KR102180603B1 - Amino group and [18f] fluorine-introduced proton-emitting tomographic radioactive compound - Google Patents

Amino group and [18f] fluorine-introduced proton-emitting tomographic radioactive compound Download PDF

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KR102180603B1
KR102180603B1 KR1020180144373A KR20180144373A KR102180603B1 KR 102180603 B1 KR102180603 B1 KR 102180603B1 KR 1020180144373 A KR1020180144373 A KR 1020180144373A KR 20180144373 A KR20180144373 A KR 20180144373A KR 102180603 B1 KR102180603 B1 KR 102180603B1
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이상윤
막수드 알람 모하메드
이지혜
이도 타츠오
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Abstract

본 발명은 뇌신경염증 표적 양성자방출단층촬영(PET, Positron Emission Tomography)에 사용되는 방사성 화합물에 관한 것이다. 본 발명 화합물은 아민기 및 [18F]플루오르가 도입된 PET용 방사성 화합물을 포함한다.
본 발명에 따르면, 다양한 모핵구조에 [18F]플루오르페닐(또는 [18F]플루오르알킬) 및 최적화된 아미드기가 도입된 신규 뇌신경염증 표적용 PET 방사성 화합물을 개발하여 뇌신경염증 진단에 사용함으로써, 높은 TSPO 친화도를 나타내어 뇌신경염증 영상을 위한 이상적인 약동학적 정보를 제공할 수 있는 효과가 있다.The present invention relates to a radioactive compound used for cerebral nerve inflammation target proton emission tomography (PET, Positron Emission Tomography). The compound of the present invention includes a radioactive compound for PET into which an amine group and [ 18 F] fluorine are introduced.
According to the present invention, a novel PET radioactive compound for targeting cranial nerve inflammation, in which [ 18 F] fluorophenyl (or [ 18 F] fluoroalkyl) and an optimized amide group were introduced into various parental structures, was developed and used for diagnosis of cranial nerve inflammation, It shows TSPO affinity and has the effect of providing ideal pharmacokinetic information for cranial nerve inflammation imaging.

Description

아민기 및 [18F]플루오르가 도입된 뇌신경염증 진단용 양성자방출단층촬영 방사성화합물.{AMINO GROUP AND [18F] FLUORINE-INTRODUCED PROTON-EMITTING TOMOGRAPHIC RADIOACTIVE COMPOUND}A proton emission tomography radioactive compound for the diagnosis of cranial nerve inflammation in which amine groups and [18F] fluorine are introduced. {AMINO GROUP AND [18F] FLUORINE-INTRODUCED PROTON-EMITTING TOMOGRAPHIC RADIOACTIVE COMPOUND}

본 발명은 뇌신경염증 진단용 양성자방출단층촬영(PET, Positron Emission Tomography)에 사용되는 방사성 화합물에 관한 것으로서, 더욱 상세하게는 translocator protein (TSPO)와의 결합친화도가 높은 것으로 알려진 피라졸로피리미딘 모핵을 가지는 유도체들로부터 다양한 알킬기 또는 아릴기로 치환된 아미드기 및 [18F]플루오르벤젠이 도입된 PET용 방사성 리간드와 이를 통해 최적화된 치환된 아미드기를 중심으로 하는 다양한 모핵 결합에 관한 것이다.The present invention relates to a radioactive compound used in Positron Emission Tomography (PET) for diagnosing cranial nerve inflammation, and more particularly, having a pyrazolopyrimidine nucleus known to have a high binding affinity to a translocator protein (TSPO). The present invention relates to a radioligand for PET into which an amide group and [ 18 F] fluorobenzene substituted with various alkyl or aryl groups from the derivatives are introduced, and various parent nucleus bonds centered on a substituted amide group optimized therethrough.

