 이용하여 수득한 실험동물의 양전자 단층 촬영 영상이다.FIG. 1 is a positron emission tomographic image of an experimental animal obtained using the triphosphonium salt ([ 18 F] FPTP) described in the conventional patent No. 1172157.
2 is a positron emission tomographic image of an experimental animal obtained using [ 18 F] FEPP according to an embodiment of the present invention.
3 is a positron emission tomographic image of an experimental animal obtained using [ 18 F] FDPP according to an embodiment of the present invention.
본 발명의 다른 일 관점에 따르면, 하기 화학식 I을 갖는 신규 화합물 또는 그의 허용가능한 염이 제공된다:According to another aspect of the present invention there is provided a novel compound having the formula (I): < EMI ID =
(상기 식에서 X1은 O, S, N, 또는 C이고, X2 내지 X10은 각각 독립적으로 C 또는 N으로, 상기 X2 내지 X10 중 적어도 하나 이상은 N이고, 상기 L1 및 L2는 각각 독립적으로 탄소수 1 내지 6인 포화 또는 불포화 알킬렌기, 탄소수 6 또는 10의 아릴렌기, 또는
상기 화합물은 하기와 같은 반응식에 의해 제조가 될 수 있다:The compound can be prepared by the following reaction scheme:
상기 화합물 또는 그의 허용가능한 염은 (4-((tert-butoxycarbonyl)amino)butyl)diphenyl(pyridin-3-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)(phenyl)di(pyridin-3-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)tri(pyridin-3-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)diphenyl(pyrimidin-4-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)tri(pyrimidin-4-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)di(pyridin-2-yl)(pyrimidin-4-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)(pyridin-2-yl)di(pyrimidin-4-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)diphenyl(1,2,3-triazin-4-yl)phosphonium,(4-((tert-butoxycarbonyl)amino)butyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)tri(1,2,3-triazin-4-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)(phenyl)(pyridin-2-yl)(1,2,3-triazin-4-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)(pyridin-2-yl)di(1,2,3-triazin-4-yl)phosphonium, (4-((tert-butoxycarbonyl)amino)butyl)(pyrimidin-4-yl)di(1,2,3-triazin-4-yl)phosphonium, (4-aminobutyl)diphenyl(pyrimidin-5-yl)phosphonium, (5-aminopropyl)diphenyl(pyridin-3-yl)phosphonium, (5-aminopropyl)(phenyl)di(pyridin-3-yl)phosphonium, (5-aminopropyl)tri(pyridin-3-yl)phosphonium, (5-aminopropyl)diphenyl(pyrimidin-4-yl)phosphonium, (5-aminopropyl)(phenyl)di(pyrimidin-4-yl)phosphonium 또는 (5-aminopropyl)tri(pyrimidin-4-yl)phosphonium일 수 있다.The compound or an acceptable salt thereof may be prepared by reacting (4 - ((tert-butoxycarbonyl) amino) butyl) diphenyl (pyridin-3-yl) phosphonium, (4- (tert-butoxycarbonyl) amino) -3-yl) phosphonium, (4 - ((tert-butoxycarbonyl) amino) butyl) tri (pyridin-3- ) phosphonium, (4 - ((tert-butoxycarbonyl) amino) butyl) tri (pyrimidin-4-yl) phosphonium, (4 - ((tert-butoxycarbonyl) amino) butyl) (pyridin-2-yl) (4 - ((tert-butoxycarbonyl) amino) butyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, (1,2,3-triazin-4-yl) phosphonium, (4 - ((tert-butoxycarbonyl) amino) butyl) phosphonium, (4 - ((tert-butoxycarbonyl) amino) butyl (phenyl) (pyridin-2-yl) (1,2,3-triazin- (pyridin-2-yl) di (1,2,3-triazin-4-yl) phosphonium, (4 - ((tert-butoxycarbonyl) amino) butyl) , 2,3-triazin-4-yl) phosphonium, (4-aminobutyl) diphenyl (pyrimidin-5-yl) phosphonium, (5-aminopropyl) diphenyl (5-aminopropyl) phenyl di (pyridin-3-yl) phosphonium, (5-aminopropyl) tri (pyrimidin-4-yl) phosphonium or (5-aminopropyl) tri (pyrimidin-4-yl) phosphonium.
상기 "허용가능한 염"은 무기산 또는 유기산을 이용한 염이 바람직하며, 더욱 바람직하게는 메톡시, 아세톡시, 트리플루오로아세톡시 음이온 등과 같은 지방족을 이용한 염, 염화물, 브롬화물, 요오드화물, 방향족 또는 아릴지방족 카르복실산염, 질산염, 황산염, 인산염, 설폰산염, 메실산염, 베실산염, 토실산염 등의 염일 수 있으나 이에 한정되는 것은 아니다. 또한 본 발명의 허용 가능한 염은 -OTos, F-, Cl-, Br-, 또는 I-를 이용한 염들도 포함된다. 그러나 이들로 본 발명의 허용 가능한 염이 한정되는 것은 아니다The "acceptable salt" is preferably a salt with an inorganic or organic acid, more preferably a salt with an aliphatic such as methoxy, acetoxy, trifluoroacetoxy anion, etc., a chloride, a bromide, an iodide, Aliphatic carboxylic acid salts, aliphatic carboxylic acid salts, nitrate salts, sulfate salts, phosphate salts, sulfonate salts, mesylate salts, besylate salts and tosylate salts. In addition, acceptable salts of the present invention, -OTos, F - also includes salts with -, Cl -, Br -, or I. However, these do not limit the acceptable salts of the present invention
본 발명의 다른 일 관점에 따르면, 상기 화합물 또는 그의 허용가능한 염의 R1이 118F, 76Br, 123I, 124I, 및 31I로 구성되는 군으로부터 선택되는 하나 이상의 방사성 동위원소로 치환된, 방사성 화합물 또는 그의 허용가능한 염이 제공된다.According to another aspect of the invention, the compound or a acceptable salt thereof R 1 118 F, 76 Br, 123 I, substituted with one or more radioisotopes selected from the group consisting of 124 I, and 31 I, A radioactive compound or an acceptable salt thereof is provided.
상기 방사성 화합물 또는 그의 허용가능한 염은 [18F](4-(6-fluoronicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)(phenyl)di(pyridin-3-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)tri(pyridin-3-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)(phenyl)di(pyridin-3-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)tri(pyridin-3-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyridin-3-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)tri(pyridin-3-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyridin-3-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)tri(pyridin-3-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyridin-3-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)tri(pyridin-3-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)diphenyl(pyrimidin-4-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)tri(pyrimidin-4-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)di(pyrimidin-4-yl)(1,2,3-triazin-4-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)tri(1,2,3-triazin-4-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)diphenyl(pyrimidin-4-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)tri(pyrimidin-4-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)di(pyrimidin-4-yl)(1,2,3-triazin-4-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)tri(1,2,3-triazin-4-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)diphenyl(pyrimidin-4-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)tri(pyrimidin-4-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)di(pyrimidin-4-yl)(1,2,3-triazin-4-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)tri(1,2,3-triazin-4-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)diphenyl(pyrimidin-4-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)tri(pyrimidin-4-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)di(pyrimidin-4-yl)(1,2,3-triazin-4-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)tri(1,2,3-triazin-4-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)diphenyl(pyrimidin-4-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)tri(pyrimidin-4-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)di(pyrimidin-4-yl)(1,2,3-triazin-4-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)tri(1,2,3-triazin-4-yl)phosphonium, [18F](4-fluorobutyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [18F](4-fluorobutyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [18F](4-fluorobutyl)tri(1,2,3-triazin-4-yl)phosphonium, [18F](4-fluorobutyl)diphenyl(pyrimidin-4-yl)phosphonium, [18F](4-fluorobutyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [18F](4-fluorobutyl)tri(pyrimidin-4-yl)phosphonium, [18F](4-fluorobutyl)(phenyl)di(pyridin-3-yl)phosphonium, [18F](4-fluorobutyl)tri(pyridin-3-yl)phosphonium, [76Br](4-bromobutyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [76Br](4-bromobutyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [76Br](4-bromobutyl)tri(1,2,3-triazin-4-yl)phosphonium, [76Br](4-bromobutyl)diphenyl(pyrimidin-4-yl)phosphonium, [76Br](4-bromobutyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [76Br](4-bromobutyl)tri(pyrimidin-4-yl)phosphonium, [76Br](4-bromobutyl)(phenyl)di(pyridin-3-yl)phosphonium, [76Br](4-bromobutyl)tri(pyridin-3-yl)phosphonium, [123I](4-iodobutyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [123I](4-iodobutyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [123I](4-iodobutyl)tri(1,2,3-triazin-4-yl)phosphonium, [123I](4-iodobutyl)diphenyl(pyrimidin-4-yl)phosphonium, [123I](4-iodobutyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [123I](4-iodobutyl)tri(pyrimidin-4-yl)phosphonium, [123I](4-iodobutyl)(phenyl)di(pyridin-3-yl)phosphonium, [123I](4-iodobutyl)tri(pyridin-3-yl)phosphonium, [124I](4-iodobutyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [124I](4-iodobutyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [124I](4-iodobutyl)tri(1,2,3-triazin-4-yl)phosphonium, [124I](4-iodobutyl)diphenyl(pyrimidin-4-yl)phosphonium, [124I](4-iodobutyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [124I](5-iodopentyl)tri(pyrimidin-4-yl)phosphonium, [124I](5-iodopentyl)(phenyl)di(pyridin-3-yl)phosphonium, [124I](5-iodopentyl)tri(pyridin-3-yl)phosphonium, [131I](4-iodobutyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [131I](4-iodobutyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [131I](4-iodobutyl)tri(1,2,3-triazin-4-yl)phosphonium, [131I](4-iodobutyl)diphenyl(pyrimidin-4-yl)phosphonium, [131I](4-iodobutyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [131I](4-iodobutyl)tri(pyrimidin-4-yl)phosphonium, [131I](4-iodobutyl)(phenyl)di(pyridin-3-yl)phosphonium, [131I](4-iodobutyl)tri(pyridin-3-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)(phenyl)di(pyridin-3-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)tri(pyridin-3-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)diphenyl(pyrimidin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)tri(1,2,3-triazin-4-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)(phenyl)di(pyridin-3-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)tri(pyridin-3-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)diphenyl(pyrimidin-4-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)tri(1,2,3-triazin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyridin-3-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)tri(pyridin-3-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)diphenyl(pyrimidin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)tri(1,2,3-triazin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyridin-3-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)tri(pyridin-3-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)diphenyl(pyrimidin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)tri(1,2,3-triazin-4-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyridin-3-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)tri(pyridin-3-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)diphenyl(pyrimidin-4-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, 또는 [131I](2-(2-iodoethoxy)ethyl)tri(1,2,3-triazin-4-yl)phosphonium일 수 있다.The radioactive compound or a acceptable salt thereof, is [18 F] (4- (6 -fluoronicotinamido) butyl) diphenyl (pyridin-3-yl) phosphonium, [18 F] (4- (6-fluoronicotinamido) butyl) (phenyl) di (pyridin-3-yl) phosphonium, [18 F] (4- (6-fluoronicotinamido) butyl) tri (pyridin-3-yl) phosphonium, [76 Br] (4- (6-bromonicotinamido) butyl) diphenyl ( pyridin-3-yl) phosphonium, [76 Br] (4- (6-bromonicotinamido) butyl) (phenyl) di (pyridin-3-yl) phosphonium, [76 Br] (4- (6-bromonicotinamido) butyl) tri (pyridin-3-yl) phosphonium, [I 123] (4- (-6 iodonicotinamido) butyl) diphenyl (pyridin-3-yl) phosphonium, [I 123] (4- (-6 iodonicotinamido) butyl) (phenyl) di (pyridin-3-yl) phosphonium, [123 I] (4- (6-iodonicotinamido) butyl) tri (pyridin-3-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) diphenyl ( pyridin-3-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) (phenyl) di (pyridin-3-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) tri (pyridin-3-yl) phosphonium , [131 I] (4- (6-iodonicotinamido) butyl) diphenyl (pyridin-3-yl) phosphonium, [131 I] (4- (6-iodonicotinamido ) butyl) (phenyl) di (pyridin-3-yl) phosphonium, [131 I] (4- (6-iodonicotinamido) butyl) tri (pyridin-3-yl) phosphonium, [ 18 F] (4- (6- fluoronicotinamido) butyl) diphenyl (pyrimidin-4-yl) phosphonium, [18 F] (4- (6-fluoronicotinamido) butyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [18 F] (4- (6 -fluoronicotinamido) butyl) tri (pyrimidin-4-yl) phosphonium, [18 F] (4- (6-fluoronicotinamido) butyl) di (pyrimidin-4-yl) (1,2 , 3-triazin-4-yl ) phosphonium, [18 F] (4- (6-fluoronicotinamido) butyl) tri (1,2,3-triazin-4-yl) phosphonium, [76 Br] (4- (6 -bromonicotinamido) butyl) diphenyl (pyrimidin- 4-yl) phosphonium, [76 Br] (4- (6-bromonicotinamido) butyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [76 Br] (4- ( 6-bromonicotinamido) butyl) tri ( pyrimidin-4-yl) phosphonium, [76 Br] (4- (6-bromonicotinamido) butyl) di (pyrimidin-4-yl) (1,2,3-triazin-4-yl ) phosphonium, [76 Br] ( 4- (6-bromonicotinamido) butyl) tri (1,2,3-triazin-4-yl) phosphonium, [123 I] (4- (6-iodonicotinamido) butyl) diphenyl (pyrimidin -4-yl) phosphonium, [ 123 I] (4- (6-iodonic otinamido) butyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [123 I] (4- (6-iodonicotinamido) butyl) tri (pyrimidin-4-yl) phosphonium, [123 I] (4- (6 (1,2,3-triazin-4-yl) phosphonium, [ 123 I] (4- (6-iodonicotinamido) butyl) triazin-4-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) diphenyl (pyrimidin-4-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) (phenyl) di (pyrimidin-4-yl) phosphonium , [124 I] (4- (6-iodonicotinamido) butyl) tri (pyrimidin-4-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) di (pyrimidin (1,2,3-triazin-4-yl) phosphonium, [ 124 I] (4- (6- iodonicotinamido) butyl) [131 I] (4- (6 -iodonicotinamido) butyl) diphenyl (pyrimidin-4-yl) phosphonium, [131 I] (4- (6-iodonicotinamido) butyl) (phenyl) di (pyrimidin-4-yl) phosphonium , [131 I] (4- ( 6-iodonicotinamido) butyl) tri (pyrimidin-4-yl) phosphonium, [131 I] (4- (6-iodonicotinamido) butyl) di (pyrimidin-4-yl) (1, 2,3-triazin-4-yl) phosphonium, [ 131 I] (4- (6-iodonicotinamide do) butyl) tri (1,2,3- triazin-4-yl) phosphonium, [18 F] (4-fluorobutyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [18 F] ( 4-fluorobutyl) (phenyl) di (1,2,3-triazin-4-yl) phosphonium, [18 F] (4-fluorobutyl) tri (1,2,3-triazin-4-yl) phosphonium, [18 F] (4-fluorobutyl) diphenyl (pyrimidin-4-yl) phosphonium, [18 F] (4-fluorobutyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [18 F] (4-fluorobutyl) tri ( pyrimidin-4-yl) phosphonium, [18 F] (4-fluorobutyl) (phenyl) di (pyridin-3-yl) phosphonium, [18 F] (4-fluorobutyl) tri (pyridin-3-yl) phosphonium, [ 76 Br] (4-bromobutyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [76 Br] (4-bromobutyl) (phenyl) di (1,2,3-triazin-4-yl) phosphonium, [76 Br] (4 -bromobutyl) tri (1,2,3-triazin-4-yl) phosphonium, [76 Br] (4-bromobutyl) diphenyl (pyrimidin-4-yl) phosphonium, [76 Br] (4-bromobutyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [76 Br] (4-bromobutyl) tri (pyrimidin-4-yl) phosphonium, [76 Br] (4-bromobutyl) (phenyl) di (pyridin-3-yl) phosphonium , [76 Br] (4-bromobutyl) tri (pyridin-3-yl) phosphonium, [123 I] (4-io dobutyl) diphenyl (1,2,3-triazin- 4-yl) phosphonium, [123 I] (4-iodobutyl) (phenyl) di (1,2,3-triazin-4-yl) phosphonium, [123 I] (4-iodobutyl) tri (1,2,3 -triazin-4-yl) phosphonium, [123 I] (4-iodobutyl) diphenyl (pyrimidin-4-yl) phosphonium, [123 I] (4-iodobutyl) ( phenyl) di (pyrimidin-4- yl) phosphonium, [123 I] (4-iodobutyl) tri (pyrimidin-4-yl) phosphonium, [123 I] (4-iodobutyl) (phenyl) di (pyridin-3-yl ) phosphonium, [123 I] ( 4-iodobutyl) tri (pyridin-3-yl) phosphonium, [124 I] (4-iodobutyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [124 I Phosphonium, [ 124 I] (4-iodobutyl) tri (1,2,3-triazin-4-yl) phosphonium, [124 I] (4-iodobutyl ) diphenyl (pyrimidin-4-yl) phosphonium, [124 I] (4-iodobutyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [124 I] (5-iodopentyl) tri (pyrimidin-4-yl) phosphonium, [124 I] (5-iodopentyl) (phenyl) di (pyridin-3-yl) phosphonium, [124 