TWI818946B - Radioactive nuclide marking compounds and imaging agents containing them - Google Patents
Radioactive nuclide marking compounds and imaging agents containing them Download PDFInfo
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- TWI818946B TWI818946B TW108101192A TW108101192A TWI818946B TW I818946 B TWI818946 B TW I818946B TW 108101192 A TW108101192 A TW 108101192A TW 108101192 A TW108101192 A TW 108101192A TW I818946 B TWI818946 B TW I818946B
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- C—CHEMISTRY; METALLURGY
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- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
本發明提供一種同時具有tau蛋白親和性及澱粉樣蛋白親和性之放射性核種標識化合物；含有放射性核種標識化合物之用於tau蛋白及/或澱粉樣蛋白之圖像化的成像劑；含有放射性核種標識化合物之用於因tau蛋白及/或澱粉樣蛋白之凝聚而引起的疾病之圖像診斷的放射性醫藥。 一種下述通式(1)所示之放射性核種標識化合物或其鹽。 (式中，X表示放射性碘原子、18 F或11 CH3 ， 吡啶與噁唑係以碳原子鍵結， 吡啶係以碳原子與咪唑并吡啶鍵結)。The present invention provides a radioactive nuclear species labeling compound that has both tau protein affinity and amyloid protein affinity; an imaging agent containing a radioactive nuclear species labeling compound for imaging tau protein and/or amyloid protein; and a radioactive nuclear species labeling compound. The compound is a radioactive medicine used for image diagnosis of diseases caused by aggregation of tau protein and/or amyloid protein. A radioactive nuclide species identification compound represented by the following general formula (1) or a salt thereof. (In the formula ,
Description
本發明係關於一種放射性核種標識化合物及含有其之成像劑。The present invention relates to a radionuclide identification compound and an imaging agent containing the same.
於老齡化日趨嚴重之日本，認知障礙症患者數呈逐步增多之態勢，成為嚴重的社會問題。根據日本厚勞省研究班於2013年發表之統計，65歲以上之15%患有認知障礙症，推定認知障礙症患者有462萬人，作為其後備軍之輕度認知障礙(Mild Cognitive Impairment，MCI)患者有400萬人。就該統計中之認知障礙症患者之明細而言，報告有按照如下順序阿爾茨海默型認知障礙症(Alzheimer's Disease，AD)高達67.6%、血管性認知障礙症高達19.5%、Lewy小體型認知障礙症(Dementia with Lewy bodie，DLB)高達4.3%(非專利文獻1)。另外，於其他統計中，報告有額顳葉變性(Frontotemporal Lobar Degeneration，FTLD)患者占初老期認知障礙症患者中之約20%，AD次多(非專利文獻2、3)。此種認知障礙症患者數量之推移於日本以外之國家亦同樣。In Japan, which is increasingly aging, the number of patients with dementia is gradually increasing and has become a serious social problem. According to statistics published by the Japanese Ministry of Health, Labor and Welfare Research Group in 2013, 15% of people over 65 years old suffer from Alzheimer's disease, and there are estimated to be 4.62 million people with Alzheimer's disease. Mild Cognitive Impairment (MCI) is the reserve force. ) has 4 million patients. Regarding the breakdown of patients with dementia in this statistics, the following order is reported: Alzheimer's Disease (AD) as high as 67.6%, vascular dementia as high as 19.5%, and Lewy small cognitive impairment. Dementia with Lewy bodie (DLB) is as high as 4.3% (Non-Patent Document 1). In addition, according to other statistics, it is reported that patients with frontotemporal lobar degeneration (FTLD) account for approximately 20% of early-stage dementia patients, with the second largest number being AD (non-patent documents 2 and 3). This change in the number of patients with dementia is also true in countries other than Japan.
如上所述認知障礙症被分為各種各樣之病型，於AD患者、部分DLB患者、以及部分FTLD患者等中，稱為澱粉樣蛋白或tau蛋白之蛋白質自發病之數十年前就開始於腦內凝聚並蓄積，導致認知功能下降或神經細胞死亡(非專利文獻4、5、6)。於AD患者之腦內蓄積有澱粉樣蛋白，並且同時蓄積有tau蛋白(非專利文獻5)。DLB患者之40%以上於腦內蓄積有澱粉樣蛋白或tau蛋白(非專利文獻7、8)。另一方面，FTLD患者之約半數於腦內僅蓄積有tau蛋白，無澱粉樣蛋白之蓄積(大腦皮質基底節變性病(Corticobasal Degeneration，CBD)、進行性核上性麻痺(Progressive Supranuclear Palsy，PSP)、皮克氏病(Pick's disease，PiD)、嗜銀顆粒性認知障礙症(Argirophilic grain dementia，AGD)等；FTLD-tau)(非專利文獻2、3、6)。另外，報告有神經原纖維變化(NFT)型老年期認知障礙症(Senile dementia of the NFT type，SD-NFT)係tau蛋白以海馬區域為中心蓄積，但無澱粉樣蛋白蓄積之認知障礙症，占認知障礙症高齡者解剖檢查例之1.7～5.6%(非專利文獻9)。As mentioned above, dementia is divided into various types. In AD patients, some DLB patients, and some FTLD patients, the protein called amyloid or tau begins decades before the onset of the disease. It aggregates and accumulates in the brain, causing cognitive function decline or nerve cell death (Non-Patent Documents 4, 5, 6). Amyloid is accumulated in the brain of AD patients, and tau protein is also accumulated in the brain (Non-Patent Document 5). More than 40% of DLB patients have amyloid or tau protein accumulated in the brain (Non-Patent Documents 7 and 8). On the other hand, about half of FTLD patients only have tau protein accumulated in the brain and no accumulation of amyloid protein (Corticobasal Degeneration (CBD), Progressive Supranuclear Palsy (PSP) ), Pick's disease (PiD), Argirophilic grain dementia (AGD), etc.; FTLD-tau) (Non-Patent Documents 2, 3, 6). In addition, it has been reported that Senile dementia of the NFT type (SD-NFT) is a form of dementia in which tau protein accumulates centered in the hippocampus, but amyloid protein does not accumulate. It accounts for 1.7 to 5.6% of the anatomical examination cases of elderly people with dementia (Non-Patent Document 9).