중추신경계의 소교세포(microglial cell)는 신경계의 활성화, 항상성 유지에 기여하며, 신경계 친화성 물질(neurotrophin)이나 산화 질소나 염증을 유발하는 사이토카인 등을 분비하여 신경세포의 유지 또는 자멸(apoptosis) 등을 일으키는 기능을 가지고 있다. 실제로 알츠하이머병, 파킨슨병, 헌팅턴병 등 다양한 퇴행성 신경계 질환, 뇌 경색 또는 뇌손상, 그리고 뇌 감염 등의 질환에서 소교세포의 활성화가 보고되었다. 또한 알츠하이머병의 발병 및 진행요인인 베타아밀로이드의 침착은 소교세포의 활성화를 유발한다고 알려져 있다.The microglial cells of the central nervous system contribute to the activation and maintenance of homeostasis of the nervous system, and the maintenance or apoptosis of nerve cells by secreting neurotrophins, nitric oxide, or cytokines that cause inflammation. It has a function that causes the back. In fact, activation of microglial cells has been reported in various degenerative neurological diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, brain infarction or brain injury, and brain infections. In addition, it is known that the deposition of beta-amyloid, a factor in the onset and progression of Alzheimer's disease, causes activation of microglial cells.

현재 소교세포의 활성화는 미토콘드리아의 막에 존재하는 18 kDa의 translocator protein (TSPO)의 발현 증가로 일어나며, 질병이 발생한 지 수 시간 내에 시작되어 수 일간 지속된다고 보고되었다. 그러므로 다양한 중추 신경계 질환에서 소교세포의 TSPO 발현 정도의 측정은 신경 염증 과정 중에 소교세포 활성화를 평가하는 생체 내 바이오 마커로 활용될 수 있다. At present, activation of microglial cells is reported to occur due to an increase in the expression of the 18 kDa translocator protein (TSPO) present in the mitochondrial membrane, starting within a few hours after the onset of the disease and lasting for several days. Therefore, measurement of the degree of TSPO expression of microglia in various central nervous system diseases can be used as an in vivo biomarker to evaluate microglia activation during neuroinflammatory processes.

실제로 1984년에 TSPO 평가를 위한 양전자방출단층촬영(PET, Positron Emission Tomography)용 방사성추적자로 탄소-11(반감기 20.4분)를 표지한 [11C]-(R)-PK11195 ((R)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide)가 최초로 개발되었으며, 이는 이소퀴놀린 결합 단백질(isoquinoline binding protein, IBP)에 결합하는 것으로 알려져 있다. In fact, in 1984, [11C]-(R)-PK11195 ((R)-N- labeled carbon-11 (half-life 20.4 minutes) as a radiotracer for positron emission tomography (PET) for TSPO evaluation. methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide) was first developed, and it is known to bind to isoquinoline binding protein (IBP).

그러나 [11C]-(R)-PK11195는 사용된 방사성동위원소 탄소-11의 짧은 반감기와 리간드 PK11195의 비특이적 결합 및 낮은 신호 대 잡음비(signal to noise ratio)의 문제로 인하여 널리 사용하기에는 제한적이었다. 그 결과 지난 20년간 뇌신경염증 영상을 위한 다양한 새로운 방사성추적자가 개발되어 왔으며, 그 중의 한가지로서 [11C]-(R)-PK11195에 비하여 4배 이상 섭취가 되고 신체 내 대사물이 뇌혈관장벽(blood brain barrier)을 통과하지 않은 [11C]DAA1106 (N-5-fluoro-2-phenoxy phenyl)-N-(2,5-dimethoxybenzyl)acetamide) 등이 개발되었다. 하지만 [11C]DAA1106 또한 TSPO에 낮은 특정 신호(specific signal)를 보이는 문제점이 있음이 발표되었다. [11C]DAA1106가 갖는 약동학적 단점을 극복하기 위해 개발된 [11C]PBR28 (N-acetyl-N-(2-[11C]methoxy benzyl)-2-phenoxy-5-pyridinamine)은 [11C]DAA1106가 갖는 기본 화학적 구조를 유지하면서 높은 신호 대 잡음 비(Signal-to-noise)의 특성을 가져 뇌신경염증 영상 방사성추적자로서 다양한 유효성이 검증되어 임상 연구가 진행되고 있다. 하지만 [11C]PBR28 또한 반감기가 짧은 탄소-11로 표지 된 화합물이기 때문에 생산 후에 단시간 사용이 가능한 방사성추적자이며, 동반되는 방사선 피폭 가능성이 높을 뿐만 아니라, 한 번 생산 시 보유 PET 장비 수에 따라 최대 2명의 환자에게만 적용할 수 있다는 단점이 있다.

