TWI653052B - Preparation of [18f] t807 derivatives and uses thereof - Google Patents
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Abstract
本發明係關於[18F]T807的N-烷基類似物及其製備方法,以及包含該等[18F]T807的N-烷基類似物的組合物及其用途,例如作為Tau蛋白顯影劑。 The present invention relates to an N-alkyl analog of [ 18 F]T807 and a process for the preparation thereof, and a composition comprising the N-alkyl analog of such [ 18 F]T807 and its use, for example, as a Tau protein developer .
Description
本發明係關於[18F]T807的N-烷基類似物及其製備方法,以及包含該[18F]T807的N-烷基類似物的組合物及其用途。 The present invention relates to N-alkyl analogs of [ 18 F]T807 and processes for their preparation, and to compositions comprising the N-alkyl analogs of [ 18 F]T807 and uses thereof.
阿滋海默症(Alzheimer’ disease,AD)是全世界死亡和殘疾最常見的原因之一,並具有顯著的臨床和社會經濟影響。其特徵在於海馬迴及皮質中神經元的退化以及神經炎斑點和神經纖維纏結的出現〈Goedert et al.,Science.314,777-781(2006);Huang et al.,Cell.148,1204-1222(2012)〉,而神經纖維纏結的主要成分是過度磷酸化的Tau蛋白及其所形成的配對狀螺旋形神經絲(paired helical filament,PHF)。阿滋海默症被認為是由於大腦中折疊異常的β類澱粉蛋白質和Tau蛋白質堆積而造成(Hashimoto M,Rockenstein E,Crews L,Masliah E.Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases.Neuromolecular Med.2003,4(1-2):21-36)。針對β類澱粉蛋白及τ〈Tau〉蛋白的正子造影(positron emission tomography,PET)造影劑將可用於非侵入性地監測阿滋海默症藥物療法的反應並促進阿滋海默症藥物的發展。[18F]T807已被證明是一種有前途的PHF-Tau蛋白示蹤劑(tracer),可用於在人類中研究阿滋海默症(Chien et al.,J Alzheimers Dis.34, 457-468(2013))。發明人先前已開發出這種造影劑的改進合成(Huang et al.,J Labelled Cpd Radiopharm.58,S170(2015))並將其用於臨床研究。然而,仍需要使患者體內之PHF-Tau顯影能力提昇的改良技術,以擴大臨床效益。 Alzheimer' disease (AD) is one of the most common causes of death and disability worldwide, with significant clinical and socioeconomic impacts. It is characterized by degeneration of neurons in the hippocampus and cortex and the appearance of neuritic spots and neurofibrillary tangles (Goedert et al. , Science . 314, 777-781 (2006); Huang et al. , Cell . 148, 1204-1222) . (2012)>, and the main component of neurofibrillary tangles is the hyperphosphorylated Tau protein and its paired helical filaments (PHF). Alzheimer's disease is thought to be caused by the accumulation of abnormal beta-starch protein and Tau protein in the brain (Hashimoto M, Rockstein E, Crews L, Masliah E. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's Diseases. Neuromolecular Med. 2003, 4(1-2): 21-36). A positron emission tomography (PET) contrast agent for beta-amyloid protein and τ<Tau> protein will be used to non-invasively monitor the response to Alzheimer's drug therapy and promote the development of Alzheimer's disease drugs. . [ 18 F]T807 has proven to be a promising PHF-Tau protein tracer for the study of Alzheimer's disease in humans (Chien et al. , J Alzheimers Dis . 34, 457-468 (2013)). The inventors have previously developed an improved synthesis of such contrast agents (Huang et al. , J Labelled Cpd Radiopharm . 58, S170 (2015)) and used them in clinical studies. However, there is still a need for improved techniques for improving the ability to develop PHF-Tau in patients to expand clinical benefits.
為了改善[18F]T807的腦攝取,發明人合成了[18F]T807的三種N-烷基類似物,並評估它們作為PHF-Tau蛋白造影劑的效果。結果發現這些[18F]T807類似物在正常小鼠中的親脂性及全腦攝取均顯著高於[18F]T807本身,故相較於[18F]T807係顯影能力顯著提昇之PHF-Tau蛋白造影劑。 In order to improve the brain uptake of [ 18 F]T807, the inventors synthesized three N-alkyl analogs of [ 18 F]T807 and evaluated their effects as a PHF-Tau protein contrast agent. It was found that the lipophilicity and whole brain uptake of these [ 18 F]T807 analogues in normal mice were significantly higher than that of [ 18 F]T807 itself, so PHF- was significantly improved compared to the [ 18 F]T807 system. Tau protein contrast agent.