I] (5-iodopentyl) tri (pyridin-3-yl) phosphonium , [131 I] (4- iodobutyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [131 I] (4-iodobutyl) ( phenyl) di (1,2,3-triazin- 4-yl) phosphonium, [131 I] (4-iodobutyl) tri (1,2,3-triazin-4-yl) phosphonium, [131 I] (4- iodobutyl) diphenyl (pyrimidin-4- yl) phosphonium, [131 I] (4-iodobutyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [131 I] (4-iodobutyl) tri (pyrimidin-4-yl ) phosphonium, [131 I] ( 4-iodobutyl) (phenyl) di (pyridin-3-yl) phosphonium, [131 I] (4-iodobutyl) tri (pyridin-3-yl) phosphonium, [18 F] (2 - (2-fluoroethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) (phenyl) di (pyridin-3-yl) phosphonium, [18 F] ( 2- (2-fluoroethoxy) ethyl) tri (pyridin-3-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) diphenyl (pyrimidin-4-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) ( phenyl) di (pyrimidin-4-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [18 F 2- (2-fluoroethoxy) ethyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [ 18 F] 3-triazin-4-yl) phosphonium, [ 18 F] (2- (2- fluoroethoxy) ethyl) tri (1,2,3-triazin- um, [76 Br] (2- (2-bromoethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium, [76 Br] (2- (2-bromoethoxy) ethyl) (phenyl) di (pyridin-3-yl ) phosphonium, [76 Br] ( 2- (2-bromoethoxy) ethyl) tri (pyridin-3-yl) phosphonium, [76 Br] (2- (2-bromoethoxy) ethyl) diphenyl (pyrimidin-4-yl) phosphonium , [76 Br] (2- ( 2-bromoethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [76 Br] (2- (2-bromoethoxy) ethyl) (phenyl) di (pyrimidin-4 -yl) phosphonium, [76 Br] (2- (2-bromoethoxy) ethyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) ( phenyl) di (1,2,3-triazin- 4-yl) phosphonium, [76 Br] (2- (2-bromoethoxy) ethyl) tri (1,2,3-triazin-4-yl) phosphonium, [123 I] (2- (2-iodoethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium, [ 123 I] 123 I] (2- (2- iodoethoxy) ethyl) tri (pyridin-3-yl) phosphonium, [123 I] (2- (2-iodoethoxy) ethyl) diphenyl (pyrimidin-4-yl) phosphonium, [123 I ] (2- (2-iodoethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [123 I] (2- (2-iodoethoxy) ethyl) (phenyl ) di (pyrimidin-4-yl ) phosphonium, [123 I] (2- (2-iodoethoxy) ethyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [123 I] (2- (2 (1,2,3-triazin-4-yl) phosphonium, [ 123 I] (2- (2-iodoethoxy) ethyl) yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (pyridin-3 -yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) tri (pyridin-3-yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) diphenyl (pyrimidin-4-yl ) phosphonium, [124 I] ( 2- (2-iodoethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (pyrimidin -4-yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl (1,2,3-triazin-4-yl) phosphonium, [ 124 I] (2- (2-iodoethoxy) ethyl) tri (1,2,3- [131 I] (2- (2 -iodoethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium, [131 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (pyridin-3-yl) phosphonium , [ 131 I] (2- (2-iodoethoxy ) ethyl) tri (pyridin-3-yl) phosphonium, [131 I] (2- (2-iodoethoxy) ethyl) diphenyl (pyrimidin-4-yl) phosphonium, [131 I] (2- (2-iodoethoxy) ethyl ) (phenyl) di (pyrimidin-4-yl) phosphonium, [131 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [131 I] (2- (2 -iodoethoxy) ethyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [131 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (1 , 2,3-triazin-4-yl) phosphonium, or [ 131 I] (2- (2-iodoethoxy) ethyl) tri (1,2,3-triazin-4-yl) phosphonium.
본 발명의 다른 일 관점에 따르면, 상기 화합물 또는 그의 허용가능한 염의 R1이 118F, 76Br, 123I, 124I 및 131I로 구성되는 군으로부터 선택되는 하나 이상의 방사성 동위원소로 치환된, 방사성 화합물 또는 그의 허용가능한 염이 제공된다.According to another aspect of the invention, the compound or a acceptable salt thereof R 1 118 F, 76 Br, 123 I, substituted with one or more radioisotopes selected from the group consisting of 124 I and 131 I, radioactive A compound or an acceptable salt thereof is provided.
본 발명의 다른 일 관점에 따르면, 상기 화학식 I의 화합물 또는 그의 허용가능한 염의 R1을 18F, 76Br, 123I, 124I 및 131I로 구성되는 군으로부터 선택되는 하나 이상의 방사성 동위원소로 치환하는 단계를 포함하는 방사성 화합물 또는 그의 허용가능한 염의 제조방법이 제공된다.According to another aspect of the present invention, replacing the compound or a acceptable salt thereof, R 1 in the formula (I) with one or more radioisotopes selected from the group consisting of 18 F, 76 Br, 123 I, 124 I and 131 I ≪ / RTI > or a pharmaceutically acceptable salt thereof, is provided.
본 발명의 다른 일 관점에 따르면, 상기 화학식 I의 화합물 또는 그의 허용가능한 염의 R1을 18F, 76Br, 123I, 124I, 및 131I로 구성되는 군으로부터 선택되는 하나 이상의 방사성 동위원소로 치환하는 단계를 포함하는 방사성 화합물 또는 그의 허용가능한 염의 제조방법이 제공된다.According to another aspect of the invention, the compound or a acceptable salt thereof, R 1 in the formula (I) with one or more radioisotopes selected from the group consisting of 18 F, 76 Br, 123 I, 124 I, and 131 I There is provided a process for preparing a radioactive compound, or an acceptable salt thereof, comprising the step of substituting.
이때, 치환방법은 한정되지 않으며, 상황에 따라 당업자가 적절하게 선택할 수 있다는 것은 자명하다. 예컨대, 당업자는 상기 화학식 1의 화합물 또는 이의 허용 가능한 염에, 118F, 76Br, 123I, 124I, 및 131I 등을 가하여 R1의 치환기를 방사성 동위원소로 치환할 수 있다.At this time, the substitution method is not limited, and it is obvious that a person skilled in the art can appropriately select according to the situation. For example, one skilled in the art can substitute the substituent of R 1 with a radioisotope by adding 118 F, 76 Br, 123 I, 124 I, and 131 I to the compound of Formula 1 or an acceptable salt thereof.
선택적으로 상기 제조방법은 상기와 같은 치환방법 대신 하기와 같은 반응식으로 수행될 수 있다.Alternatively, the above production method can be carried out by the following reaction formula instead of the above substitution method.
본 발명의 다른 일 관점에 따르면, 하기 화학식 II의 구조를 갖는 화합물 및 방사성 동위 금속원소를 포함하는 방사성 금속 착물이 제공된다:According to another aspect of the present invention there is provided a radial metal complex comprising a compound having a structure of formula II and a radioisotope element:
(상기 식에서 X1은 O, S, N, 또는 C이고, X2 내지 X10은 각각 독립적으로 C 또는 N으로, 상기 X2 내지 X10 중 적어도 하나 이상은 N이며, 상기 L1 및 L2는 각각 독립적으로 탄소수 1 내지 6인 포화 또는 불포화 알킬렌기, 탄소수 6 또는 10의 아릴렌기, 또는
상기 방사성 금속 착물에 있어서, 상기 킬레이터는 NOTA(1,4,7-triazacyclononane-N,N',N''-triacetic acid), DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), TETA(1,4,8,11-tetraazacyclotetradecane-N',N",N"'-tetraacetic acid), DTPA(diethylenetriaminepentaacetic acid), EDTA(ethylenediamine tetraacetate), NTA(nitrilotriacetic acid) 또는 상기 킬레이터의 유도체일 수 있다.Wherein the chelator is selected from the group consisting of NOTA (1,4,7-triazacyclononane-N, N ', N "-triacetic acid), DOTA (1,4,7,10- tetraazacyclododecane- Tetraacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-N ', N' ', N' '- tetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EDTA (ethylenediamine tetraacetate), nitrilotriacetic acid ) Or a derivative of the chelator.
상기 방사성 착물에 있어서, 상기 방사성 동위 금속원소는 44Sc, 64Cu, 66Cu, 67Ga, 68Ga, 71Ga, 115Ga, 89Y, 86Y, 90Y, 89Zr, 99mTc, 111In, 또는 177Lu일 수 있다.In the above radioactive complex, wherein the radioactive metallic element is 44 Sc, 64 Cu, 66 Cu , 67 Ga, 68 Ga, 71 Ga, 115 Ga, 89 Y, 86 Y, 90 Y, 89 Zr, 99m Tc, 111 In , Or 177 Lu.
본 발명의 다른 일 관점에 따르면, 상기 방사성 화합물 또는 그의 허용가능한 염 또는 상기 방사성 금속 착물을 유효성분으로 포함하는 양전자 방출 단층촬영(PET)용 조영제가 제공된다.According to another aspect of the present invention, there is provided a contrast agent for positron emission tomography (PET) comprising the radioactive compound or an acceptable salt thereof or the radioactive metal complex as an active ingredient.
실제 사용에 있어서, 본 발명의 일실시예에 따른 PET용 조영제는 통상적인 약제학적 조제 기술에 따른 약학적으로 허용되는 담체와 조합될 수 있다. 상기 담체는, 예를 들어 경구 또는 (정맥내 투여를 비롯한) 비경구 투여에 바람직한 제조에 따라 광범위하게 다양한 형태를 지닐 수 있다. For practical use, the contrast agent for PET according to one embodiment of the present invention may be combined with a pharmaceutically acceptable carrier according to conventional pharmaceutical preparation techniques. Such carriers may have a wide variety of forms depending on the preparation desired, for example, for oral or parenteral administration (including intravenous administration).