[선행기술문헌]
-중국특허공개공보 제106866675호
-미국특허공보 제9458161호However, [11C]-(R)-PK11195 was limited in widespread use due to the short half-life of the radioisotope carbon-11 used, the nonspecific binding of the ligand PK11195, and the problem of low signal to noise ratio. As a result, various new radiotracers have been developed for cranial nerve inflammation imaging over the past 20 years, and as one of them, it consumes more than four times more than [11C]-(R)-PK11195, and metabolites in the body are blood vessel barriers. [11C]DAA1106 (N-5-fluoro-2-phenoxy phenyl)-N-(2,5-dimethoxybenzyl)acetamide), which did not pass through the brain barrier), were developed. However, it was reported that [11C]DAA1106 also had a problem of showing a low specific signal to TSPO. [11C]PBR28 (N-acetyl-N-(2-[11C]methoxy benzyl)-2-phenoxy-5-pyridinamine) was developed to overcome the pharmacokinetic disadvantages of [11C]DAA1106, and [11C]DAA1106 It has a high signal-to-noise characteristic while maintaining its basic chemical structure, and has been proven to be a radioactive tracer for neuroinflammation images, and clinical studies are being conducted. However, since [11C]PBR28 is also a compound labeled with carbon-11 with a short half-life, it is a radiotracer that can be used for a short time after production, and the possibility of accompanying radiation exposure is high, as well as a maximum of 2 depending on the number of PET equipment held in one production. The disadvantage is that it can only be applied to two patients.

[Prior technical literature]
-Chinese Patent Publication No. 106866675
-US Patent Publication No.9458161

본 발명은 높은 결합친화도를 가지는 모핵구조에 [18F]플루오르벤젠 또는 [18F]플루오르알킬 및 최적화된 아미드기가 도입된 신규 뇌신경염증 표적용 PET 방사성 화합물을 개발하여 뇌신경염증 진단에 사용함으로써, 높은 TSPO 친화도를 나타내어 뇌신경염증 영상을 위한 이상적인 약동학적 정보를 제공하는 것을 목적으로 한다.The present invention develops a novel PET radioactive compound for targeting cranial nerve inflammation in which [ 18 F] fluorobenzene or [ 18 F] fluoroalkyl and an optimized amide group is introduced into the parental structure having high binding affinity, and is used for diagnosis of cranial nerve inflammation, It aims to provide ideal pharmacokinetic information for cranial nerve inflammation imaging by showing high TSPO affinity.

상기 목적을 달성을 위하여 본 발명은 PET용 방사성 화합물에 있어서, [18F]플루오로벤젠기를 포함한다. In order to achieve the above object, the present invention includes a [ 18 F]fluorobenzene group in the radioactive compound for PET.

바람직하게는, 상기 화합물은 하기 화학식 1로 표시되는 화합물일 수 있다.Preferably, the compound may be a compound represented by the following formula (1).

[화학식 1][Formula 1]

Figure 112018116092428-pat00001
Figure 112018116092428-pat00001

상기 식에서, X는 2차 아민이다.In the above formula, X is a secondary amine.

또한 상기 목적을 달성을 위하여 본 발명은 하기 화학식 2 내지 10 화합물로 표시되는 PET용 방사성 화합물을 제공한다.In addition, in order to achieve the above object, the present invention provides a radioactive compound for PET represented by the following Chemical Formulas 2 to 10 compounds.