過去，開發大量將澱粉樣蛋白或tau蛋白圖像化之放射性藥劑，但該等放射性藥劑僅與澱粉樣蛋白或tau蛋白中之任一個之親和性較高(專利文獻1～4)，因此，無法將蓄積於腦內之澱粉樣蛋白及tau蛋白兩者同時圖像化。另一方面，與澱粉樣蛋白及tau蛋白兩者具有高親和性之放射性藥劑能夠將蓄積於腦內之澱粉樣蛋白及tau蛋白兩者同時圖像化。因此，此種放射性藥物可於發病前之早期廣泛地同時檢出以AD或FTLD-tau為代表之於腦內蓄積有澱粉樣蛋白、tau蛋白或其兩者之多種多樣的認知障礙相關疾病，有助於早期診斷、早期治療(非專利文獻10、11)。 [先前技術文獻] [專利文獻]In the past, a large number of radioactive agents for imaging amyloid or tau proteins have been developed. However, these radioactive agents only have high affinity for either amyloid or tau protein (Patent Documents 1 to 4). Therefore, It is not possible to image both amyloid and tau proteins accumulated in the brain at the same time. On the other hand, radioactive agents with high affinity for both amyloid and tau proteins can simultaneously image both amyloid and tau proteins accumulated in the brain. Therefore, this radioactive drug can widely and simultaneously detect a variety of cognitive impairment-related diseases, such as AD or FTLD-tau, which accumulate amyloid protein, tau protein, or both in the brain at an early stage before the onset of disease. It is helpful for early diagnosis and early treatment (Non-Patent Documents 10, 11). [Prior technical literature] [Patent Document]
[專利文獻1]國際公開第2005/016888號說明書 [專利文獻2]國際公開第2008/078424號說明書 [專利文獻3]國際公開第2007/063946號說明書 [專利文獻4]國際公開第2014/097474號說明書 [非專利文獻][Patent Document 1] International Publication No. 2005/016888 Specification [Patent Document 2] International Publication No. 2008/078424 Specification [Patent Document 3] International Publication No. 2007/063946 Specification [Patent Document 4] International Publication No. 2014/097474 Specification [Non-patent literature]
[非專利文獻1]朝田隆，厚生勞動科學研究費輔助金 認知障礙症對策綜合研究事業都市部中之認知障礙症患病率與對認知障礙症之生活功能障礙的對策 平成23～24年度綜合研究報告書 [非專利文獻2] Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology. 2002; 58: 1615-21. [非專利文獻3] Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak TH, Kril JJ, Halliday GM. Clinicopathological correlates in frontotemporal dementia. Ann Neurol. 2004; 56: 399-406. [非專利文獻4] Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001; 24: 1121-59. [非專利文獻5]德田隆彥，阿爾茨海默病之病態發現假說:其Paradigm Shift，京府醫大志，2016；125：797-804. [非專利文獻6]吉村教秋，關於額顳葉變性(Frontotemporal Lobar Degeneration)-特別是關於MND與伴隨運動系統外封入體之額顳葉變性認知障礙症，弘前醫療福祉大學，2009；1：1-22. [非專利文獻7] Shimada H, Shinotoh H, Hirano S, Miyoshi M, Sato K, Tanaka N, Ota T, Fukushi K, Irie T, Ito H, Higuchi M, Kuwabara S, Suhara T. β-Amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord. 2013; 28: 169-75. [非專利文獻8] Gomperts SN, Locascio JJ, Makaretz SJ, Schultz A, Caso C, Vasdev N, Sperling R, Growdon JH, Dickerson BC, Johnson K. Tau PET imaging in the Lewy body diseases. JAMA Neuro1. 2016; 73: 1334-41. [非專利文獻9]山田正仁，神經原纖維變化型老年期認知障礙症，認知神經科學，2015；17：32-9. [非專利文獻10] Villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC. Tau imaging: early progress and future directions. Lancet Neurol. 2015; 14: 114-24. [非專利文獻11] Rowe CC and Villemagne VL Brain amyloid imaging. J Nucl Med. 2011; 52: 1733-40.[Non-patent document 1] Asada Takashi, Comprehensive study on the prevalence of dementia and measures against life dysfunction caused by dementia in the Comprehensive Research Project on Dementia Countermeasures under the Health, Labor and Welfare Science Research Grants Fund, Urban Division, FY2023-24 research report [Non-patent document 2] Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology. 2002; 58: 1615-21. [Non-patent document 3] Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak TH, Kril JJ, Halliday GM. Clinicopathological correlates in frontotemporal dementia. Ann Neurol. 2004; 56: 399-406. [Non-patent document 4] Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001; 24: 1121-59. [Non-patent document 5] Tokuda Takahiko, Pathological discovery hypothesis of Alzheimer's disease: Its Paradigm Shift, Kyofu Medical University, 2016; 125: 797-804. [Non-patent document 6] Yoshimura Kyouaki, on frontotemporal lobar degeneration - especially on MND and frontotemporal lobar degeneration and cognitive impairment associated with external closure of the motor system, Hirosaki University of Health and Welfare, 2009; 1: 1-22. [Non-patent document 7] Shimada H, Shinotoh H, Hirano S, Miyoshi M, Sato K, Tanaka N, Ota T, Fukushi K, Irie T, Ito H, Higuchi M, Kuwabara S, Suhara T. β-Amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord. 2013; 28: 169-75. [Non-patent document 8] Gomperts SN, Locascio JJ, Makaretz SJ, Schultz A, Caso C, Vasdev N, Sperling R, Growdon JH, Dickerson BC, Johnson K. Tau PET imaging in the Lewy body diseases. JAMA Neuro1. 2016; 73: 1334-41. [Non-patent document 9] Masahito Yamada, Neurofibrillary change-type senile cognitive impairment, Cognitive Neuroscience, 2015; 17: 32-9. [Non-patent document 10] Villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC. Tau imaging: early progress and future directions. Lancet Neurol. 2015; 14: 114-24. [Non-patent document 11] Rowe CC and Villemagne VL Brain amyloid imaging. J Nucl Med. 2011; 52: 1733-40.
[發明所欲解決之問題][Problem to be solved by the invention]
本發明之課題在於提供一種同時具有tau蛋白親和性及澱粉樣蛋白親和性之放射性核種標識化合物。 又，本發明之課題在於提供一種含有放射性核種標識化合物之用於tau蛋白及/或澱粉樣蛋白之圖像化的成像劑。 又，本發明之課題在於提供一種含有放射性核種標識化合物之用於因tau蛋白及/或澱粉樣蛋白之凝聚而引起之疾病的圖像診斷之放射性醫藥。 [解決問題之技術手段]The object of the present invention is to provide a radioactive nuclide species labeling compound that has both tau protein affinity and amyloid protein affinity. Furthermore, an object of the present invention is to provide an imaging agent containing a radioactive nuclide labeling compound for imaging tau protein and/or amyloid protein. Furthermore, an object of the present invention is to provide a radioactive medicine containing a radionuclide labeling compound for image diagnosis of diseases caused by aggregation of tau protein and/or amyloid protein. [Technical means to solve problems]
因此，本發明之發明者對同時具有tau蛋白親和性及澱粉樣蛋白親和性之化合物進行了研究，結果發現，公開具有澱粉樣蛋白親和性之化合物之國際公開第2007/63946號中記載之化合物中，下述通式(1)所示之化合物亦具備tau蛋白親和性，作為用於tau蛋白及/或澱粉樣蛋白之圖像化之成像劑、以及用於因tau蛋白及/或澱粉樣蛋白之凝聚而引起的疾病之圖像診斷的放射性醫藥較為有用，從而完成了本發明。Therefore, the inventors of the present invention conducted research on compounds having both tau protein affinity and amyloid affinity. As a result, they found that the compound described in International Publication No. 2007/63946 which discloses a compound having amyloid affinity Among them, the compound represented by the following general formula (1) also has tau protein affinity and can be used as an imaging agent for imaging tau protein and/or amyloid protein, and for imaging tau protein and/or amyloid protein. The present invention was completed because radioactive medicine is useful for image diagnosis of diseases caused by protein aggregation.
即，本發明提供以下之[1]～[21]。That is, the present invention provides the following [1] to [21].
[1]一種放射性核種標識化合物或其鹽，其係下述通式(1)所示。[1] A radionuclide species labeling compound or a salt thereof, represented by the following general formula (1).