아울러, 본 발명의 일 실시예에 따른 조영제는 0.1 mg/kg 내지 1 g/kg의 용량으로 투여될 수 있으며, 더 바람직하게는 0.1 mg/kg 내지 500 mg/kg의 투여량으로 투여된다. 한편, 상기 투여량은 일간 또는 연간 허용되는 방사능 피폭양의 범위 내에서 환자의 나이, 성별 및 상태에 따라 적절히 조절될 수 있다. In addition, the contrast agent according to one embodiment of the present invention may be administered at a dose of 0.1 mg / kg to 1 g / kg, more preferably 0.1 mg / kg to 500 mg / kg. On the other hand, the dose can be appropriately adjusted according to the age, sex, and condition of the patient within the range of the amount of radiation exposure permitted for the day or the year.
본 발명의 일 실시예에 따른 조영제는 학학적으로 허용되는 담체를 비롯한 불활성 성분을 추가로 포함한다. 본 명세서에서 사용된 "학학적으로 허용된 담체"란 조성물, 구체적으로 의약 조성물의 활성 물질을 제외한 성분을 지칭하는 용어이다. 제약상 허용되는 담체의 예로는 결합제, 붕해제, 희석제, 충진제, 활택제, 가용화제 또는 유화제 및 염이 포함된다. The contrast agent according to one embodiment of the present invention further comprises an inert component, including a pharmaceutically acceptable carrier. As used herein, the term " pharmaceutically acceptable carrier "is a term referring to a composition, specifically a component other than the active ingredient of the pharmaceutical composition. Examples of pharmaceutically acceptable carriers include binders, disintegrants, diluents, fillers, lubricants, solubilizers or emulsifiers and salts.
상기 신규 조영제는 비경구 투여로 상기 개체에 투여될 수 있으며, 상기 비경구 투여는 정맥내 투여(intravenous injection), 복강내 투여(intraperitoneal injection), 근육내 투여(intramuscular injection), 또는 피하 투여(subcutaneous injection)일 수 있으나, 정맥내 투여가 가장 바람직하다.The new contrast agent may be administered to the subject by parenteral administration, and the parenteral administration may be by intravenous injection, intraperitoneal injection, intramuscular injection, or subcutaneous injection. injection, but intravenous administration is most preferred.
이하, 실시예 및 실험예를 통하여 본 발명을 더 상세히 설명한다. 그러나 본 발명은 이하에서 개시되는 실시예에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 수 있는 것으로, 이하의 실시예는 본 발명의 개시가 완전하도록 하며, 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되는 것이다. Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. It should be understood, however, that the invention is not limited to the disclosed embodiments, but may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, Is provided to fully inform the user.
실시예 1: 전구체의 제조Example 1: Preparation of precursor
1-1: 디페닐(피리딘-3-일(5-(토실옥시)펜틸)포스포니움 염의 제조1-1: Preparation of diphenyl (pyridin-3-yl (5- (tosyloxy) pentyl) phosphonium salt
0 ℃에서 정제된 피리딘 30 ㎖에 부테인-1,4-디올 15.0 mmol과 4-메틸벤젠-1-설포닐 클로라이드 8.58 g(45.0 mmol)를 첨가한 후 실온에서 2시간 동안 교반하였다. 2시간 교반 후 소량의 물을 사용하여 반응을 종결시키고 80 ㎖의 CH2Cl2와 1.0 M HCl 170 ㎖를 이용하여 피리딘을 제거한 후 추출한 CH2Cl2층에 남아 있는 피리딘을 50 ㎖의 물을 이용하여 완전히 제거하였다. Na2SO4로 CH2Cl2층의 수분을 제거하고 필터링하였다. 필터한 여액을 증발 건조한 후 컬럼 크로마토그래피를 이용하여 생성물 프로판-1,5-디일 비스(4-메틸벤젠설포네이트)[propane-1,5-diyl bis(4-methylbenzenesulfonate)]을 분리, 정제 하였다.15.0 mmol of butane-1,4-diol and 8.58 g (45.0 mmol) of 4-methylbenzene-1-sulfonyl chloride were added to 30 ml of purified pyridine at 0 ° C, followed by stirring at room temperature for 2 hours. After stirring for 2 hours, the reaction was terminated by using a small amount of water, pyridine was removed by using 80 ml of CH 2 Cl 2 and 1.0 M HCl (170 ml), and pyridine remaining in the extracted CH 2 Cl 2 layer was extracted with 50 ml of water . The water of the CH 2 Cl 2 layer was removed with Na 2 SO 4 and filtered. The filtered filtrate was evaporated to dryness, and then the product propane-1,5-diyl bis (4-methylbenzenesulfonate) was separated and purified by column chromatography .
이어 상기 프로판-1,5-디일 비스(4-메틸벤젠설포네이트) 1.0 g을 3-(디페닐포스피노)피리딘[3-(diphenylphosphino)pyridine] 1.2 g이 용해된 5 ㎖의 톨루엔에 첨가한 후, 열풍기로 다시 가열하였다. 합성된 디페닐(피리딘-3-일(5-(토실옥시)펜틸)포스포니움[diphenyl(pyridin-3-yl)(5-(tosyloxy)pentyl)phosphonium] 염을 실온에서 식힌 후 준-정제 컬럼(semi-preparative column)을 이용하여 분리 정제하였다. 1.0 g of the above-mentioned propane-1,5-diylbis (4-methylbenzenesulfonate) was added to 5 ml of toluene in which 1.2 g of 3- (diphenylphosphino) pyridine was dissolved After that, it was heated again with a hot air. The salt of the synthesized diphenyl (pyridin-3-yl (5- (tosyloxy) pentyl) phosphonium [diphenyl (3-yl) Followed by separation and purification using a semi-preparative column.
1-2: (4-아미노부틸)디페닐(피리딘-3-일) 포스포니움 염의 제조1-2: Preparation of (4-aminobutyl) diphenyl (pyridin-3-yl) phosphonium salt
터트-부틸 (4-하이드록시부틸)카르바메이트[tert-butyl (4-hydroxybutyl)carbamate] 1.8 g을 메틸렌클로라이드 용매 하에서 4-메틸벤젠-1-설포닐 클로라이드 6.2 g과 반응시킨 후, 미반응산물을 컬럼 그로마토그래피를 이용하여 제거한 후, 용매를 휘발시켜 4-((터트-부톡시카르보닐)아미노)부틸 4-메틸벤젠설포네이트[4-((tert-butoxycarbonyl)amino)butyl 4-methylbenzenesulfonate] 4.2 g을 수득하였다.1.8 g of tert-butyl (4-hydroxybutyl) carbamate was reacted with 6.2 g of 4-methylbenzene-1-sulfonyl chloride in a methylene chloride solvent, The product was removed by column chromatography and the solvent was evaporated to give 4 - ((tert-butoxycarbonyl) amino) butyl 4-methylbenzenesulfonate [4- (tert- methylbenzenesulfonate] 4.2 g was obtained.
이어 상기 4-((터트-부톡시카르보닐)아미노)부틸 4-메틸벤젠설포네이트 1.0 g을 3-(디페닐포스피노)피리딘[3-(diphenylphosphino)pyridine] 1.2g이 용해된 5 ㎖의 톨루엔에 첨가한 후, 열풍기로 다시 가열하였다. 합성된 (4-터트-부톡시카르보닐)아미노)부틸)디페닐(피리딘-3-일)포스포니움 염[(4-((tert-butoxycarbonyl)amino)butyl)diphenyl(pyridin-3-yl)phosphonium]을 수득하였다.Then, 1.0 g of the 4 - ((tert-butoxycarbonyl) amino) butyl 4-methylbenzenesulfonate was dissolved in 5 ml of a solution of 1.2 g of 3- (diphenylphosphino) pyridine After adding to toluene, it was heated again with a hot air stream. Butyl (4-tert-butoxycarbonyl) amino) butyl) diphenyl (pyridin-3-yl) ) phosphonium].
상기 (4-터트-부톡시카르보닐)아미노)부틸)디페닐(피리딘-3-일)포스포니움 염을 산조건에서 반응시켜 (4-아미노부틸)디페닐(피리딘-3-일) 포스포니움 [(4-aminobutyl)diphenyl(pyridin-3-yl)phosphonium] 염 0.6 g을 수득하였다.(Pyridin-3-yl) phosphonium salt was reacted with (4-tert-butoxycarbonyl) amino) butyl) diphenyl 0.6 g of [(4-aminobutyl) diphenyl (pyridin-3-yl) phosphonium] salt was obtained.