[화학식 2][Formula 2]

Figure 112018116092428-pat00002
상기 식에서, X는 [18F]플루오로알킬기이다.
Figure 112018116092428-pat00002
In the above formula, X is a [ 18 F]fluoroalkyl group.

[화학식 3][Formula 3]

Figure 112018116092428-pat00003
상기 식에서, X는 [18F]플루오로알킬기이다.
Figure 112018116092428-pat00003
In the above formula, X is a [ 18 F]fluoroalkyl group.

[화학식 4][Formula 4]

Figure 112018116092428-pat00004
상기 식에서, X는 o-[18F], m-[18F] 및 p-[18F]로 이루어진 군으로부터 선택되는 하나이다.
Figure 112018116092428-pat00004
In the above formula, X is one selected from the group consisting of o-[ 18 F], m-[ 18 F] and p-[ 18 F].

[화학식 5][Formula 5]

Figure 112018116092428-pat00005
Figure 112018116092428-pat00005

[화학식 6][Formula 6]

Figure 112018116092428-pat00006
상기 식에서, X는 [18F]플루오로알킬기이다.
Figure 112018116092428-pat00006
In the above formula, X is a [ 18 F]fluoroalkyl group.

[화학식 7][Formula 7]

Figure 112018116092428-pat00007
상기 식에서, X는 [18F]플루오로알킬기이다.
Figure 112018116092428-pat00007
In the above formula, X is a [ 18 F]fluoroalkyl group.

[화학식 8][Formula 8]

Figure 112018116092428-pat00008
상기 식에서, X 는 [18F]플루오르 또는 [18F]플루오로알콕시기이다.
Figure 112018116092428-pat00008
In the above formula, X is a [ 18 F]fluoro or [ 18 F]fluoroalkoxy group.

[화학식 9][Formula 9]

Figure 112018116092428-pat00009
상기 식에서, x는 [18F]플루오로알킬기이다.
Figure 112018116092428-pat00009
In the above formula, x is a [ 18 F]fluoroalkyl group.

[화학식 10][Formula 10]

Figure 112018116092428-pat00010
상기 식에서, X는 [18F]플루오로알킬기이다.
Figure 112018116092428-pat00010
In the above formula, X is a [ 18 F]fluoroalkyl group.

상기와 같은 본 발명에 따르면, 본 발명은 [18F]플루오르알킬 또는 [18F]플루오르벤젠 및 N,N-에틸페닐아미드기가 도입된 신규 뇌신경염증 표적용 PET 방사성 화합물을 개발하여 뇌신경염증 진단에 사용함으로써, 높은 TSPO 친화도를 나타내어 뇌신경염증 영상을 위한 이상적인 약동학적 정보를 제공할 수 있는 효과가 있다.According to the present invention as described above, the present invention is to develop a new PET radioactive compound for targeting cranial nerve inflammation in which [ 18 F] fluoroalkyl or [ 18 F] fluorobenzene and N,N -ethylphenylamide groups are introduced to diagnose cranial nerve inflammation. By using it, it has the effect of showing high TSPO affinity to provide ideal pharmacokinetic information for cranial nerve inflammation imaging.

도 1은 본 발명의 실시예에 따른 피라졸로피리미딘 모핵을 가지는 유도체들을 분석하여 보다 높은 결합친화도를 가지는 PET 방사성 화합물을 개발하는 원리를 나타내는 도면이다.
도 2는 본 발명의 실시예에 따른 화학식 1 화합물들의 IC50 값을 나타내는 그래프이다.1 is a view showing the principle of developing a PET radioactive compound having a higher binding affinity by analyzing derivatives having a pyrazolopyrimidine parent nucleus according to an embodiment of the present invention.
2 is a graph showing IC 50 values of compounds of Formula 1 according to an embodiment of the present invention.

이하, 본 발명의 실시예를 상세히 설명한다.Hereinafter, an embodiment of the present invention will be described in detail.

본 발명의 일 형태에 따른 PET용 방사성 화합물은 [18F]플루오로 벤질기를 포함한다. 상기 화합물은 하기 화학식 1로 표시될 수 있다. The radioactive compound for PET according to one embodiment of the present invention includes a [ 18 F]fluoro benzyl group. The compound may be represented by the following formula (1).