[化1] [Chemical 1]
(式中，X表示放射性碘原子、18 F或11 CH3 ， 吡啶與噁唑係以碳原子鍵結， 吡啶係以碳原子與咪唑并吡啶鍵結)。 [2]如[1]之放射性核種標識化合物或其鹽，其由下述通式(2)表示。(In the formula , [2] The radionuclide species labeling compound of [1] or a salt thereof, which is represented by the following general formula (2).
[化2] [Chemicalization 2]
(式中，X表示放射性碘原子、18 F或11 CH3 )。 [3]如[1]或[2]之放射性核種標識化合物或其鹽，其中X為123 I、124 I、125 I或131 I。 [4]一種成像劑，其含有如[1]至[3]中任一項之放射性核種標識化合物或其鹽，上述成像劑用於tau蛋白及/或澱粉樣蛋白之圖像化。 [5]一種成像劑，其含有如[1]至[3]中任一項之放射性核種標識化合物或其鹽，上述成像劑用於tau蛋白之圖像化。 [6]一種放射性醫藥，其含有如[1]至[3]中任一項之放射性核種標識化合物或其鹽，上述放射性醫藥用於因tau蛋白及/或澱粉樣蛋白之凝聚而引起之疾病的圖像診斷。 [7]一種放射性醫藥，其含有如[1]至[3]中任一項之放射性核種標識化合物或其鹽，上述放射性醫藥用於因tau蛋白之凝聚而引起之疾病的圖像診斷。 [8]一種化合物或其鹽，其係下述通式(3)所示。(In the formula, X represents a radioactive iodine atom, 18 F or 11 CH 3 ). [3] The radionuclide identification compound or salt thereof as in [1] or [2], wherein X is 123 I, 124 I, 125 I or 131 I. [4] An imaging agent containing the radionuclide labeling compound or a salt thereof according to any one of [1] to [3], which is used for imaging tau protein and/or amyloid protein. [5] An imaging agent containing the radionuclide species labeling compound or a salt thereof according to any one of [1] to [3], which is used for imaging tau protein. [6] A radioactive medicine containing a radioactive nuclide labeling compound or a salt thereof according to any one of [1] to [3], the above-mentioned radioactive medicine being used for diseases caused by aggregation of tau protein and/or amyloid protein image diagnosis. [7] A radioactive medicine containing the radionuclide labeling compound or a salt thereof according to any one of [1] to [3], the radioactive medicine being used for image diagnosis of diseases caused by aggregation of tau protein. [8] A compound or a salt thereof represented by the following general formula (3).
[化3] [Chemical 3]
(式中，R表示三烷基錫烷基， 吡啶與噁唑係以碳原子鍵結， 吡啶係以碳原子與咪唑并吡啶鍵結)。 [9]如[8]之化合物或其鹽，其由下述通式(4)表示。(In the formula, R represents a trialkylstannyl group, Pyridine and oxazole are bonded by carbon atoms. Pyridine is bonded to imidazopyridine with carbon atoms). [9] The compound of [8] or a salt thereof, which is represented by the following general formula (4).
[化4] [Chemical 4]
(式中，R表示三烷基錫烷基。) [10]一種如[1]至[3]中任一項之放射性核種標識化合物或其鹽之用途，其係用於製造tau蛋白及/或澱粉樣蛋白之圖像化所使用之成像劑。 [11]一種如[1]至[3]中任一項之放射性核種標識化合物或其鹽之用途，其係用於製造tau蛋白之圖像化所使用之成像劑。 [12]一種如[1]至[3]中任一項之放射性核種標識化合物或其鹽之用途，其係用於製造因tau蛋白及/或澱粉樣蛋白之凝聚而引起的疾病之圖像診斷所使用之放射性醫藥。 [13]一種如[1]至[3]中任一項之放射性核種標識化合物或其鹽之用途，其係用於製造因tau蛋白之凝聚而引起之疾病的圖像診斷所使用之放射性醫藥。 [14]如[1]至[3]中任一項之放射性核種標識化合物或其鹽，其用於tau蛋白及/或澱粉樣蛋白之圖像化。 [15]如[1]至[3]中任一項之放射性核種標識化合物或其鹽，其用於tau蛋白之圖像化。 [16]如[1]至[3]中任一項之放射性核種標識化合物或其鹽，其用於因tau蛋白及/或澱粉樣蛋白之凝聚而引起之疾病的圖像診斷。 [17]如[1]至[3]中任一項之放射性核種標識化合物或其鹽，其用於因tau蛋白之凝聚而引起之疾病的圖像診斷。 [18]一種tau蛋白及/或澱粉樣蛋白之圖像化方法，其特徵在於，投予如[1]至[3]中任一項所述之放射性核種標識化合物或其鹽。 [19]一種tau蛋白之圖像化方法，其特徵在於投予，如[1]至[3]中任一項之放射性核種標識化合物或其鹽。 [20]一種因tau蛋白及/或澱粉樣蛋白之凝聚而引起之疾病的圖像診斷方法，其特徵在於，投予如[1]至[3]中任一項之放射性核種標識化合物或其鹽。 [21]一種因tau蛋白之凝聚而引起之疾病的圖像診斷方法，其特徵在於，投予如[1]至[3]中任一項之放射性核種標識化合物或其鹽。 [發明之效果](In the formula, R represents a trialkylstannyl group.) [10] Use of a radioactive nuclide labeling compound or a salt thereof according to any one of [1] to [3], which is used to produce an imaging agent for imaging tau protein and/or amyloid protein. [11] Use of a radionuclide labeling compound or a salt thereof according to any one of [1] to [3], which is an imaging agent used to produce images of tau protein. [12] Use of a radioactive nuclide labeling compound or a salt thereof according to any one of [1] to [3], which is used to create images of diseases caused by aggregation of tau protein and/or amyloid protein Radiopharmaceuticals used in diagnosis. [13] Use of a radioactive nuclide labeling compound or a salt thereof according to any one of [1] to [3], which is used to produce radioactive medicine for image diagnosis of diseases caused by aggregation of tau protein . [14] The radioactive nuclide labeling compound or salt thereof according to any one of [1] to [3], which is used for imaging tau protein and/or amyloid protein. [15] The radioactive nuclide labeling compound or salt thereof according to any one of [1] to [3], which is used for imaging of tau protein. [16] The radionuclide labeling compound or salt thereof according to any one of [1] to [3], which is used for image diagnosis of diseases caused by aggregation of tau protein and/or amyloid protein. [17] The radionuclide labeling compound or salt thereof according to any one of [1] to [3], which is used for image diagnosis of diseases caused by aggregation of tau protein. [18] A method for imaging tau protein and/or amyloid protein, characterized by administering the radioactive nuclide labeling compound or a salt thereof according to any one of [1] to [3]. [19] A method for imaging tau protein, characterized by administering a radioactive nuclide labeling compound or a salt thereof according to any one of [1] to [3]. [20] An image diagnosis method for diseases caused by aggregation of tau protein and/or amyloid protein, characterized by administering a radioactive nuclide labeling compound as in any one of [1] to [3] or its salt. [21] An image diagnosis method for diseases caused by aggregation of tau protein, characterized by administering a radioactive nuclide labeling compound or a salt thereof according to any one of [1] to [3]. [Effects of the invention]
通式(1)所示之放射性核種標識化合物或其鹽(本發明化合物(1))具有對於tau蛋白及澱粉樣蛋白之親和性。因此，本發明化合物(1)作為用於tau蛋白及/或澱粉樣蛋白之圖像化的成像劑較為有用。另外，本發明化合物(1)作為用於因tau蛋白及/或澱粉樣蛋白之凝聚而引起之疾病的圖像診斷之放射性醫藥較為有用。The radioactive nuclide labeling compound represented by the general formula (1) or its salt (compound (1) of the present invention) has affinity for tau protein and amyloid protein. Therefore, the compound (1) of the present invention is useful as an imaging agent for imaging tau protein and/or amyloid protein. In addition, the compound (1) of the present invention is useful as a radioactive medicine for image diagnosis of diseases caused by aggregation of tau protein and/or amyloid protein.