1-3: (2-(2-aminoethoxy)ethyl)diphenyl(pyridin-2-yl)phosphonium 염의 제조1-3: Preparation of (2- (2-aminoethoxy) ethyl) diphenyl (pyridin-2-yl) phosphonium salt
2,2'-옥시디에탄올(2,2'-oxydiethanol) 1.59 g을 4-메틸벤젠-1-설포닐 클로라이드 8.58 g(45.0 mmol)를 첨가한 후 실온에서 2시간 동안 교반하였다. 2시간 교반 후 소량의 물을 사용하여 반응을 종결시키고 80 ㎖의 CH2Cl2와 1.0 M HCl 170 ㎖를 이용하여 피리딘을 제거한 후 추출한 CH2Cl2층에 남아 있는 피리딘을 50 ㎖의 물을 이용하여 완전히 제거하였다. Na2SO4로 CH2Cl2층의 수분을 제거하고 필터링하였다. 필터한 여액을 증발 건조한 후 컬럼 크로마토그래피를 이용하여 생성물 oxybis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate)을 분리, 정제 하였다.1.59 g of 2,2'-oxydiethanol was added to 8.58 g (45.0 mmol) of 4-methylbenzene-1-sulfonyl chloride, followed by stirring at room temperature for 2 hours. After stirring for 2 hours, the reaction was terminated by using a small amount of water, pyridine was removed by using 80 ml of CH 2 Cl 2 and 1.0 M HCl (170 ml), and pyridine remaining in the extracted CH 2 Cl 2 layer was extracted with 50 ml of water . The water of the CH 2 Cl 2 layer was removed with Na 2 SO 4 and filtered. The filtered filtrate was evaporated to dryness, and then the product oxybis (ethane-2,1-diyl) bis (4-methylbenzenesulfonate) was separated and purified by column chromatography.
이어 oxybis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate) 1.0 g을 3-(디페닐포스피노)피리딘[3-(diphenylphosphino)pyridine] 1.2 g이 용해된 5 ㎖의 톨루엔에 첨가한 후, 열풍기로 다시 가열하였다. 합성된 (2-(2-aminoethoxy)ethyl)diphenyl(pyridin-2-yl)phosphonium 염을 실온에서 식힌 후 준-정제 컬럼(semi-preparative column)을 이용하여 분리 정제하였다. 1.0 g of oxybis (ethane-2,1-diyl) bis (4-methylbenzenesulfonate) was added to 5 ml of toluene in which 1.2 g of 3- (diphenylphosphino) pyridine was dissolved , And then heated again with a hot air blower. The synthesized (2- (2-aminoethoxy) ethyl) diphenyl (pyridin-2-yl) phosphonium salt was cooled at room temperature and separated and purified using a semi-preparative column.
1-4: (2-(2-아미노에톡시)에틸)디페닐(피리딘-3-일) 디페닐(피리딘-3-일)포스포니움 염의 제조 1-4: Preparation of (2- (2-aminoethoxy) ethyl) diphenyl (pyridin-3-yl) diphenyl (pyridin-3- yl) phosphonium salt
터트-부틸 (2-(2-하이드록시)에틸)카르바메이트[tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate] 1.8 g을 메틸렌클로라이드 용매 하에서 4-메틸벤젠-1-설포닐 클로라이드 6.2g과 반응시킨 후, 미반응산물을 컬럼 그로마토그래피를 이용하여 제거한 후, 용매를 휘발시켜 2-(2-(터트-부톡시카르보닐)아미노)에톡시)에틸 4-메틸벤젠설포네이트[2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate] 3.8 g을 수득하였다.1.8 g of tert-butyl (2- (2-hydroxyethoxy) ethyl) carbamate was dissolved in 4-methylbenzene-1-sulfonyl chloride After removing the unreacted product by column chromatography, the solvent was evaporated to obtain 2- (2-tert-butoxycarbonyl) amino) ethoxy) ethyl 4-methylbenzenesulfonate [2- (2 - ((tert-butoxycarbonyl) amino) ethoxy) ethyl 4-methylbenzenesulfonate] 3.8 g was obtained.
그런 다음, 상기 2-(2-(터트-부톡시카르보닐)아미노)에톡시)에틸 4-메틸벤젠설포네이트 1.0 g을 3-(디페닐포스피노)피리딘[3-(diphenylphosphino)pyridine] 1.2 g이 용해된 5 ㎖의 톨루엔에 첨가한 후, 열풍기로 다시 가열하였다. 합성된 2-(2-(2-((터트-부톡시메틸)아미노)에톡시)에틸)디페닐(피리딘-3-일)포스포니움[(2-(2-((tert-butoxymethyl)amino)ethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium] 염 0.76g을 수득하였다.Then, 1.0 g of the above 2- (2- (tert-butoxycarbonyl) amino) ethoxy) ethyl 4-methylbenzenesulfonate was added to the mixture of 3- (diphenylphosphino) pyridine 1.2 g, dissolved in 5 ml of toluene, and then heated with hot air. (2- (2 - ((tert-butoxymethyl) amino) ethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium [ amino) ethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium salt.
실시예 2: 방사성 화합물을 제조의 제조Example 2: Preparation of radioactive compound
2-1: [2-1: [ 1818 F](4-fluoropentyl)diphenyl(pyridin-2-yl)phosphonium 염의 제조F] (4-fluoropentyl) diphenyl (pyridin-2-yl) phosphonium salt
상기 실시예 1-1에서 제조된 디페닐(피리딘-3-일(5-(토실옥시)펜틸)포스포니움 10 mg을 아세토나이트릴용매 하에서 무담채 K18F와 반응시켜 [18F](4-fluorobutyl)diphenyl(pyridin-3-yl)phosphonium을 수득하였으며, 이를 [18F]FDPP로 명명하였다.10 mg of the diphenyl (pyridin-3-yl (5- (tosyloxy) pentyl) phosphonium prepared in Example 1-1 was reacted with silane coupling agent K 18 F in an acetonitrile solvent to obtain [ 18 F] 4-fluorobutyl) diphenyl (pyridin-3-yl) phosphonium, which was named [ 18 F] FDPP.
2-2: [2-2: [ 1818 F](2-(2-fluoroethoxy)ethyl)diphenyl(pyridin-2-yl)phosphonium 염의 제조F] (2- (2-fluoroethoxy) ethyl) diphenyl (pyridin-2-yl) phosphonium salt
상기 실시예 1-3에서 제조된 (2-(2-aminoethoxy)ethyl)diphenyl(pyridin-2-yl)phosphonium 10 mg을 아세토나이트릴용매 하에서 무담채 K18F와 반응시켜 [18F](2-(2-fluoroethoxy)ethyl)diphenyl(pyridin-2-yl)phosphonium을 제조하였으며 이를 [18F]FEPP로 명명하였다.10 mg of (2- (2-aminoethoxy) ethyl) diphenyl (pyridin-2-yl) phosphonium prepared in Example 1-3 was reacted with siliceous K 18 F in acetonitrile solvent to obtain [ 18 F] - (2-fluoroethoxy) ethyl) diphenyl (pyridin-2-yl) phosphonium was prepared and named [ 18 F] FEPP.
2-3: [2-3: [ 1818 F](4-fluorobutyl)diphenyl(pyridin-3-yl)phosphonium 염의 제조F] (4-fluorobutyl) diphenyl (pyridin-3-yl) phosphonium salt
상기 실시예 1-1에서 제조된 디페닐(피리딘-3-일(4-(토실옥시)부틸)포스포니움 염을 사용하는 대신 하기와 같은 방법으로 [18F](4-fluorobutyl)diphenyl(pyridin-3-yl)phosphonium 염을 제조하였다.Instead of using the diphenyl (pyridin-3-yl (4- (tosyloxy) butyl) phosphonium salt prepared in Example 1-1, [ 18 F] (4-fluorobutyl) diphenyl pyridin-3-yl) phosphonium salt.
우선, 부테인-1,4-디올 15.0 mmol과 4-메틸벤젠-1-설포닐 클로라이드 8.58 g(45.0 mmol)를 첨가한 후 실온에서 2시간 동안 교반하였다. 2시간 교반 후 소량의 물을 사용하여 반응을 종결시키고 80 ㎖의 CH2Cl2와 1.0 M HCl 170 ㎖를 이용하여 피리딘을 제거한 후 추출한 CH2Cl2층에 남아 있는 피리딘을 50 ㎖의 물을 이용하여 완전히 제거하였다. Na2SO4로 CH2Cl2층의 수분을 제거하고 필터링하였다. 필터한 여액을 증발 건조한 후 컬럼 크로마토그래피를 이용하여 생성물 부테인-1,4-디일 비스(4-메틸벤젠설포네이트)[butane-1,4-diyl bis(4-methylbenzenesulfonate)]을 분리, 정제 하였다.First, 15.0 mmol of butane-1,4-diol and 8.58 g (45.0 mmol) of 4-methylbenzene-1-sulfonyl chloride were added, followed by stirring at room temperature for 2 hours. After stirring for 2 hours, the reaction was terminated by using a small amount of water, pyridine was removed by using 80 mL of CH 2 Cl 2 and 1.0 M HCl (170 mL), and pyridine remaining in the extracted CH 2 Cl 2 layer was dissolved in 50 mL of water . The water of the CH 2 Cl 2 layer was removed with Na 2 SO 4 and filtered. The filtered filtrate was evaporated to dryness, and then the product butane-1,4-diyl bis (4-methylbenzenesulfonate) was separated and purified by column chromatography Respectively.
아세토나이트릴 용매 하에서 상기 제조된 부테인-1,4-디일 비스(4-메틸벤젠설포네이트) 4 mg에 K18F을 반응시켜 [18F]4-플루오로부틸-4-메틸벤젠설포테이트[4-fluorobuty-4-methylbenzenesulfonate]를 수득하였다.4 mg of butane-1,4-diyl bis (4-methylbenzenesulfonate) was reacted with K 18 F in the presence of acetonitrile to prepare [ 18 F] 4-fluorobutyl-4-methylbenzenesulfonate [4-fluorobuty-4-methylbenzenesulfonate].