[화학식 1][Formula 1]

Figure 112018116092428-pat00011
Figure 112018116092428-pat00011

상기 식에서, X는 2차 아민이다.In the above formula, X is a secondary amine.

상기 화학식 1 화합물인 PET 리간드는 피라졸로피리미딘 모핵을 가지는 유도체들로부터 디자인될 수 있다. 보다 상세하게는 PET 영상에서 방사성 리간드의 가장 중요한 특성은 결합친화도로서 현재까지 알려진 가장 결합친화도가 높은 TSPO PET 리간드 중 하나는 [18F]DPA-714이다. 따라서 [18F]DPA-714와 그의 유도체들을 분석하여 보다 높은 결합친화도를 가지는 상기 화학식 1 화합물인 PET 리간드를 개발할 수 있다. 도 1을 참조하면, DPA-714에 비해 이의 유도체인 FDPA는 불소를 직접 벤젠고리에 치환시키므로 보다 높은 결합친화도를 보여주었고 반면 피라졸로 고리에서의 두 개의 메틸기를 에틸기로 치환할 경우 최대 50배의 결합친화도 향상을 보여주었다. 따라서 이 두 가지를 병합하고 아래쪽 아미드기를 탐색한 결과 화학식 1 형태의 화합물을 도출할 수 있었다. 화학식 1 화합물의 제조 방법은 실시예에 기재된 바와 같다.The PET ligand of the compound of Formula 1 may be designed from derivatives having a pyrazolopyrimidine parent nucleus. In more detail, the most important property of the radioligand in PET images is the binding affinity, and one of the TSPO PET ligands with the highest binding affinity known to date is [ 18 F]DPA-714. Therefore, by analyzing [ 18 F]DPA-714 and its derivatives, it is possible to develop a PET ligand, the compound of Formula 1, having a higher binding affinity. 1, compared to DPA-714, its derivative, FDPA, showed higher binding affinity because it directly substituted fluorine into the benzene ring. On the other hand, when two methyl groups in the pyrazole ring were substituted with an ethyl group, up to 50 times Showed improved binding affinity. Therefore, as a result of merging these two and searching for the lower amide group, a compound of the form of Formula 1 could be derived. The method of preparing the compound of Formula 1 is as described in Examples.

상기 화학식 1 화합물은 하기와 같이 The compound of Formula 1 is as follows

Figure 112018116092428-pat00012
,
Figure 112018116092428-pat00013
,
Figure 112018116092428-pat00014
Figure 112018116092428-pat00012
,
Figure 112018116092428-pat00013
,
Figure 112018116092428-pat00014

Figure 112018116092428-pat00015
,
Figure 112018116092428-pat00016
,
Figure 112018116092428-pat00017
Figure 112018116092428-pat00015
,
Figure 112018116092428-pat00016
,
Figure 112018116092428-pat00017

Figure 112018116092428-pat00018
,
Figure 112018116092428-pat00019
,
Figure 112018116092428-pat00020
,
Figure 112018116092428-pat00018
,
Figure 112018116092428-pat00019
,
Figure 112018116092428-pat00020
,

Figure 112018116092428-pat00021
및
Figure 112018116092428-pat00022
로 구성된 군에서 선택되는 화합물일 수 있다.
Figure 112018116092428-pat00021
And
Figure 112018116092428-pat00022
It may be a compound selected from the group consisting of.

그 외 본 발명의 일 형태에 따른 PET용 방사성 화합물은 상기 화학식 1 화합물에서 아미드기 부분을 -NRC6H5 또는 이와 유사한 형태로 유지하면서 나머지 부분을 변형한, 하기 화학식 2 내지 10으로 표시되는 화합물일 수 있다. 즉, 본 발명의 일 형태에 따른 PET용 방사성 화합물은 하기 화학 식 2로 표시되는 화합물일 수 있다.In addition, the radioactive compound for PET according to an embodiment of the present invention is a compound represented by the following Formulas 2 to 10, wherein the amide group portion of the compound of Formula 1 is maintained in -NRC 6 H 5 or a similar form while modifying the rest of the compound. Can be That is, the radioactive compound for PET according to one embodiment of the present invention may be a compound represented by the following Chemical Formula 2.