以下，詳細地說明本發明。Hereinafter, the present invention will be described in detail.
通式(1)中，X表示放射性碘原子、18 F或11 CH3 。即，本發明化合物(1)係X為放射性核種之放射性核種標識化合物。放射性碘原子表示碘之放射性同位素，較佳為123 I、124 I、125 I或131 I，更佳為123 I。In general formula (1), X represents a radioactive iodine atom, 18 F or 11 CH 3 . That is, the compound (1) of the present invention is a radionuclide-labeled compound in which X is a radionuclide. The radioactive iodine atom represents a radioactive isotope of iodine, preferably 123 I, 124 I, 125 I or 131 I, more preferably 123 I.
通式(1)中，吡啶與噁唑係以碳原子鍵結，吡啶係以碳原子與咪唑并吡啶鍵結。吡啶上之咪唑并吡啶與噁唑可為鄰位、間位或對位之任一種，較佳為對位。吡啶與咪唑并吡啶之鍵結可為吡啶之2、3、5或6位之任一種，較佳為5位。另外，吡啶與噁唑之鍵結可為吡啶之2、3、5或6位之任一種，可為噁唑之2、4或5位之任一種，較佳為吡啶之2位與噁唑之5位。因此，特別較佳為以下之通式(2)之結構。In the general formula (1), pyridine and oxazole are bonded by carbon atoms, and pyridine and imidazopyridine are bonded by carbon atoms. The imidazopyridine and oxazole on the pyridine can be in any of the ortho, meta or para positions, preferably the para position. The bond between pyridine and imidazopyridine can be any one of the 2, 3, 5 or 6 positions of pyridine, preferably the 5 position. In addition, the bond between pyridine and oxazole can be any one of the 2, 3, 5 or 6 positions of pyridine, and can be any one of the 2, 4 or 5 positions of oxazole, preferably the 2 position of pyridine and oxazole. of 5. Therefore, the structure of the following general formula (2) is particularly preferred.
[化5] [Chemistry 5]
(式中，X表示放射性碘原子、18 F或11 CH3 。)(In the formula, X represents a radioactive iodine atom, 18 F or 11 CH 3 .)
本發明化合物(1)可形成鹽，作為此種鹽，可列舉通常已知之胺基酸等鹼性基上之鹽。作為鹼性基上之鹽，例如可列舉：與鹽酸、氫溴酸、硝酸及硫酸等無機酸之鹽；與甲酸、乙酸、檸檬酸、草酸、富馬酸、馬來酸、琥珀酸、蘋果酸、酒石酸、天冬胺酸、三氯乙酸及三氟乙酸等有機羧酸之鹽；以及與甲磺酸、苯磺酸、對甲苯磺酸、均三甲苯磺酸及萘磺酸等磺酸之鹽。The compound (1) of the present invention can form a salt, and examples of such salts include generally known salts with basic groups such as amino acids. Examples of salts on a basic base include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, apple Salts of organic carboxylic acids such as acid, tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid of salt.
本發明之放射性核種標識化合物(1)可按照國際公開第2007/063946號中記載之方法來合成。通式(1)所示之放射性核種標識化合物可藉由將通式(3)所示之化合物用作標識前體進行放射性核種標識反應而獲得。The radionuclide labeling compound (1) of the present invention can be synthesized according to the method described in International Publication No. 2007/063946. The radioactive nuclide labeling compound represented by the general formula (1) can be obtained by using the compound represented by the general formula (3) as a labeling precursor to perform a radionuclide labeling reaction.
[化6] [Chemical 6]
(式中，R表示三烷基錫烷基，X、吡啶及噁唑同上。)(In the formula, R represents a trialkylstannyl group, and X, pyridine and oxazole are the same as above.)
通式(3)中，作為R所示之三烷基錫烷基，可列舉三(C1-4 烷基)錫烷基，更佳為三丁基錫烷基或三甲基錫烷基，特別較佳為三丁基錫烷基。此處，作為C1-4 烷基，可列舉甲基、乙基、正丙基、正丁基。In the general formula (3), examples of the trialkylstannylyl group represented by R include a tri(C 1-4 alkyl)stannylyl group, more preferably a tributylstannylyl group or a trimethylstannylyl group, particularly Preferred is tributylstannyl. Here, examples of the C 1-4 alkyl group include methyl, ethyl, n-propyl, and n-butyl.
放射性核種標識反應例如可藉由於對甲苯磺醯氯胺鈉等氧化劑之存在下使放射性碘化鈉與通式(3)所示之化合物反應來進行。The radionuclide labeling reaction can be performed, for example, by reacting radioactive sodium iodide with the compound represented by the general formula (3) in the presence of an oxidizing agent such as sodium p-toluenesulfonyl chloride.
本發明之成像劑或放射性醫藥可製成含有緩衝劑以使通式(1)之放射性核種標識化合物成為適當pH的製劑，亦可製成溶解於水、生理食鹽液中之製劑。亦可於製劑中適當調配用以抑制因放射線而引起之放射性核種標識化合物之分解的穩定劑。The imaging agent or radioactive medicine of the present invention can be prepared as a preparation containing a buffer to adjust the radioactive nuclide labeling compound of general formula (1) to an appropriate pH, or can be prepared as a preparation dissolved in water or physiological saline. A stabilizer for inhibiting the decomposition of the radionuclide marking compound caused by radiation may also be appropriately blended in the preparation.
本發明之放射性核種標識化合物對於tau蛋白及澱粉樣蛋白具有親和性，因此，作為將腦內之tau蛋白及/或澱粉樣蛋白圖像化之化合物較為有用。即，本發明之放射性核種標識化合物作為tau蛋白及/或澱粉樣蛋白之成像劑較為有用。因此，若使用本發明之放射性核種標識化合物，則能夠進行tau蛋白及/或澱粉樣蛋白之凝聚於腦中蓄積之疾病的圖像診斷。作為tau蛋白及/或澱粉樣蛋白之凝聚於腦中蓄積之疾病，例如可列舉包括AD、MCI、DLB、CBD、PSP、PiD、AGD之FTLD-tau或SD-NFT，作為tau蛋白之凝聚於腦中蓄積之疾病，例如可列舉包括CBD、PSP、PiD、AGD之FTLD-tau或SD-NFT。 實施例The radionuclide labeling compound of the present invention has affinity for tau protein and amyloid protein, and therefore is useful as a compound for imaging tau protein and/or amyloid protein in the brain. That is, the radionuclide labeling compound of the present invention is useful as an imaging agent for tau protein and/or amyloid protein. Therefore, if the radioactive nuclide labeling compound of the present invention is used, image diagnosis of diseases in which tau protein and/or amyloid protein aggregate and accumulate in the brain can be performed. Examples of diseases in which tau protein and/or amyloid protein aggregate and accumulate in the brain include FTLD-tau or SD-NFT including AD, MCI, DLB, CBD, PSP, PiD, and AGD. Examples of diseases that accumulate in the brain include FTLD-tau or SD-NFT including CBD, PSP, PiD, and AGD. Example
其次，列舉實施例，進一步詳細地說明本發明，但本發明並不限定於該等實施例。Next, although an Example is given and this invention is demonstrated in further detail, this invention is not limited to these Examples.