因此,本發明提供一種下式化合物,
其中R係C1-3烷基。在一實施例中,該R係甲基、乙基、或正丙基。 Wherein R is a C 1-3 alkyl group. In one embodiment, the R is methyl, ethyl, or n-propyl.
本發明亦提供一種診斷性組合物,其包含下式化合物,
其中R係C1-3烷基;及醫藥上可接受之載劑或稀釋劑(如生理食鹽水等)。在一實施例中,該R係甲基、乙基、或正丙基。 Wherein R is a C 1-3 alkyl group; and a pharmaceutically acceptable carrier or diluent (eg, physiological saline, etc.). In one embodiment, the R is methyl, ethyl, or n-propyl.
本發明進一步提供一種組合物在製備Tau蛋白造影劑的用途,其中該組合物包含下式化合物:
其中R係C1-3烷基;及醫藥上可接受之載劑或稀釋劑(如生理食鹽水等)。在一實施例中,該R係甲基、乙基、或正丙基。 Wherein R is a C 1-3 alkyl group; and a pharmaceutically acceptable carrier or diluent (eg, physiological saline, etc.). In one embodiment, the R is methyl, ethyl, or n-propyl.
本發明更進一步提供一種製造下式化合物之方法,
其中R係C1-3烷基;該方法包含使由下式表示之化合物:
與K[18F]/K2.2.2反應。在一實施例中,該R係甲基、乙基、或正丙基。 Reacts with K[ 18 F]/K 2.2.2 . In one embodiment, the R is methyl, ethyl, or n-propyl.
圖1係[18F]T807及其N-烷基類似物的半製備型HPLC純化。 Figure 1 is a semi-preparative HPLC purification of [ 18 F]T807 and its N-alkyl analog.
圖2係健康對照者(70歲女性)與阿滋海默症患者(85歲女性)的死後人腦額葉相鄰切片,該等切片的厚度為10μm且經[18F]T807及其N-烷基類似物培養(185kBq/切片)(n=1)。 Figure 2 is a section of a healthy control (70-year-old female) and a patient with Alzheimer's disease (85-year-old female) with a marginal slice of the human frontal lobe. The thickness of these sections is 10 μm and passes through [ 18 F]T807 and its N-alkane. The base analog was cultured (185 kBq/slice) (n = 1).
圖3係[18F]T807及其N-烷基類似物在正常小鼠(n=3)中的全腦microPET時間-活性曲線。 3 lines [18 F] T807-alkyl and N- whole brain microPET time like in normal mice (n = 3) - The activity profile.
本發明可能以不同的形式實施,並不僅限於下列文中所提及的實例。下列實施例僅作為本發明不同面向及特點中的代表。 The invention may be embodied in different forms and is not limited to the examples mentioned below. The following examples are merely representative of the various aspects and features of the present invention.
如先前所報導,[18F]T807係透過TraceLab FXFN模組合成(Huang et al.,J Labelled Cpd Radiopharm.58,S170(2015))。簡言之,在DMSO中用K[18F]/K2.2.2在130℃下對相應的硝基前驅物進行親核芳族氟化,反應10分鐘,然後用HCl進行水解反應,並用半製備型HPLC(Phenomenex Luna(2)HILIC,5μm,10×250mm,0.1% HCl,3ml/min,254nm)純化以得到最終產物(1)。[18F]T807的三個N-烷基類似物(3)(其中R係甲基、乙基、或正丙基,對應的化合物分別稱為[18F]NM-T807、[18F]NE-T807、[18F]NP-T807)則是以相似方法由相應的硝基前驅物(2)合成,只是沒有後續的水解反應(方案1,圖1)。 As previously reported, [ 18 F]T807 was synthesized by the TraceLab FX FN module (Huang et al. , J Labelled Cpd Radiopharm . 58, S170 (2015)). Briefly, the corresponding nitro precursor was subjected to nucleophilic aromatic fluorination with K[ 18 F]/K 2.2.2 in DMSO at 130 ° C for 10 minutes, followed by hydrolysis with HCl and half Preparative HPLC (Phenomenex Luna (2) HILIC, 5 μm, 10×250 mm, 0.1% HCl, 3 ml/min, 254 nm) was purified to give the final product (1) . Three N-alkyl analogs of [ 18 F]T807 (3) (wherein R is a methyl group, an ethyl group, or a n-propyl group, and the corresponding compounds are respectively referred to as [ 18 F]NM-T807, [ 18 F] NE-T807, [18 F] NP-T807) is based on a method similar to the synthesis from the corresponding nitro precursors (2), but no subsequent hydrolysis reactions (scheme 1, Figure 1).