[화학식 2][Formula 2]

Figure 112018116092428-pat00023
상기 식에서, X는 [18F]플루오로알킬기이다. 이 경우 상기 화학식 2 화합물은
Figure 112018116092428-pat00023
In the above formula, X is a [ 18 F]fluoroalkyl group. In this case, the compound of Formula 2 is

Figure 112018116092428-pat00024
,
Figure 112018116092428-pat00025
및
Figure 112018116092428-pat00026
로 구성된 군에서 선택되는 화합물일 수 있다.
Figure 112018116092428-pat00024
,
Figure 112018116092428-pat00025
And
Figure 112018116092428-pat00026
It may be a compound selected from the group consisting of.

본 발명의 일 형태에 따른 PET용 방사성 화합물은 하기 화학식 3으로 표시되는 화합물일 수 있다.The radioactive compound for PET according to an embodiment of the present invention may be a compound represented by Formula 3 below.

[화학식 3][Formula 3]

Figure 112018116092428-pat00027
상기 식에서, X는 [18F]플루오로알킬기이다. 상기 화학식 3 화합물은
Figure 112018116092428-pat00027
In the above formula, X is a [ 18 F]fluoroalkyl group. The compound of Formula 3 is

Figure 112018116092428-pat00028
,
Figure 112018116092428-pat00029
및
Figure 112018116092428-pat00030
로 구성된 군으로부터 선택되는 화합물일 수 있다.
Figure 112018116092428-pat00028
,
Figure 112018116092428-pat00029
And
Figure 112018116092428-pat00030
It may be a compound selected from the group consisting of.

본 발명의 일 형태에 따른 PET용 방사성 화합물은 하기 화학식 4로 표시되는 화합물일 수 있다.The radioactive compound for PET according to an embodiment of the present invention may be a compound represented by Formula 4 below.

[화학식 4][Formula 4]

Figure 112018116092428-pat00031
상기 식에서, X는 o-[18F], m-[18F] 및 p-[18F]로 이루어진 군으로부터 선택되는 하나일 수 있다.
Figure 112018116092428-pat00031
In the above formula, X may be one selected from the group consisting of o-[ 18 F], m-[ 18 F] and p-[ 18 F].

본 발명의 일 형태에 따른 PET용 방사성 화합물은 하기 화학식 5로 표시되는 화합물일 수 있다.The radioactive compound for PET according to an embodiment of the present invention may be a compound represented by Formula 5 below.

[화학식 5][Formula 5]

Figure 112018116092428-pat00032
Figure 112018116092428-pat00032

본 발명의 일 형태에 따른 PET용 방사성 화합물은 하기 화학식 6으로 표시되는 화합물일 수 있다.The radioactive compound for PET according to one embodiment of the present invention may be a compound represented by the following formula (6).

[화학식 6][Formula 6]

Figure 112018116092428-pat00033
상기 식에서, X는 [18F]플루오로알킬기이다. 상기 화학식 6 화합물은
Figure 112018116092428-pat00033
In the above formula, X is a [ 18 F]fluoroalkyl group. The compound of Formula 6 is

Figure 112018116092428-pat00034
,
Figure 112018116092428-pat00035
및
Figure 112018116092428-pat00036
로 구성된 군으로부터 선택되는 화합물일 수 있다.
Figure 112018116092428-pat00034
,
Figure 112018116092428-pat00035
And
Figure 112018116092428-pat00036
It may be a compound selected from the group consisting of.

본 발명의 일 형태에 따른 PET용 방사성 화합물은 하기 화학식 7로 표시되는 화합물일 수 있다.The radioactive compound for PET according to one embodiment of the present invention may be a compound represented by the following formula (7).