實施例1：DRK092N標識前體(化合物10)之合成 化合物10按照下述所示之反應流程合成。Example 1: Synthesis of DRK092N labeling precursor (compound 10) Compound 10 was synthesized according to the reaction scheme shown below.
[化7] [Chemical 7]
實施例1-1：化合物2之合成 於氬氣氛圍下，將50.9 g之化合物1之二乙基醚溶液848 mL冷卻，於-62℃以下耗時30分鐘滴加1.64 mol/L之n-BuLi己烷溶液131 mL。於該溫度下攪拌30分鐘後，耗時10分鐘滴加21.5 g之脫水N,N-二甲基乙醯胺。加入氯化銨水溶液，於室溫攪拌2天。利用乙酸乙酯進行萃取，利用無水硫酸鎂對有機層進行乾燥後，於減壓下濃縮。不進行更多之精製，化合物2直接用於以下之反應。Example 1-1: Synthesis of Compound 2 Under an argon atmosphere, 848 mL of a diethyl ether solution of 50.9 g of compound 1 was cooled, and 131 mL of a 1.64 mol/L n-BuLi hexane solution was added dropwise at a temperature below -62°C for 30 minutes. After stirring at this temperature for 30 minutes, 21.5 g of dehydrated N,N-dimethylacetamide was added dropwise over 10 minutes. Ammonium chloride aqueous solution was added and stirred at room temperature for 2 days. The mixture was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. Compound 2 was used directly in the following reaction without further purification.
實施例1-2：化合物3之合成 於化合物2之甲苯溶液830 mL中加入40.0 g之1,2-乙二醇與12.3 g之對甲苯磺酸一水合物，除去生成之水並回流20小時。冷卻後，加入碳酸鈉水溶液，加入少量之乙酸乙酯進行萃取。對獲得之有機層進行水洗，利用無水硫酸鎂進行乾燥後，於減壓下濃縮。 利用矽膠柱色譜法(流動相：庚烷/乙酸乙酯＝9/1～7/3)對濃縮殘渣進行精製，從而獲得24.3 g之化合物3(產率46%)。1 H-NMR (CDCl3 ) δ: 8.48 (1H, s), 7.63 (1H, dd, J＝8.2, 4.1 Hz), 7.45 (1H, dd, J＝8.2, 4.1Hz), 4.08-4.05 (2H, m), 3.81-3.75 (2H, m), 1.67 (3H, s).Example 1-2: Synthesis of compound 3. Add 40.0 g of 1,2-ethylene glycol and 12.3 g of p-toluenesulfonic acid monohydrate to 830 mL of toluene solution of compound 2, remove the generated water and reflux for 20 hours. . After cooling, add sodium carbonate aqueous solution and add a small amount of ethyl acetate for extraction. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was purified using silica gel column chromatography (mobile phase: heptane/ethyl acetate = 9/1 to 7/3) to obtain 24.3 g of compound 3 (yield 46%). 1 H-NMR (CDCl 3 ) δ: 8.48 (1H, s), 7.63 (1H, dd, J＝8.2, 4.1 Hz), 7.45 (1H, dd, J＝8.2, 4.1Hz), 4.08-4.05 (2H , m), 3.81-3.75 (2H, m), 1.67 (3H, s).
實施例1-3：化合物4之合成 於氬氣氛圍下，將24.2 g之化合物3之二乙基醚溶液519 mL冷卻，於-68℃以下耗時30分鐘滴加1.64 mol/L之n-BuLi己烷溶液60.5 mL。於該溫度下攪拌30分鐘後，耗時15分鐘滴加脫水DMF 18.8 g。加入碳酸氫鈉水溶液，攪拌至達到室溫。利用乙酸乙酯進行萃取，利用無水硫酸鎂對有機層進行乾燥後，於減壓下濃縮。利用矽膠柱色譜法(流動相：庚烷/乙酸乙酯＝90/10～85/15)對濃縮殘渣進行精製，藉此獲得8.71 g之化合物4(產率45%)。1 H-NMR (CDC13 ) δ: 10.09 (1H, s), 8.91-8.90 (1H, m), 7.99-7.94 (2H, m), 4.11-4.09 (2H, m), 3.82-3.78 (2H, m), 1.69 (3H, s).Example 1-3: Synthesis of Compound 4 In an argon atmosphere, 519 mL of a diethyl ether solution of 24.2 g of Compound 3 was cooled, and 1.64 mol/L of n- was added dropwise over 30 minutes at a temperature below -68°C. BuLi hexane solution 60.5 mL. After stirring at this temperature for 30 minutes, 18.8 g of dehydrated DMF was added dropwise over 15 minutes. Add aqueous sodium bicarbonate solution and stir until room temperature is reached. The mixture was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified using silica gel column chromatography (mobile phase: heptane/ethyl acetate = 90/10~85/15), thereby obtaining 8.71 g of compound 4 (yield 45%). 1 H-NMR (CDC1 3 ) δ: 10.09 (1H, s), 8.91-8.90 (1H, m), 7.99-7.94 (2H, m), 4.11-4.09 (2H, m), 3.82-3.78 (2H, m), 1.69 (3H, s).
實施例1-4：化合物6之合成 於氬氣氛圍下，於8.50 g之化合物4之二乙基醚溶液315 mL中加入21.6 g之化合物5與15.2 g之碳酸鉀，攪拌2.5小時。將反應混合物於減壓下濃縮後，加入水，利用乙酸乙酯進行萃取。利用無水硫酸鎂對有機層進行乾燥後，於減壓下濃縮。利用矽膠柱色譜法(第一次，流動相：僅乙酸乙酯，第二次，流動相：甲苯～乙酸乙酯)對濃縮殘渣進行精製，藉此獲得9.35 g之化合物6(產率91%)。l H-NMR (CDCl3 ) δ: 8.76 (1H, d, J＝2.3Hz), 7.98 (1H, s), 7.86 (1H, dd, J＝8.2, 2.3Hz), 7.71 (2H, s), 7.65 (2H, d, J＝8.2Hz), 4.10-4.08 (2H, m) 3.81-3.80 (2H, m) 1.69 (3H, s).Example 1-4: Synthesis of Compound 6 Under an argon atmosphere, 21.6 g of Compound 5 and 15.2 g of potassium carbonate were added to 315 mL of a solution of 8.50 g of Compound 4 in diethyl ether, and the mixture was stirred for 2.5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (first time, mobile phase: only ethyl acetate, second time, mobile phase: toluene to ethyl acetate), thereby obtaining 9.35 g of compound 6 (yield 91%) ). l H-NMR (CDCl 3 ) δ: 8.76 (1H, d, J＝2.3Hz), 7.98 (1H, s), 7.86 (1H, dd, J＝8.2, 2.3Hz), 7.71 (2H, s), 7.65 (2H, d, J＝8.2Hz), 4.10-4.08 (2H, m) 3.81-3.80 (2H, m) 1.69 (3H, s).
