KR20200059529A - 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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KR20200059529A
KR20200059529A KR1020180144373A KR20180144373A KR20200059529A KR 20200059529 A KR20200059529 A KR 20200059529A KR 1020180144373 A KR1020180144373 A KR 1020180144373A KR 20180144373 A KR20180144373 A KR 20180144373A KR 20200059529 A KR20200059529 A KR 20200059529A
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이상윤
막수드 알람 모하메드
이지혜
이도 타츠오
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(의료)길의료재단
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    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
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Abstract

The present invention relates to a radioactive compound used for positron emission tomography (PET) targeting brain neuroinflammation. The compound according to the present invention comprises an amine group and [^18F]fluorine-introduced PET radioactive compound. According to the present invention, the novel PET radioactive compound for targeting brain neuroinflammation, in which [^18F]fluorophenyl (or [^18F]fluoroalkyl) and an optimized amide group are introduced into various mother nucleus structures, is developed to be used for diagnosing brain neuroinflammation, so that an effect of providing ideal pharmacokinetic information for brain neuroinflammation images can be achieved through the compound showing high TSPO affinity.

Description

아민기 및 [18F]플루오르가 도입된 뇌신경염증 진단용 양성자방출단층촬영 방사성화합물.{AMINO GROUP AND [18F] FLUORINE-INTRODUCED PROTON-EMITTING TOMOGRAPHIC RADIOACTIVE COMPOUND}AMINO GROUP AND [18F] FLUORINE-INTRODUCED PROTON-EMITTING TOMOGRAPHIC RADIOACTIVE COMPOUND} for the diagnosis of cranial neuropathy with the introduction of amine groups and [18F] fluor.

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 neuropathy, and more particularly, having a pyrazolopyrimidine parent nucleus known to have high binding affinity with translocator protein (TSPO). It is related to various parental nucleus bonds centered on a amide group substituted with various alkyl groups or aryl groups from derivatives and a radioactive ligand for PET in which [ 18 F] fluorbenzene is introduced, and a substituted amide group optimized thereby.

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 homeostasis of the nervous system, and the maintenance or apoptosis of nerve cells by secreting neurotrophin, nitric oxide or cytokines causing inflammation, etc. It has the function of causing back. In fact, activation of microglia in various degenerative nervous system diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, brain infarction or brain injury, and brain infection has been reported. It is also known that the deposition of beta amyloid, which is the development and progression factor of Alzheimer's disease, causes activation of microglia.

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. It has been reported that the activation of microglia now occurs due to the increased expression of the 18 kDa translocator protein (TSPO) present in the mitochondrial membrane, and begins within a few hours of the disease and lasts for several days. Therefore, measurement of the degree of TSPO expression of microglia in various central nervous system diseases can be utilized as an in vivo biomarker to evaluate microglia activation during the neuro-inflammatory process.

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, [11C]-(R) -PK11195 ((R) -N-), which labeled carbon-11 (half-life 20.4 min) as a radiotracer for Positron Emission Tomography (PET) for TSPO evaluation in 1984 methyl-N- (1-methylpropyl) -1- (2-chlorophenyl) isoquinoline-3-carboxamide) was first developed, and 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.However, [11C]-(R) -PK11195 was limited for widespread use due to the short half-life of the radioisotope carbon-11 used and the non-specific binding of ligand PK11195 and the problem of low signal to noise ratio. As a result, in the past 20 years, various new radiotracers for cranial neuropathy imaging have been developed, and as one of them, it is ingested more than 4 times compared to [11C]-(R) -PK11195 and metabolites in the body are the blood vessel barrier of the brain [11C] DAA1106 (N-5-fluoro-2-phenoxy phenyl) -N- (2,5-dimethoxybenzyl) acetamide), which did not cross the brain barrier, was developed. However, [11C] DAA1106 has also been reported to have a problem with low specific signals in TSPO. [11C] PBR28 (N-acetyl-N- (2- [11C] methoxy benzyl) -2-phenoxy-5-pyridinamine) developed to overcome the pharmacokinetic disadvantages of [11C] DAA1106 is [11C] DAA1106 It has the characteristics of high signal-to-noise ratio while maintaining the basic chemical structure, and various studies have been conducted as clinical radiotracers for cranial neuropathy imaging. However, since [11C] PBR28 is also a compound labeled with carbon-11, which has a short half-life, it is a radioactive tracer that can be used for a short period of time after production. It has the disadvantage that it can only be applied to patients.