[화학식 7][Formula 7]

Figure 112018116092428-pat00037
상기 식에서, X는 [18F]플루오로알킬기이다. 상기 화학식 7 화합물은
Figure 112018116092428-pat00037
In the above formula, X is a [ 18 F]fluoroalkyl group. The compound of Formula 7 is

Figure 112018116092428-pat00038
,
Figure 112018116092428-pat00039
및
Figure 112018116092428-pat00040
로 구성된 군으로부터 선택되는 화합물일 수 있다.
Figure 112018116092428-pat00038
,
Figure 112018116092428-pat00039
And
Figure 112018116092428-pat00040
It may be a compound selected from the group consisting of.

본 발명의 일 형태에 따른 PET용 방사성 화합물은 하기 화학식 8로 표시되는 화합물일 수 있다.The radioactive compound for PET according to an embodiment of the present invention may be a compound represented by Formula 8 below.

[화학식 8][Formula 8]

Figure 112018116092428-pat00041
상기 식에서, X 는 [18F]플루오르 또는 [18F]플루오로알콕시기이다. 상기 화학식 8 화합물은
Figure 112018116092428-pat00041
In the above formula, X is a [ 18 F]fluoro or [ 18 F]fluoroalkoxy group. The compound of Formula 8 is

Figure 112018116092428-pat00042
,
Figure 112018116092428-pat00043
,
Figure 112018116092428-pat00044
, 및
Figure 112018116092428-pat00045
로 구성된 군에서 선택되는 화합물일 수 있다.
Figure 112018116092428-pat00042
,
Figure 112018116092428-pat00043
,
Figure 112018116092428-pat00044
, And
Figure 112018116092428-pat00045
It may be a compound selected from the group consisting of.

본 발명의 일 형태에 따른 PET용 방사성 화합물은 하기 화학식 9로 표시되는 화합물.The radioactive compound for PET according to one embodiment of the present invention is a compound represented by the following formula (9).

[화학식 9][Formula 9]

Figure 112018116092428-pat00046
상기 식에서, x는 [18F]플루오로알킬기이다. 상기 화학식 9 화합물은
Figure 112018116092428-pat00046
In the above formula, x is a [ 18 F]fluoroalkyl group. The compound of Formula 9 is

Figure 112018116092428-pat00047
,
Figure 112018116092428-pat00047
,

Figure 112018116092428-pat00048
및
Figure 112018116092428-pat00048
And

Figure 112018116092428-pat00049
로 구성된 군에서 선택되는 화합물일 수 있다.
Figure 112018116092428-pat00049
It may be a compound selected from the group consisting of.

본 발명의 일 형태에 따른 PET용 방사성 화합물은 하기 화학식 10으로 표시되는 화합물.The radioactive compound for PET according to one embodiment of the present invention is a compound represented by the following formula (10).

[화학식 10][Formula 10]

Figure 112018116092428-pat00050
상기 식에서, X는 [18F]플루오로알킬기이다. 상기 화학식 10 화합물은
Figure 112018116092428-pat00050
In the above formula, X is a [ 18 F]fluoroalkyl group. The compound of Formula 10 is

Figure 112018116092428-pat00051
,
Figure 112018116092428-pat00052
및
Figure 112018116092428-pat00051
,
Figure 112018116092428-pat00052
And

Figure 112018116092428-pat00053
로 구성된 군에서 선택되는 화합물일 수 있다.
Figure 112018116092428-pat00053
It may be a compound selected from the group consisting of.

이하, 실시예 및 측정예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예 및 측정예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예 및 측정예에 의해 제한되는 것으로 해석되지는 않는 것은 당 업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples and measurement examples. These examples and measurement examples are for illustrative purposes only, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not construed as being limited by these examples and measurement examples. will be.