實施例1-5：化合物7之合成 於9.25 g之化合物6之THF溶液50 mL中加入1 mo1/L鹽酸50 mL，於50℃攪拌1小時。冷卻後，加入飽和碳酸氫鈉水溶液，利用乙酸乙酯萃取。利用無水硫酸鎂對有機層進行乾燥後，於減壓下濃縮。利用矽膠柱色譜法(流動相：乙酸乙酯)對濃縮殘渣進行精製，藉此獲得3.20 g之化合物7(產率42%)。1 H-NMR (CDCl3 ) δ: 9.17 (1H, d, J＝2.3Hz), 8.32 (1H, dd, J＝8.2, 2.3Hz), 8.04 (1H, s), 7.85 (1H, s), 7.78 (1H, d, J＝8.2Hz), 2.66 (3H, s).Example 1-5: Synthesis of compound 7. Add 50 mL of 1 mol/L hydrochloric acid to 50 mL of a THF solution of 9.25 g of compound 6, and stir at 50°C for 1 hour. After cooling, a saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified using silica gel column chromatography (mobile phase: ethyl acetate) to obtain 3.20 g of compound 7 (yield 42%). 1 H-NMR (CDCl 3 ) δ: 9.17 (1H, d, J＝2.3Hz), 8.32 (1H, dd, J＝8.2, 2.3Hz), 8.04 (1H, s), 7.85 (1H, s), 7.78 (1H, d, J＝8.2Hz), 2.66 (3H, s).
實施例1-6：化合物8之合成 於3.10 g之化合物7之二氯甲烷溶液65 mL中加入9.50 g之三乙胺，繼而，於0℃加入5.04 g之溴三甲基矽烷。於0℃攪拌30分鐘後，於室溫攪拌18小時。追加2.20 g之溴三甲基矽烷，攪拌30分鐘，進而追加2.04 g之三甲基矽烷，攪拌30分鐘。於反應溶液中加入水，利用氯仿萃取後，利用無水硫酸鎂對有機層進行乾燥後，於減壓下濃縮。於濃縮殘渣中加入45 mL之THF，於冰冷下加入2.93 g之N-溴琥珀醯亞胺，於室溫攪拌1小時。將反應溶液於減壓下濃縮，利用矽膠色譜法(流動相：庚烷/乙酸乙酯＝2/1～4/3)對濃縮殘渣進行精製，藉此獲得1.92 g之化合物8(產率43%)。1 H-NMR (CDCl3 ) δ: 9.22-9.21 (1H, m), 8.36 (1H, dd, J＝8.2, 2.3Hz), 8.05 (1H, s), 7.88 (1H, s), 7.80 (1H, d, J＝8.2Hz), 4.43 (2H, s).Example 1-6: Synthesis of compound 8. Add 9.50 g of triethylamine to 65 mL of a dichloromethane solution of 3.10 g of compound 7, and then add 5.04 g of bromotrimethylsilane at 0°C. After stirring at 0°C for 30 minutes, the mixture was stirred at room temperature for 18 hours. Add 2.20 g of bromotrimethylsilane and stir for 30 minutes. Then add 2.04 g of trimethylsilane and stir for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 45 mL of THF was added to the concentrated residue, and 2.93 g of N-bromosuccinimide was added under ice cooling, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the concentrated residue was purified using silica gel chromatography (mobile phase: heptane/ethyl acetate = 2/1 to 4/3), thereby obtaining 1.92 g of compound 8 (yield 43 %). 1 H-NMR (CDCl 3 ) δ: 9.22-9.21 (1H, m), 8.36 (1H, dd, J＝8.2, 2.3Hz), 8.05 (1H, s), 7.88 (1H, s), 7.80 (1H , d, J＝8.2Hz), 4.43 (2H, s).
實施例1-7：化合物9之合成 於1.88 g之化合物8之乙腈溶液15 mL中加入1.55 g之2-胺基-5-碘吡啶，回流2小時。冷卻後進行過濾，利用乙腈清洗固體。利用混合溶液(水15 mL、甲醇15 mL、飽和碳酸氫鈉水溶液7.5 mL)將粗精製物懸浮攪拌，並進行過濾。利用水與甲醇、乙酸乙酯清洗粗精製物，獲得1.89 g之化合物9(產率69%)。1 H-NMR (CDCl3 ) δ: 9.22-9.21 (1H, m), 8.96-8.97 (1H, m), 8.57 (1H, s), 8.50 (1H, s), 8.43 (1H, dd, J＝8.2, 1.8Hz), 7.86 (1H, d, J＝8.7Hz), 7.85 (1H, s), 7.49 (2H, s).Example 1-7: Synthesis of compound 9. Add 1.55 g of 2-amino-5-iodopyridine to 15 mL of an acetonitrile solution of 1.88 g of compound 8, and reflux for 2 hours. After cooling, it was filtered, and the solid was washed with acetonitrile. The crude purified product was suspended and stirred in a mixed solution (15 mL of water, 15 mL of methanol, and 7.5 mL of saturated aqueous sodium bicarbonate solution), and then filtered. The crude product was washed with water, methanol, and ethyl acetate to obtain 1.89 g of compound 9 (yield 69%). 1 H-NMR (CDCl 3 ) δ: 9.22-9.21 (1H, m), 8.96-8.97 (1H, m), 8.57 (1H, s), 8.50 (1H, s), 8.43 (1H, dd, J＝ 8.2, 1.8Hz), 7.86 (1H, d, J＝8.7Hz), 7.85 (1H, s), 7.49 (2H, s).
實施例1-8：化合物10之合成 於氬氣氛圍下，於0.33 g之化合物9之1,4-二噁烷溶液16.5 mL中加入三乙胺1.65 mL及0.99 g之雙(三丁基錫)、49.1 mg之四(三苯基膦)鈀(0)，於100℃攪拌16小時。將反應溶液於減壓下濃縮，利用矽膠色譜法(流動相：庚烷/乙酸乙酯＝4/1～3/2)對濃縮殘渣進行精製，藉此獲得0.14 g之化合物10(產率30%)。1 H-NMR (CDCl3 ) δ: 9.15 (1H, m), 8.40 (1H, dd, J＝8.2, 2.3Hz), 8.02 (1H, s), 7.99 (1H, s), 7.95 (1H, s), 7.76 (1H, d, J＝8.2Hz), 7.73 (1H, s), 7.62 (1H, d, J＝8.7Hz), 7.22 (1H, d, J＝8.7Hz), 1.63-1.49 (6H, m), 1.41-1.31 (6H, m), 1.22-1.05 (6H, m), 0.91 (9H, t, J＝7.3Hz)。Example 1-8: Synthesis of Compound 10 Under an argon atmosphere, 1.65 mL of triethylamine and 0.99 g of bis(tributyltin) were added to 16.5 mL of 1,4-dioxane solution of 0.33 g of compound 9. 49.1 mg of tetrakis(triphenylphosphine)palladium(0), stirred at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the concentrated residue was purified by silica gel chromatography (mobile phase: heptane/ethyl acetate = 4/1 to 3/2), thereby obtaining 0.14 g of compound 10 (yield 30 %). 1 H-NMR (CDCl 3 ) δ: 9.15 (1H, m), 8.40 (1H, dd, J＝8.2, 2.3Hz), 8.02 (1H, s), 7.99 (1H, s), 7.95 (1H, s) ), 7.76 (1H, d, J＝8.2Hz), 7.73 (1H, s), 7.62 (1H, d, J＝8.7Hz), 7.22 (1H, d, J＝8.7Hz), 1.63-1.49 (6H , m), 1.41-1.31 (6H, m), 1.22-1.05 (6H, m), 0.91 (9H, t, J＝7.3Hz).