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 is used for brain inflammation diagnostics to develop a [18 F] fluorine benzene or [18 F] fluoroalkyl and optimized amide group introduced new brain inflammation table applies PET a radioactive compound in mohaek structure having a high binding affinity, It aims to provide high pharmacokinetic information for cranial neuropathy 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 a radioactive compound for PET.

바람직하게는, 상기 화합물은 하기 화학식 1로 표시되는 화합물일 수 있다.Preferably, the compound may be a compound represented by Formula 1 below.

[화학식 1][Formula 1]

Figure pat00001
Figure 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.

[화학식 2][Formula 2]

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

[화학식 3][Formula 3]

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

[화학식 4][Formula 4]

Figure pat00004
상기 식에서, X는 o-[18F], m-[18F] 및 p-[18F]로 이루어진 군으로부터 선택되는 하나이다.
Figure 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 pat00005
Figure pat00005

[화학식 6][Formula 6]

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

[화학식 7][Formula 7]

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

[화학식 8][Formula 8]

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

[화학식 9][Formula 9]

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

[화학식 10][Formula 10]

Figure pat00010
상기 식에서, X는 [18F]플루오로알킬기이다.
Figure 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.In accordance with the present invention as described above, the present invention is [18 F] fluoroalkyl or [18 F] fluoro benzene and N, N - the nerve inflammation diagnostics to develop ethyl phenylamide group is a novel brain inflammation table applied introduced PET radioactive compound By using it, it exhibits high TSPO affinity, and has the effect of providing ideal pharmacokinetic information for cranial neuropathy 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, embodiments 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 Formula 1 below.

[화학식 1][Formula 1]

Figure pat00011
Figure 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 Formula 1 may be designed from derivatives having a pyrazolopyrimidine parent nucleus. In more detail, the most important property of the radioactive ligand in PET imaging is binding affinity, and one of the highest binding affinity TSPO PET ligands known to date is [ 18 F] DPA-714. Therefore, by analyzing [ 18 F] DPA-714 and its derivatives, it is possible to develop the PET ligand, which is the compound of Formula 1, which has a higher binding affinity. Referring to FIG. 1, compared to DPA-714, FDPA, a derivative thereof, substituted fluorine directly on the benzene ring, and thus showed higher binding affinity, whereas when two methyl groups in the pyrazolo ring were substituted with ethyl groups, up to 50 times The binding affinity was improved. Therefore, by combining these two and searching for the amide group at the bottom, it was possible to derive the compound of Formula 1 form. The method for 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 pat00012
,
Figure pat00013
,
Figure pat00014
Figure pat00012
,
Figure pat00013
,
Figure pat00014

Figure pat00015
,
Figure pat00016
,
Figure pat00017
Figure pat00015
,
Figure pat00016
,
Figure pat00017

Figure pat00018
,
Figure pat00019
,
Figure pat00020
,
Figure pat00018
,
Figure pat00019
,
Figure pat00020
,

Figure pat00021
및
Figure pat00022
로 구성된 군에서 선택되는 화합물일 수 있다.
Figure pat00021
And
Figure 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 one embodiment of the present invention is a compound represented by the following Chemical Formulas 2 to 10, wherein the remaining part is modified while maintaining the amide group part in -NRC 6 H 5 or a similar form in the Chemical Formula 1 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 pat00023
상기 식에서, X는 [18F]플루오로알킬기이다. 이 경우 상기 화학식 2 화합물은
Figure pat00023
In the above formula, X is a [ 18 F] fluoroalkyl group. In this case, the compound of Formula 2

Figure pat00024
,
Figure pat00025
및
Figure pat00026
로 구성된 군에서 선택되는 화합물일 수 있다.
Figure pat00024
,
Figure pat00025
And
Figure 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 one embodiment of the present invention may be a compound represented by Formula 3 below.

[화학식 3][Formula 3]

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

Figure pat00028
,
Figure pat00029
및
Figure pat00030
로 구성된 군으로부터 선택되는 화합물일 수 있다.
Figure pat00028
,
Figure pat00029
And
Figure 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 one embodiment of the present invention may be a compound represented by the following Chemical Formula 4.

[화학식 4][Formula 4]

Figure pat00031
상기 식에서, X는 o-[18F], m-[18F] 및 p-[18F]로 이루어진 군으로부터 선택되는 하나일 수 있다.
Figure 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 one embodiment of the present invention may be a compound represented by the following Chemical Formula 5.

[화학식 5][Formula 5]

Figure pat00032
Figure 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 Formula 6 below.