상기 [18F]4-플루오로부틸-4-메틸벤젠설포테이트을 톨루엔 용매 하에서 3-(디페닐포스피노)피리딘[3-(diphenylphosphino)pyridine] 5 ㎎와 반응시켜 [18F](4-fluorobutyl)diphenyl(pyridin-3-yl)phosphonium 염을 수득하였다.[ 18 F] 4-fluorobutyl-4-methylbenzenesulfonate was reacted with 5 mg of 3- (diphenylphosphino) pyridine in a toluene solvent to obtain [ 18 F] (4-fluorobutyl ) diphenyl (pyridin-3-yl) phosphonium salt.
2-4: (4-(6-[2-4: Preparation of (4- (6- [ 1818 F]fluoronicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium 염의 제조F] fluoronicotinamido) butyl) diphenyl (pyridin-3-yl) phosphonium salt
상기 실시예 1-2에서 제조된 (4-아미노부틸)디페닐(피리딘-3-일) 포스포니움 염 4 mg을 아세토나이트릴 용매 하에서 2,3,5,6-테트라플로로페닐 6-[18F]플루오로니코티네이트[2,3,5,6-tetrafluorophenyl 6-fluoronicotinate]과 반응시켜 (4-(6-[18F]플루오로니코티아미도)부틸)디페닐(피리딘-3-일)포스포니움 [(4-(6-[18F]fluoronicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium]염을 수득하였다. 4 mg of (4-aminobutyl) diphenyl (pyridin-3-yl) phosphonium salt prepared in Example 1-2 was dissolved in acetonitrile solvent to obtain 2,3,5,6-tetrafluorophenyl 6- [18 F] fluoro-titanate Ronnie carbonate [2,3,5,6-tetrafluorophenyl 6-fluoronicotinate] and reacting (4- (6- [18 F] thiazol Nikko shown fluorophenyl) butyl) phenyl-di (pyridin-3- (4- (6- [ 18 F] fluoronicotinamido) butyl) diphenyl (pyridin-3-yl) phosphonium salt.
2-4: (2-(2-(6-[2-4: Preparation of (2- (2- (6- [ 1818 F]fluoronicotinamido)ethoxy)ethyl)diphenyl(pyridin-3-yl) phosphonium 염의 제조F] fluoronicotinamido) ethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium salt
아세토나이트릴 용매 하에서 상기 실시예 1-4에서 제조된 2-(2-(2-((터트-부톡시메틸)아미노)에톡시)에틸)디페닐(피리딘-3-일)포스포니움 염 4 mg 및 2,3,5,6-테트라플로로페닐 6-[18F]플루오로니코티네이트을 혼합하여 반응시켜 (2-(2-(6-[18F]플루오로니코틴아미도(에톡시)에틸)디페닐(피리딘-3-일)포스포니움[(2-(2-(6-[18F]fluoronicotinamido)ethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium] 염을 수득하였다. (2- ((tert-butoxymethyl) amino) ethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium salt prepared in Example 1-4, 4 mg and 2,3,5,6-tetrafluorophenyl 6- [ 18 F] fluoronicotinate were mixed and reacted to obtain (2- (2- (6- [ 18 F] fluoronicotinamide ) Ethyl) diphenyl (pyridin-3-yl) phosphonium salt of (2- (2- (6- [ 18 F] fluoronicotinamido) ethoxy) ethyl) diphenyl (pyridin-3- yl) phosphonium salt.
실험예 1: 방사성 화합물을 이용항 소동물 PET 조영Experimental Example 1: Animal animal PET imaging using a radioactive compound
본 발명자들은 상기 실시예 2-1 및 2-2에서 각각 제조된 방사성 화합물 [18F]FDPP 및 [18F]FEPP을 각각 200 μCi의 투여량으로 BALB/c 야생형 마우스에 꼬리정맥을 통해 정맥주사하고 30, 60분 시간이 경과한 후 소동물용 양전자 단층 촬영장치로 전신 영상을 촬영하였다. 대조군으로는 특허 제1172157호에서 합성된 (5-[18F]fluoropentyl)triphenylphosphonium 염([18F]FPTP)을 사용하였다.[ 18 F] FDPP and [ 18 F] FEPP prepared in Examples 2-1 and 2-2 described above were intravenously injected into the BALB / c wild-type mouse through the tail vein at a dose of 200 μCi, respectively After 30 and 60 minutes, whole body images were taken with a positron tomography system for small animals. As a control, 5- [ 18 F] fluoropentyl) triphenylphosphonium salt ([ 18 F] FPTP) synthesized in Japanese Patent No. 1172157 was used.
그 결과 도 1 내지 3에서 나타난 바와 같이, 본 발명의 일 실시예에 따른 방사성 화합물은 종래의 방사성 화합물인 [18F]FPTP에 비하여 심장에서의 신호 최대값이 큰폭으로 상승하였다. 도 1은 종래기술의 [18F]FPTP 투여 시 실험동물의 심장을 포함한 전신에 대한 PET 영상이고, 도 2 및 도 3은 각각 본 발명의 일 실시예에 따른 방사성 화합물인 [18F]FEPP 및 [18F]FDPP의 투여 이후 촬영한 PET 영상이다. 상기 결과는 본 발명의 일 실시예에 따른 방사성 화합물이 심장에서의 섭취율이 더 좋아졌음을 의미하는 것이다.As a result, as shown in FIGS. 1 to 3, the radioactive compound according to one embodiment of the present invention greatly increased the maximum signal value at the heart as compared with [ 18 F] FPTP, which is a conventional radioactive compound. FIG. 1 is a PET image of a whole body including the heart of an experimental animal when administered with [ 18 F] FPTP of the prior art, and FIGS. 2 and 3 are photographs of [ 18 F] FEPP and a radioactive compound according to an embodiment of the present invention, [ 18 F] PET images taken after administration of FDPP. The above results indicate that the radioactive compound according to one embodiment of the present invention has a better uptake rate at the heart.
더구나, 본 발명의 일 실시예에 따른 [18F]FEPP의 경우 [18F]FDPP와 비교시 갈비뼈의 윤곽이 거의 나타나지 않는 것으로 나타났는데, 이는 [18F]FEPP의 경우 뼈에서의 흡수율이 [18F]FDPP 보다 낮음을 의미하는 것이다. 이는 방사성 동위원소와 포스포니움염 사이에 존재하는 링커에 탄소 이외의 헤테로원자가 존재할 경우 심장에 대한 선택성이 더욱 향상됨을 의미하는 것이다.Further, was shown to be that if a [18 F] FEPP according to one embodiment of the present invention substantially the outline of the rib compared to [18 F] FDPP appear, which the absorption in the case of [18 F] FEPP bone [ 18 F] FDPP. This means that the presence of a heteroatom other than carbon in the linker existing between the radioactive isotope and the phosphonium salt further enhances the selectivity to the heart.
본 발명은 상술한 실시예 및 실험예를 통해 보다 상세히 설명되었다. 그러나 상기 실시예 및 실험예는 본 발명을 보다 완전히 설명하기 위한 것으로서, 본 발명의 보호범위가 상기 실시예 및 실험예로 제한되지 않음은 본 발명이 속한 기술분야의 통상의 기술을 가진자에게 자명하다고 할 것이다. 따라서, 본 발명의 실질적인 보호범위는 후술할 특허청구범위에 기재된 바에 정해진다.The present invention has been described in detail with reference to the above-described embodiments and experimental examples. It should be understood, however, that the invention is not to be limited to the details given herein, but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. . Therefore, the scope of protection of the present invention is set forth in the following claims.