(實施例2)125 I標識化合物9(125 I-DRK092N)之合成 將化合物10用作標識前體，製備125 I標識化合物9。 於1.0 mg/mL之化合物10之甲醇溶液60 μL、0.3 M磷酸緩衝液(pH5.5)210 μL、[125 I]碘化鈉溶液(333MBq)25 μL之混合溶液中添加0.1 mg/mL之對甲苯磺醯氯胺鈉(Sodium p-toluenesulfonchloramide)水溶液60 μL。於室溫放置2分鐘後，添加2.0 mg/mL之焦亞硫酸鈉水溶液300 μL，使反應結束。使用逆相柱(SHISEIDO CAPCELLPAK C18 UG120，6.0×150 mm)、以50%甲醇水溶液之流動相對反應混合物進行分離精製。將獲得之HPLC分取液通入固相萃取柱(Sep-Pak LightC18)，利用乙醇萃取保持之標識化合物。適量地添加乙醇及50 mmo1/L抗壞血酸水溶液使最終獲得37 MBq/mL之5.0 mmo1/L抗壞血酸/90%乙醇水溶液之組成，製備目標物之溶液。使用TLC(展開溶劑：95%甲醇水溶液，逆相矽膠板：Whatman，KC18F)分析放射化學性純度，結果為96%。(Example 2) Synthesis of 125 I-labeled compound 9 ( 125 I-DRK092N) Compound 10 was used as a labeling precursor to prepare 125 I-labeled compound 9. To a mixed solution of 60 μL of 1.0 mg/mL compound 10 in methanol, 210 μL of 0.3 M phosphate buffer (pH5.5), and 25 μL of [ 125 I] sodium iodide solution (333MBq), 0.1 mg/mL 60 μL of sodium p-toluenesulfonchloramide aqueous solution. After standing at room temperature for 2 minutes, 300 μL of 2.0 mg/mL sodium metabisulfite aqueous solution was added to complete the reaction. A reverse phase column (SHISEIDO CAPCELLPAK C18 UG120, 6.0×150 mm) was used to separate and purify the reaction mixture with a mobile phase of 50% methanol aqueous solution. The obtained HPLC fraction was passed into a solid-phase extraction column (Sep-Pak LightC18), and ethanol was used to extract the retained labeled compounds. Add appropriate amounts of ethanol and 50 mmol/L ascorbic acid aqueous solution to obtain a final composition of 37 MBq/mL of 5.0 mmol/L ascorbic acid/90% ethanol aqueous solution, and prepare a solution of the target substance. The radiochemical purity was analyzed using TLC (developing solvent: 95% methanol aqueous solution, reverse phase silica gel plate: Whatman, KC18F), and the result was 96%.
(實施例3)正常小鼠體內分佈試驗 利用生理食鹽水將實施例2中獲得之125 I-DRK092N稀釋，對1組4～5隻之8週齡FVB小鼠(雄25～30 g)自尾靜脈每1隻投予200 μL(108.4 kBq)，於2、10、30、60分鐘後斷頭、採血，其後取出器官，稱量濕重量，利用γ計數器(PerkinElmer Wallac Wizard 3”1480)測定放射活性。將結果示於表1。表1中表示血液、各器官之放射活性(每單位重量投予量之百分比(每g組織之注射劑量的百分比，% of injection dose/g tissue，1 mL血液視為1 g)、僅甲狀腺投予量之百分比(注射劑量之百分比，% of injection dose))之Mean±SD。(Example 3) Distribution test in normal mice The 125 I-DRK092N obtained in Example 2 was diluted with physiological saline, and a group of 4 to 5 8-week-old FVB mice (male 25 to 30 g) were subjected to 200 μL (108.4 kBq) was administered to each animal in the tail vein. After 2, 10, 30, and 60 minutes, the head was decapitated and blood was collected. The organs were then removed, and the wet weight was measured using a gamma counter (PerkinElmer Wallac Wizard 3” 1480). The radioactivity was measured. The results are shown in Table 1. Table 1 shows the radioactivity of blood and each organ (percentage of injection dose/g tissue, 1 mL of blood is regarded as 1 g), and the mean ± SD is only the percentage of the thyroid dose (% of injection dose)).
[表1]
125 I-DRK092N顯示較高之腦轉移性，可確認其後來自腦之迅速之排出。 125 I-DRK092N showed higher brain metastasis, confirming its subsequent rapid elimination from the brain.
(實施例4)使用進行性核上性麻痹(PSP)患者解剖檢查腦組織切片之體外結合試驗 4-1：體外放射自顯影(In vitro autoradiography) 由實施了未固定凍結之PSP患者死後腦製作20 μm厚之腦切片。利用PBS將實施例2中獲得之125 I-DRK092N稀釋成0.5 nM，製成培養液。將腦切片浸漬於培養液中，靜置1小時。其後，利用PBS清洗2分鐘×2次。於顯影板(富士膠片股份有限公司製造之MS2025E)中密接2小時，利用生物顯影分析儀(富士膠片股份有限公司製造之BAS5000)進行圖像之讀取以及定量分析。另外，使用11 C-PiB(澱粉樣蛋白顯影藥劑之金標準，培養液濃度1 nM)，進行同樣之實驗。(Example 4) In vitro binding test using autopsy brain tissue sections of progressive supranuclear palsy (PSP) patients 4-1: In vitro autoradiography Produced from postmortem brains of PSP patients subjected to unfixed freezing 20 μm thick brain sections. The 125 I-DRK092N obtained in Example 2 was diluted to 0.5 nM with PBS to prepare a culture medium. Immerse the brain slices in the culture medium and let stand for 1 hour. Thereafter, the cells were washed with PBS for 2 minutes × 2 times. The image was closely connected to a developing plate (MS2025E manufactured by Fujifilm Co., Ltd.) for 2 hours, and the image was read and quantitatively analyzed using a biological imaging analyzer (BAS5000 manufactured by Fujifilm Co., Ltd.). In addition, the same experiment was performed using 11 C-PiB (the gold standard of amyloid imaging agent, culture solution concentration: 1 nM).