[화학식 6][Formula 6]

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

Figure pat00034
,
Figure pat00035
및
Figure pat00036
로 구성된 군으로부터 선택되는 화합물일 수 있다.
Figure pat00034
,
Figure pat00035
And
Figure 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 Chemical Formula 7.

[화학식 7][Formula 7]

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

Figure pat00038
,
Figure pat00039
및
Figure pat00040
로 구성된 군으로부터 선택되는 화합물일 수 있다.
Figure pat00038
,
Figure pat00039
And
Figure 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 one embodiment of the present invention may be a compound represented by the following Chemical Formula 8.

[화학식 8][Formula 8]

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

Figure pat00042
,
Figure pat00043
,
Figure pat00044
, 및
Figure pat00045
로 구성된 군에서 선택되는 화합물일 수 있다.
Figure pat00042
,
Figure pat00043
,
Figure pat00044
, And
Figure 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 pat00046
상기 식에서, x는 [18F]플루오로알킬기이다. 상기 화학식 9 화합물은
Figure pat00046
In the above formula, x is a [ 18 F] fluoroalkyl group. Compound 9 is

Figure pat00047
,
Figure pat00047
,

Figure pat00048
및
Figure pat00048
And

Figure pat00049
로 구성된 군에서 선택되는 화합물일 수 있다.
Figure 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 pat00050
상기 식에서, X는 [18F]플루오로알킬기이다. 상기 화학식 10 화합물은
Figure pat00050
In the above formula, X is a [ 18 F] fluoroalkyl group. Compound 10 is

Figure pat00051
,
Figure pat00052
및
Figure pat00051
,
Figure pat00052
And

Figure pat00053
로 구성된 군에서 선택되는 화합물일 수 있다.
Figure 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 only for illustrating the present invention, it is apparent to those skilled in the art that the scope of the present invention is not to be construed as 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 containing a pyrrozolo-pyrimidine ring of a new structure that is believed to have high binding affinity to TSPO was performed as follows.

합성과정Synthesis process

Figure pat00054
Figure pat00054

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

Figure pat00055
Figure pat00055

합성된 화학식 1 화합물들.Synthesized Formula 1 compounds.

Figure pat00056
Figure 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, V1 to V11 secondary amines were added to the precursor of the compound of Formula 1 to synthesize the final Formula 1 compounds.

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 radioactive ligand that competitively binds TSPO. Using human leukocytes containing TSPO protein, [3H] PK11195 and various concentrations of ligands were mixed together to obtain the binding fraction of [3H] PK11195 according to the concentration, and IC50 was obtained therefrom. As shown in Table 1 and FIG. 2, PK11195 and DPA-714 were also performed in order to grasp the accuracy of the experiment and compare it with existing ligands. As a result of obtaining the binding affinity as an IC 50 value, compounds 4,5,7,9,10,11 showed a very high binding affinity, and in particular, the compound 9 was about 62.4 times higher than DPA-714 It showed affinity and showed high potential as a PET ligand for cranial neuropathy.

Figure pat00057
Figure pat00057

Claims (19)

[18F]플루오로벤질기를 포함하는 PET용 방사성 화합물.
 [18 F] Radioactive compounds for PET containing the fluoroalkyl group benzyl.
제1항에 있어서,
상기 화합물은 하기 화학식 1로 표시되는 화합물:
[화학식 1]
Figure pat00058

상기 식에서 X는 2차 아민이다.
According to claim 1,
The compound is a compound represented by Formula 1:
[Formula 1]
Figure pat00058

In the above formula, X is a secondary amine.
제2항에 있어서,
상기 화합물은
Figure pat00059
,
Figure pat00060
,
Figure pat00061

Figure pat00062
,
Figure pat00063
,
Figure pat00064

Figure pat00065
,
Figure pat00066
,
Figure pat00067
,
Figure pat00068
및
Figure pat00069
로 구성된 군으로부터 선택되는 화합물.
According to claim 2,
The compound
Figure pat00059
,
Figure pat00060
,
Figure pat00061

Figure pat00062
,
Figure pat00063
,
Figure pat00064

Figure pat00065
,
Figure pat00066
,
Figure pat00067
,
Figure pat00068
And
Figure pat00069
A compound selected from the group consisting of.
하기 화학식 2로 표시되는 화합물:
[화학식 2]
Figure pat00070

상기 식에서,
X는 [18F]플루오로알킬기이다
Compound represented by the following formula (2):
[Formula 2]
Figure pat00070

In the above formula,
X is [ 18 F] fluoroalkyl group
제4항에 있어서,
상기 화합물은
Figure pat00071
,
Figure pat00072
및
Figure pat00073
로 구성된 군으로부터 선택되는 화합물.
The method of claim 4,
The compound
Figure pat00071
,
Figure pat00072
And
Figure pat00073
A compound selected from the group consisting of.
하기 화학식 3으로 표시되는 화합물.
[화학식 3]
Figure pat00074

상기 식에서,
X는 [18F]플루오로알킬기이다.