Claims (9)
(상기 식에서 X1은 O, S, N, 또는 C이고, X2 내지 X10은 각각 독립적으로 C 또는 N으로, 상기 X2 내지 X10 중 적어도 하나 이상은 N이고, 상기 L1 및 L2는 각각 독립적으로 탄소수 1 내지 6인 포화 또는 불포화 알킬렌기, 탄소수 6 또는 10의 아릴렌기, 또는
Wherein X 1 is O, S, N, or C, each of X 2 to X 10 is independently C or N, at least one of X 2 to X 10 is N, and L 1 and L 2 Each independently represent a saturated or unsaturated alkylene group having 1 to 6 carbon atoms, an arylene group having 6 or 10 carbon atoms,
[18F](4-(6-fluoronicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)(phenyl)di(pyridin-3-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)tri(pyridin-3-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)(phenyl)di(pyridin-3-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)tri(pyridin-3-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyridin-3-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)tri(pyridin-3-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyridin-3-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)tri(pyridin-3-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)diphenyl(pyridin-3-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyridin-3-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)tri(pyridin-3-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)diphenyl(pyrimidin-4-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)tri(pyrimidin-4-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)di(pyrimidin-4-yl)(1,2,3-triazin-4-yl)phosphonium, [18F](4-(6-fluoronicotinamido)butyl)tri(1,2,3-triazin-4-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)diphenyl(pyrimidin-4-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)tri(pyrimidin-4-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)di(pyrimidin-4-yl)(1,2,3-triazin-4-yl)phosphonium, [76Br](4-(6-bromonicotinamido)butyl)tri(1,2,3-triazin-4-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)diphenyl(pyrimidin-4-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)tri(pyrimidin-4-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)di(pyrimidin-4-yl)(1,2,3-triazin-4-yl)phosphonium, [123I](4-(6-iodonicotinamido)butyl)tri(1,2,3-triazin-4-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)diphenyl(pyrimidin-4-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)tri(pyrimidin-4-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)di(pyrimidin-4-yl)(1,2,3-triazin-4-yl)phosphonium, [124I](4-(6-iodonicotinamido)butyl)tri(1,2,3-triazin-4-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)diphenyl(pyrimidin-4-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)tri(pyrimidin-4-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)di(pyrimidin-4-yl)(1,2,3-triazin-4-yl)phosphonium, [131I](4-(6-iodonicotinamido)butyl)tri(1,2,3-triazin-4-yl)phosphonium, [18F](4-fluorobutyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [18F](4-fluorobutyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [18F](4-fluorobutyl)tri(1,2,3-triazin-4-yl)phosphonium, [18F](4-fluorobutyl)diphenyl(pyrimidin-4-yl)phosphonium, [18F](4-fluorobutyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [18F](4-fluorobutyl)tri(pyrimidin-4-yl)phosphonium, [18F](4-fluorobutyl)(phenyl)di(pyridin-3-yl)phosphonium, [18F](4-fluorobutyl)tri(pyridin-3-yl)phosphonium, [76Br](4-bromobutyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [76Br](4-bromobutyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [76Br](4-bromobutyl)tri(1,2,3-triazin-4-yl)phosphonium, [76Br](4-bromobutyl)diphenyl(pyrimidin-4-yl)phosphonium, [76Br](4-bromobutyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [76Br](4-bromobutyl)tri(pyrimidin-4-yl)phosphonium, [76Br](4-bromobutyl)(phenyl)di(pyridin-3-yl)phosphonium, [76Br](4-bromobutyl)tri(pyridin-3-yl)phosphonium, [123I](4-iodobutyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [123I](4-iodobutyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [123I](4-iodobutyl)tri(1,2,3-triazin-4-yl)phosphonium, [123I](4-iodobutyl)diphenyl(pyrimidin-4-yl)phosphonium, [123I](4-iodobutyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [123I](4-iodobutyl)tri(pyrimidin-4-yl)phosphonium, [123I](4-iodobutyl)(phenyl)di(pyridin-3-yl)phosphonium, [123I](4-iodobutyl)tri(pyridin-3-yl)phosphonium, [124I](4-iodobutyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [124I](4-iodobutyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [124I](4-iodobutyl)tri(1,2,3-triazin-4-yl)phosphonium, [124I](4-iodobutyl)diphenyl(pyrimidin-4-yl)phosphonium, [124I](4-iodobutyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [124I](5-iodopentyl)tri(pyrimidin-4-yl)phosphonium, [124I](5-iodopentyl)(phenyl)di(pyridin-3-yl)phosphonium, [124I](5-iodopentyl)tri(pyridin-3-yl)phosphonium, [131I](4-iodobutyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [131I](4-iodobutyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [131I](4-iodobutyl)tri(1,2,3-triazin-4-yl)phosphonium, [131I](4-iodobutyl)diphenyl(pyrimidin-4-yl)phosphonium, [131I](4-iodobutyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [131I](4-iodobutyl)tri(pyrimidin-4-yl)phosphonium, [131I](4-iodobutyl)(phenyl)di(pyridin-3-yl)phosphonium, [131I](4-iodobutyl)tri(pyridin-3-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)(phenyl)di(pyridin-3-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)tri(pyridin-3-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)diphenyl(pyrimidin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)tri(1,2,3-triazin-4-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)(phenyl)di(pyridin-3-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)tri(pyridin-3-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)diphenyl(pyrimidin-4-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [18F](2-(2-fluoroethoxy)ethyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [76Br](2-(2-bromoethoxy)ethyl)tri(1,2,3-triazin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyridin-3-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)tri(pyridin-3-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)diphenyl(pyrimidin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [123I](2-(2-iodoethoxy)ethyl)tri(1,2,3-triazin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyridin-3-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)tri(pyridin-3-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)diphenyl(pyrimidin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, [124I](2-(2-iodoethoxy)ethyl)tri(1,2,3-triazin-4-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)diphenyl(pyridin-3-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyridin-3-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)tri(pyridin-3-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)diphenyl(pyrimidin-4-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)(phenyl)di(pyrimidin-4-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)diphenyl(1,2,3-triazin-4-yl)phosphonium, [131I](2-(2-iodoethoxy)ethyl)(phenyl)di(1,2,3-triazin-4-yl)phosphonium, 또는 [131I](2-(2-iodoethoxy)ethyl)tri(1,2,3-triazin-4-yl)phosphonium인, 방사성 화합물 또는 그의 허용가능한 염.The method of claim 3,
[18 F] (4- (6 -fluoronicotinamido) butyl) diphenyl (pyridin-3-yl) phosphonium, [18 F] (4- (6-fluoronicotinamido) butyl) (phenyl) di (pyridin-3-yl) phosphonium , [ 18 F] (4- (6-fluoronicotinamido) butyl) tri (pyridin-3-yl) phosphonium, [ 76 Br] 76 Br] (4- (6- bromonicotinamido) butyl) (phenyl) di (pyridin-3-yl) phosphonium, [76 Br] (4- (6-bromonicotinamido) butyl) tri (pyridin-3-yl) phosphonium, [123 I] (4- (6 -iodonicotinamido) butyl) diphenyl (pyridin-3-yl) phosphonium, [123 I] (4- (6-iodonicotinamido) butyl) (phenyl) di (pyridin-3-yl) phosphonium , [123 I] (4- ( 6-iodonicotinamido) butyl) tri (pyridin-3-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) diphenyl (pyridin-3-yl) phosphonium, [ 124 I] (4- (6- iodonicotinamido) butyl) (phenyl) di (pyridin-3-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) tri (pyridin-3-yl) phosphonium, [131 I] (4- (6 -iodonicotinamido) butyl) diphenyl (pyridin-3-yl) phosphonium, [131 I] (4- (6-iodonicotinamido) butyl) (phenyl) di (pyridin-3-yl) phosphoni um, [131 I] (4- (6-iodonicotinamido) butyl) tri (pyridin-3-yl) phosphonium, [18 F] (4- (6-fluoronicotinamido) butyl) diphenyl (pyrimidin-4-yl) phosphonium, [18 F] (4- (6 -fluoronicotinamido) butyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [18 F] (4- (6-fluoronicotinamido) butyl) tri (pyrimidin-4-yl) phosphonium , [18 F] (4- ( 6-fluoronicotinamido) butyl) di (pyrimidin-4-yl) (1,2,3-triazin-4-yl) phosphonium, [18 F] (4- (6-fluoronicotinamido) butyl) tri (1,2,3-triazin- 4-yl) phosphonium, [76 Br] (4- (6-bromonicotinamido) butyl) diphenyl (pyrimidin-4-yl) phosphonium, [76 Br] (4- ( 6-bromonicotinamido) butyl) (phenyl ) di (pyrimidin-4-yl) phosphonium, [76 Br] (4- (6-bromonicotinamido) butyl) tri (pyrimidin-4-yl) phosphonium, [76 Br] (4- (1,2,3-triazin-4-yl) phosphonium, [ 76 Br] (4- (6-bromonicotinamido) butyl) 3-triazin-4-yl) phosphonium, [123 I] (4- (6-iodonicotinamido) butyl) diphenyl (pyrimidin-4-yl) phosphonium, [123 I] (4- (6-iodonicotinamido) butyl) (phenyl ) di (pyrimidin-4-yl) phosphonium, [ 123 I] ( 4- (6-iodonicotinamido) butyl) tri (pyrimidin-4-yl) phosphonium, [123 I] (4- (6-iodonicotinamido) butyl) di (pyrimidin-4-yl) (1,2,3-triazin- 4-yl) phosphonium, [123 I] (4- (6-iodonicotinamido) butyl) tri (1,2,3-triazin-4-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) diphenyl (pyrimidin-4-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl ) tri (pyrimidin-4-yl ) phosphonium, [124 I] (4- (6-iodonicotinamido) butyl) di (pyrimidin-4-yl) (1,2,3-triazin-4-yl) phosphonium, [124 I] (4- (6-iodonicotinamido ) butyl) tri (1,2,3-triazin-4-yl) phosphonium, [131 I] (4- (6-iodonicotinamido) butyl) diphenyl (pyrimidin-4-yl) phosphonium, [131 I] (4- (6-iodonicotinamido) butyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [131 I] (4- (6-iodonicotinamido) butyl) tri (pyrimidin-4-yl ) phosphonium, [131 I] ( 4- (6-iodonicotinamido) butyl) di (pyrimidin-4-yl) (1,2,3-triazin-4-yl) phosphonium, [131 I] (4- (6- iodonicotinamido) butyl) tri (1,2,3-triazin-4-yl) phosphonium, [ 18 F] (4- yl) diphenyl (1,2,3-triazin- 4-yl) phosphonium, [18 F] (4-fluorobutyl) (phenyl) di (1,2,3-triazin-4-yl) phosphonium, [18 F] Phosphonium, [ 18 F] (4-fluorobutyl) diphenyl (pyrimidin-4-yl) phosphonium, [ 18 F] (4- fluorobutyl) (4-fluorobutyl) phenyl) di (pyrimidin-4- yl) phosphonium, [18 F] (4-fluorobutyl) tri (pyrimidin-4-yl) phosphonium, [18 F] (4-fluorobutyl) (phenyl) di (pyridin-3-yl ) phosphonium, [18 F] ( 4-fluorobutyl) tri (pyridin-3-yl) phosphonium, [76 Br] (4-bromobutyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [76 Br Phosphonium, [ 76 Br] (4-bromobutyl) tri (1,2,3-triazin-4-yl) phosphonium, [76 Br] (4-bromobutyl ) diphenyl (pyrimidin-4-yl) phosphonium, [76 Br] (4-bromobutyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [76 Br] (4-bromobutyl) tri (pyrimidin-4-yl) phosphonium, [76 Br] (4-bromobutyl) (phenyl) di (pyridin-3-yl) phosphonium, [76 Br] (4-bromobutyl) tri (pyridin-3-yl) phosphonium , [ 123 I] (4-iodobutyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [ 123 I] butyl) (phenyl) di (1,2,3 -triazin-4-yl) phosphonium, [123 I] (4-iodobutyl) tri (1,2,3-triazin-4-yl) phosphonium, [123 I] (4-iodobutyl) diphenyl (pyrimidin -4-yl) phosphonium, [123 I] (4-iodobutyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [123 I] (4-iodobutyl) tri (pyrimidin- 4-yl) phosphonium, [123 I] (4-iodobutyl) (phenyl) di (pyridin-3-yl) phosphonium, [123 I] (4-iodobutyl) tri (pyridin-3-yl) phosphonium, [124 I (4-iodobutyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [ 124 I] [124 I] (4-iodobutyl ) tri (1,2,3-triazin-4-yl) phosphonium, [124 I] (4-iodobutyl) diphenyl (pyrimidin-4-yl) phosphonium, [124 I] (4 -iodobutyl) (phenyl) di (pyrimidin -4-yl) phosphonium, [124 I] (5-iodopentyl) tri (pyrimidin-4-yl) phosphonium, [124 I] (5-iodopentyl) (phenyl) di (pyridin -3-yl) phosphonium, [124 I] (5-iodopentyl) tri (pyridin-3-yl) phosphonium, [131 I] (4-iodobutyl) diphenyl (1,2,3-triazin-4-yl) phosphonium , [131 I] (4- iodobutyl) (phenyl) di (1,2,3-triazin-4-yl) phosphonium, [131 I] (4-iodobutyl) t ri (1,2,3-triazin-4- yl) phosphonium, [131 I] (4-iodobutyl) diphenyl (pyrimidin-4-yl) phosphonium, [131 I] (4-iodobutyl) (phenyl) di (pyrimidin -4-yl) phosphonium, [131 I] (4-iodobutyl) tri (pyrimidin-4-yl) phosphonium, [131 I] (4-iodobutyl) (phenyl) di (pyridin-3-yl) phosphonium, [131 I] (4-iodobutyl) tri (pyridin-3-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium, [18 F] (2- (2 -fluoroethoxy) ethyl) (phenyl) di (pyridin-3-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) tri (pyridin-3-yl) phosphonium, [18 F] (2- ( 2-fluoroethoxy) ethyl) diphenyl ( pyrimidin-4-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) ( phenyl) di (pyrimidin-4-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, [18 F] (2- (2 -fluoroethoxy) ethyl) (phenyl) di (1,2,3-triazin-4-yl) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) tri (1 , 2,3-triazin-4-yl) phosphonium, [ 76 Br] (2- (2-bromoethoxy) ethyl) diphenyl (pyridin-3- onium, [76 Br] (2- (2-bromoethoxy) ethyl) (phenyl) di (pyridin-3-yl) phosphonium, [76 Br] (2- (2-bromoethoxy) ethyl) tri (pyridin-3-yl ) phosphonium, [76 Br] ( 2- (2-bromoethoxy) ethyl) diphenyl (pyrimidin-4-yl) phosphonium, [76 Br] (2- (2-bromoethoxy) ethyl) (phenyl) di (pyrimidin-4- yl) phosphonium, [76 Br] (2- (2-bromoethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [76 Br] (2- (2-bromoethoxy) ethyl) diphenyl (1,2 , 3-triazin-4-yl ) phosphonium, [18 F] (2- (2-fluoroethoxy) ethyl) (phenyl) di (1,2,3-triazin-4-yl) phosphonium, [76 Br] (2 - (2-bromoethoxy) ethyl) tri (1,2,3-triazin-4-yl) phosphonium, [123 I] (2- (2-iodoethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium, [123 I (2- (2-iodoethoxy) ethyl) tri (pyridin-3-yl) phosphonium, [ 123 I] 123 I] (2- (2- iodoethoxy) ethyl) diphenyl (pyrimidin-4-yl) phosphonium, [123 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [123 I] (2- (2 -iodoethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [123 I] (2- (2-iodoethoxy) ethyl) d (1,2,3-triazin-4-yl) phosphonium, [ 123 I] (2- (2-iodoethoxy) ethyl) 123 I] (2- (2- iodoethoxy) ethyl) tri (1,2,3-triazin-4-yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) diphenyl (pyridin-3-yl ) phosphonium, [124 I] ( 2- (2-iodoethoxy) ethyl) (phenyl) di (pyridin-3-yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) tri (pyridin-3- yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) diphenyl (pyrimidin-4-yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (pyrimidin-4 -yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) diphenyl (1, 2,3-triazin-4-yl) phosphonium, [124 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (1,2,3-triazin-4-yl) phosphonium, [124 I] ( 2- (2-iodoethoxy) ethyl) tri (1,2,3-triazin-4-yl) phosphonium, [131 I] (2- (2-iodoethoxy) ethyl) diphenyl (pyridin-3-yl) phosphonium, [ 131 I] (2- (2- iodoethoxy) ethyl) (phenyl) di (pyridin-3-yl) phosphonium, [131 I] (2- (2-iodoethoxy) ethyl) tri (pyridin-3-yl) phosphonium, [ 131 I] (2- (2-iodoethoxy) ethyl ) diphenyl (pyrimidin-4-yl) phosphonium, [131 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [131 I ] (2- (2-iodoethoxy) ethyl) (phenyl) di (pyrimidin-4-yl) phosphonium, [131 I] (2- (2-iodoethoxy) ethyl) diphenyl (1,2,3-triazin-4- yl) phosphonium, [131 I] (2- (2-iodoethoxy) ethyl) (phenyl) di (1,2,3-triazin-4-yl) phosphonium, or [131 I] (2- (2 -iodoethoxy) ethyl) tri (1,2,3-triazin-4-yl) phosphonium, a radioactive compound or an acceptable salt thereof.
(상기 식에서 X1은 O, S, N, 또는 C이고, X2 내지 X10은 각각 독립적으로 C 또는 N으로, 상기 X2 내지 X10 중 적어도 하나 이상은 N이며, 상기 L1 및 L2는 각각 독립적으로 탄소수 1 내지 6인 포화 또는 불포화 알킬렌기, 탄소수 6 또는 10의 아릴렌기, 또는
Wherein X 1 is O, S, N, or C, each of X 2 to X 10 is independently C or N, at least one of X 2 to X 10 is N, and L 1 and L 2 Each independently represent a saturated or unsaturated alkylene group having 1 to 6 carbon atoms, an arylene group having 6 or 10 carbon atoms,
상기 킬레이터는 NOTA(1,4,7-triazacyclononane-N,N',N''-triacetic acid), DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), TETA(1,4,8,11-tetraazacyclotetradecane-N',N",N"'-tetraacetic acid), DTPA(diethylenetriaminepentaacetic acid), EDTA(ethylenediamine tetraacetate), NTA(nitrilotriacetic acid) 또는 상기 킬레이터의 유도체인, 방사성 금속 착물.The method according to claim 6,
Wherein the chelator is selected from the group consisting of NOTA (1,4,7-triazacyclononane-N, N ', N "-triacetic acid), DOTA (1,4,7,10- tetraazacyclododecane- , TETA (1,4,8,11-tetraazacyclotetradecane-N ', N'', N "' - tetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EDTA (ethylenediamine tetraacetate), NTA (nitrilotriacetic acid) Phosphorous metal complexes.
상기 방사성 동위 금속원소는 44Sc, 64Cu, 66Cu, 67Ga, 68Ga, 71Ga, 115Ga, 89Y, 86Y, 90Y, 89Zr, 99mTc, 111In, 또는 177Lu인, 방사성 금속 착물.The method according to claim 6,
Wherein the radioactive metallic element is 44 Sc, 64 Cu, 66 Cu , 67 Ga, 68 Ga, 71 Ga, 115 Ga, 89 Y, 86 Y, 90 Y, 89 Zr, 99m Tc, 111 In, or 177 Lu, Radioactive metal complex.
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