4-2：免疫染色 澱粉樣蛋白及磷酸化tau蛋白之染色利用抗Aβ(6E10，Signet Laboratories公司)抗體及抗磷酸化tau蛋白(AT8，Thermo Scientific公司)抗體來進行。將體外放射自顯影中使用之腦切片於4%多聚甲醛液(PFA)中固定一夜，利用PBS清洗殘留4%PFA。澱粉樣蛋白染色用切片進行甲酸(2分鐘)處理，磷酸化tau蛋白染色用切片進行高壓釜(檸檬酸緩衝劑(0.01 M檸檬酸鈉：0.01 M檸檬酸＝5：1)，121℃，5分鐘)處理，之後，用流水清洗5分鐘，於全部腦切片上滴加TSA封閉緩衝劑(Perkin Elmer公司TSA Fluorescein System，NEL70000)，靜置1小時後，滴加含有一次抗體(6E10，1：1000；AT8，1：1000)之封閉緩衝劑，靜置一夜。棄去一次抗體，利用PBS重複5分鐘之清洗3次。滴加含有二次抗體(具有Alexa-488螢光色素)之TSA封閉溶液，進而靜置1小時。其後，利用TSA增敏試劑盒(Perkin Elmer公司之TSA Fluorescein System，NEL70000)使螢光信號擴大，利用VECTASHILD封片劑(H-1000，Vector Laboratories Inc.)封閉，進行顯微鏡觀察。4-2: Immunostaining Staining of amyloid and phosphorylated tau was performed using anti-Aβ (6E10, Signet Laboratories) antibodies and anti-phosphorylated tau (AT8, Thermo Scientific) antibodies. Brain slices used for in vitro autoradiography were fixed in 4% paraformaldehyde (PFA) overnight, and the remaining 4% PFA was washed with PBS. Sections for amyloid staining were subjected to formic acid treatment (2 min), and sections for phosphorylated tau staining were subjected to autoclave (citric acid buffer (0.01 M sodium citrate: 0.01 M citric acid = 5:1), 121°C, 5 minutes), and then washed with running water for 5 minutes. TSA blocking buffer (Perkin Elmer TSA Fluorescein System, NEL70000) was added dropwise to all brain slices. After letting it stand for 1 hour, primary antibody (6E10, 1: 1000; AT8, 1:1000) blocking buffer and let stand overnight. Discard the primary antibody and repeat washing with PBS for 5 minutes three times. TSA blocking solution containing secondary antibody (containing Alexa-488 fluorescent dye) was added dropwise and allowed to stand for 1 hour. Thereafter, the fluorescent signal was amplified using a TSA sensitization kit (TSA Fluorescein System, NEL70000 from Perkin Elmer), sealed with VECTASHILD mounting medium (H-1000, Vector Laboratories Inc.), and observed under a microscope.
4-3：結果 將結果示於圖1。圖1-a、1-b分別為使用125 I-DRK092N及11 C-PiB之PSP患者腦的放射自顯影圖。圖1-c、1-d分別為同一PSP患者腦之磷酸化tau蛋白(AT8)與澱粉樣蛋白(6E10)之染色圖像。皮質部中之125 I-DRK092N結合明顯比白質部(WM)豐富，與磷酸化tau蛋白之分佈充分一致。於該PSP患者腦切片中，未看到澱粉樣蛋白蓄積，11 C-PiB結合亦與該結果一致，表明圖1-a所示之125 I-DRK092N特異性結合全部源自tau蛋白凝聚體。4-3: Results The results are shown in Figure 1. Figures 1-a and 1-b are autoradiograms of the brains of PSP patients using 125 I-DRK092N and 11 C-PiB respectively. Figures 1-c and 1-d are respectively staining images of phosphorylated tau protein (AT8) and amyloid protein (6E10) in the brain of the same PSP patient. The 125 I-DRK092N binding in the cortex is significantly more abundant than in the white matter (WM), which is fully consistent with the distribution of phosphorylated tau protein. In the brain slices of this PSP patient, no amyloid accumulation was seen, and the 11 C-PiB binding was consistent with this result, indicating that the specific binding of 125 I-DRK092N shown in Figure 1-a was entirely derived from tau protein aggregates.
(實施例5)使用AD患者解剖檢查腦組織切片之體外結合試驗 由經未固定凍結之非AD之人(HC，健康對照組，healthy control)、AD患者以及具有澱粉樣蛋白蓄積之澱粉樣前體蛋白(APP)強制表現小鼠(APP-Tg，Tg2576，24個月齡)之死後腦以20 μm厚製作切片，按照與實施例4同樣之方式進行125 I-DRK092N及11 C-PiB之體外放射自顯影。 將結果示於圖2。上段為同一HC之腦中之125 I-DRK092N(左、中)與11 C-PiB(右)之放射自顯影，中段為同一AD患者腦中之125 I-DRK092N(左、中)與11 C-PiB(右)之放射自顯影，下段為APP-Tg腦中之125 I-DRK092N之放射自顯影。就人腦(HC及AD)而言，通常情況下於AD患者之腦中於AD病理豐富之皮質(白實線)設定感興趣區，就APP-Tg小鼠而言，於澱粉樣蛋白之蓄積豐富之皮質(白實線)及無澱粉樣蛋白蓄積之丘腦(黑實線)設定感興趣區，求出該等區域中之每單位面積之放射活性(解析軟體：Multi Gauge V2.2)。其結果，AD患者與HC之皮質中之每單位面積的放射活性之比高達約2.1，表明可藉經放射標識之DRK092N檢測AD病理。另一方面，於APP-Tg中，顳葉皮質與丘腦之每單位面積之放射活性之比高達約2.1。由此可知DRK092N亦與澱粉樣蛋白特異性地結合。(Example 5) In vitro binding test using autopsy brain tissue sections of AD patients. Non-AD humans (HC, healthy control), AD patients, and amyloid pro-amyloid cells with amyloid accumulation were tested in unfixed and frozen samples. The postmortem brains of mice with forced expression of body protein (APP) (APP-Tg, Tg2576, 24 months old) were sliced into 20 μm thick sections, and the test of 125 I-DRK092N and 11 C-PiB was carried out in the same manner as in Example 4. External autoradiography. The results are shown in Figure 2. The upper section shows the autoradiography of 125 I-DRK092N (left and middle) and 11 C-PiB (right) in the brain of the same HC. The middle section shows the autoradiography of 125 I-DRK092N (left and middle) and 11 C in the brain of the same AD patient. -Autoradiography of PiB (right), lower section is the autoradiography of 125 I-DRK092N in APP-Tg brain. As far as the human brain (HC and AD) is concerned, the region of interest is usually set in the cortex (white solid line) rich in AD pathology in the brains of AD patients. For APP-Tg mice, the region of interest is in the amyloid protein. Set regions of interest in the cortex (solid white line) where amyloid accumulation is abundant and in the thalamus (solid black line) where amyloid is not accumulated, and calculate the radioactivity per unit area in these regions (analysis software: Multi Gauge V2.2) . As a result, the ratio of radioactivity per unit area in the cortex of AD patients and HC was as high as approximately 2.1, indicating that AD pathology can be detected by radioactively labeled DRK092N. On the other hand, in APP-Tg, the ratio of radioactivity per unit area of the temporal cortex and thalamus is as high as approximately 2.1. This shows that DRK092N also specifically binds to amyloid protein.
圖1表示使用進行性核上性麻痺(PSP)患者解剖檢查腦組織切片之125 I-DRK092N與11 C-PiB之體外結合試驗以及顯示該患者腦內之磷酸化tau蛋白與澱粉樣蛋白之蓄積的免疫染色圖像。 圖2表示使用健康人(HC)、阿爾茨海默型認知障礙症(AD)患者及澱粉樣前體蛋白強制表現(APP-Tg)小鼠之解剖檢查腦組織切片之125 I-DRK092N與11 C-PiB之體外結合試驗結果。Figure 1 shows the in vitro binding test of 125 I-DRK092N and 11 C-PiB using autopsy brain tissue sections of patients with progressive supranuclear palsy (PSP) and the accumulation of phosphorylated tau protein and amyloid protein in the brain of the patient. Immunostaining images. Figure 2 shows the anatomical examination of brain tissue sections of 125 I-DRK092N and 11 using healthy humans (HC), Alzheimer's disease (AD) patients, and amyloid precursor protein forced expression (APP-Tg) mice. In vitro binding test results of C-PiB.
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