Compound represented by the formula (3).
[Formula 3]
Figure pat00074

In the above formula,
X is a [ 18 F] fluoroalkyl group.

제6항에 있어서,
상기 화합물은
Figure pat00075
,
Figure pat00076
및
Figure pat00077
로 구성된 군으로부터 선택되는 화합물.
The method of claim 6,
The compound
Figure pat00075
,
Figure pat00076
And
Figure pat00077
A compound selected from the group consisting of.
하기 화학식 4로 표시되는 화합물.
[화학식 4]
Figure pat00078

상기 식에서,
X는 o-[18F], m-[18F] 및 p-[18F]로 이루어진 군으로부터 선택되는 하나이다.
Compound represented by the following formula (4).
[Formula 4]
Figure pat00078

In the above formula,
X is one selected from the group consisting of o- [ 18 F], m- [ 18 F] and p- [ 18 F].
하기 화학식 5로 표시되는 화합물.
[화학식 5]
Figure pat00079
Compound represented by the formula (5).
[Formula 5]
Figure pat00079
 하기 화학식 6으로 표시되는 화합물.
[화학식 6]
Figure pat00080

상기 식에서,
X는 [18F]플루오로알킬기이다.
Compound represented by the formula (6).
[Formula 6]
Figure pat00080

In the above formula,
X is a [ 18 F] fluoroalkyl group.
제10항에 있어서,
상기 화합물은
Figure pat00081
,
Figure pat00082
및
Figure pat00083
로 구성된 군으로부터 선택되는 화합물.
The method of claim 10,
The compound
Figure pat00081
,
Figure pat00082
And
Figure pat00083
A compound selected from the group consisting of.
하기 화학식 7로 표시되는 화합물.
[화학식 7]
Figure pat00084

상기 식에서,
X는 [18F]플루오로알킬기이다.
Compound represented by the formula (7).
[Formula 7]
Figure pat00084

In the above formula,
X is a [ 18 F] fluoroalkyl group.
제12항에 있어서,
상기 화합물은

Figure pat00085
,
Figure pat00086
및
Figure pat00087
로 구성된 군으로부터 선택되는 화합물.
The method of claim 12,
The compound

Figure pat00085
,
Figure pat00086
And
Figure pat00087
A compound selected from the group consisting of.
하기 화학식 8로 표시되는 화합물:
[화학식 8]
Figure pat00088

상기 식에서,
X 는 [18F]플루오르 또는 [18F]플루오로알콕시기이다.
Compound represented by the formula (8):
[Formula 8]
Figure pat00088

In the above formula,
X is a [ 18 F] fluorine or [ 18 F] fluoroalkoxy group.
제14항에 있어서,
상기 화합물은
Figure pat00089
,
Figure pat00090
,
Figure pat00091
, 및
Figure pat00092
로 구성된 군에서 선택되는 화합물.
The method of claim 14,
The compound
Figure pat00089
,
Figure pat00090
,
Figure pat00091
, And
Figure pat00092
A compound selected from the group consisting of.
하기 화학식 9로 표시되는 화합물.
[화학식 9]
Figure pat00093

상기 식에서,
x는 [18F]플루오로알킬기이다.
Compound represented by the formula (9).
[Formula 9]
Figure pat00093

In the above formula,
x is a [ 18 F] fluoroalkyl group.
제16항에 있어서,
상기 화합물은
Figure pat00094
,
Figure pat00095
및
Figure pat00096
로 구성된 군에서 선택되는 화합물.
The method of claim 16,
The compound
Figure pat00094
,
Figure pat00095
And
Figure pat00096
A compound selected from the group consisting of.
하기 화학식 10으로 표시되는 화합물.
[화학식 10]
Figure pat00097

상기 식에서,
X는 [18F]플루오로알킬기이다.
Compound represented by the formula (10).
[Formula 10]
Figure pat00097

In the above formula,
X is a [ 18 F] fluoroalkyl group.
제18항에 있어서,
상기 화합물은
Figure pat00098
,
Figure pat00099
및
Figure pat00100
로 구성된 군에서 선택되는 화합물.

The method of claim 18,
The compound
Figure pat00098
,
Figure pat00099
And
Figure pat00100
A compound selected from the group consisting of.

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