실시예Example

TSPO에 대한 결합친화도가 높을 것으로 여겨지는 새로운 구조의 피리졸로-피리미딘 고리를 포함하는 화학식 1 화합물의 합성은 아래와 같이 이루어 졌다.Synthesis of the compound of Formula 1 including a pyrizolo-pyrimidine ring of a new structure, which is believed to have high binding affinity for TSPO, was carried out as follows.

합성과정Synthesis process

Figure 112020035645919-pat00103
Figure 112020035645919-pat00103

2차 아민(NHRSecondary amine (NHR 1One RR 22 ))

Figure 112018116092428-pat00055
Figure 112018116092428-pat00055

합성된 화학식 1 화합물들.Synthesized Formula 1 compounds.

Figure 112018116092428-pat00056
Figure 112018116092428-pat00056

상기 그림에 나타난 바와 같이 화학식 1 화합물의 전구체에 V1 내지 V11인 2차 아민을 첨가하여 상기 최종 화학식 1 화합물들을 합성하였다As shown in the figure above, the final compounds of Formula 1 were synthesized by adding secondary amines V1 to V11 to the precursor of the compound of Formula 1

측정예Measurement example

합성되어진 11개의 화합물들은 TSPO에 경쟁적으로 결합하는 방사성 리간드인 [3H]PK11195와 함께 in vitro binding assay를 실시하였다. TSPO 단백질이 포함된 Human Leukocytes를 이용하여 [3H]PK11195와 다양한 농도의 리간드를 함께 섞어 농도에 따른 [3H]PK11195의 결합 분율을 구하고 이를 통하여 IC50를 구하였다. 하기 표 1 및 도 2에 나타난 바와 같이, 실험의 정확도를 파악하고 기존 리간드와 비교하기 위하여 PK11195와 DPA-714도 함께 실시하였다. 결합친화도를 IC50값으로 구한 결과, 4,5,7,9,10,11번 화합물이 매우 높은 결합친화도를 보였으며, 특히 9번 화합물의 경우에는 DPA-714보다 약 62.4배 높은 결합친화도를 보여 뇌신경염증 PET 리간드로서의 높은 가능성을 보여 주었다. The synthesized 11 compounds were subjected to in vitro binding assay with [3H]PK11195, a radioligand competitively binding to TSPO. Using Human Leukocytes containing TSPO protein, [3H]PK11195 and various concentrations of ligand were mixed together to obtain the binding fraction of [3H]PK11195 according to the concentration, and IC50 was obtained through this. As shown in Tables 1 and 2 below, PK11195 and DPA-714 were also carried out in order to determine the accuracy of the experiment and to compare it with the existing ligand. As a result of calculating the binding affinity by the IC 50 value, compounds 4,5,7,9,10,11 showed very high binding affinity, especially in the case of compound 9, about 62.4 times higher than DPA-714. It showed high affinity as a PET ligand for cranial nerve inflammation.

Figure 112018116092428-pat00057
Figure 112018116092428-pat00057

Claims (19)

[18F]플루오로벤질기를 포함하는 PET용 방사성 화합물에 있어서,
상기 화합물은,
Figure 112020035645919-pat00104
,
Figure 112020035645919-pat00105
,
Figure 112020035645919-pat00106
,
Figure 112020035645919-pat00107
,
Figure 112020035645919-pat00108
,
또는
Figure 112020035645919-pat00109
로 구성된 군으로부터 선택되는 화합물.
[ 18 ] In the radioactive compound for PET containing a fluorobenzyl group,
The compound is
Figure 112020035645919-pat00104
,
Figure 112020035645919-pat00105
,
Figure 112020035645919-pat00106
,
Figure 112020035645919-pat00107
,
Figure 112020035645919-pat00108
,
or
Figure 112020035645919-pat00109
A compound selected from the group consisting of.
 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete
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WO2012168697A1 (en) 2011-06-06 2012-12-13 Imperial Innovations Limited Methods to predict binding affinity of tspo imaging agents to tspo
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WO2012168697A1 (en) 2011-06-06 2012-12-13 Imperial Innovations Limited Methods to predict binding affinity of tspo imaging agents to tspo
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