使用HPLC(Phenomenex Luna HILIC 200Å,5μm,250x4.6mm,10% EtOH(pH=2),0.75ml/min,254nm)及放射性TLC(矽石板(Silica plate),10cm,含有80μl 40% NH4OH(aq)的MeOH/CH2Cl2(20ml,1/19))測定這些造影劑的放射化學純度。藉由報導的方法(Oya et al.,Nucl Med Biol.27,249-254(2000))測量這些造影劑的log P,並且在健康對照者(70歲女性)及阿滋海默症患者(85歲女性)的死後人腦額葉切片上進行這些造影劑的體外放射自顯影術(in vitro autoradiography),如先前所報導(Chang et al.,Appl Radiat Isot,67,1397-1400(2009))。關於動物研究,將緊固的雄性ICR小鼠(n=3)靜脈注射每種造影劑約200μCi,並用Argus PET/CT掃描儀成像。用12×10秒、3×60秒、3×300秒、4×6000秒、及2×900秒的畫面產生動態正弦圖。使用eXplore Vista PET-CT MMWKS軟體獲得整個掃描(90分鐘) 的平均microPET圖像。 HPLC (Phenomenex Luna HILIC 200Å, 5 μm, 250 x 4.6 mm, 10% EtOH (pH = 2), 0.75 ml/min, 254 nm) and radioactive TLC (Silica plate, 10 cm, containing 80 μl of 40% NH4OH (aq) ) in MeOH / CH 2 Cl 2 (20ml , 1/19)) radiochemical purity of these contrast agents. The log P of these contrast agents was measured by the reported method (Oya et al. , Nucl Med Biol . 27, 249-254 (2000)), and in healthy controls (70 year old females) and Alzheimer's disease patients (85 years old). In vitro autoradiography of these contrast agents was performed on post-mortem brain frontal lobe slices of females as previously reported (Chang et al. , Appl Radiat Isot, 67, 1397-1400 (2009)). For animal studies, fastened male ICR mice (n=3) were injected intravenously with approximately 200 μCi of each contrast agent and imaged with an Argus PET/CT scanner. A dynamic sinogram is generated with a picture of 12 x 10 seconds, 3 x 60 seconds, 3 x 300 seconds, 4 x 6000 seconds, and 2 x 900 seconds. An average microPET image of the entire scan (90 minutes) was obtained using eXplore Vista PET-CT MMWKS software.
藉由此方法合成的[18F]T807、[18F]NM-T807,[18F]NE-T807及[18F]NP-T807的放射化學產率(radio chemical yield,RCY)分別為13±4(n=15)、7±6(n=5)、7±4(n=5)、及5±1%(n=5),放射化學純度>95%,且log P分別為2.05±0.10、2.00±0.10、2.11±0.17、及2.42±0.13(n=5)。放射自顯影術的研究顯示這些[18F]T807類似物在阿滋海默症患者的額葉中具有特異性結合(圖2)。在正常小鼠中[18F]T807、[18F]NM-T807,[18F]NE-T807及[18F]NP-T807的全腦攝取在注射後0.6分鐘達到最大值,並在之後被迅速洗出。這些造影劑的全腦標準攝取值(standard uptake value,SUV)分別為1.7、3.2、3.1、及5.8(圖3)。 The radiochemical yield (RCY) of [ 18 F]T807, [ 18 F]NM-T807, [ 18 F]NE-T807 and [ 18 F]NP-T807 synthesized by this method was 13 respectively. ±4 (n=15), 7±6 (n=5), 7±4 (n=5), and 5±1% (n=5), radiochemical purity >95%, and log P of 2.05, respectively ±0.10, 2.00±0.10, 2.11±0.17, and 2.42±0.13 (n=5). Autoradiography studies have shown that these [ 18 F]T807 analogs have specific binding in the frontal lobe of patients with Alzheimer's disease ( Figure 2 ). In normal mice, whole brain uptake of [ 18 F]T807, [ 18 F]NM-T807, [ 18 F]NE-T807 and [ 18 F]NP-T807 reached a maximum at 0.6 min after injection, and afterwards Was quickly washed out. The standard uptake values (SUV) of these contrast agents were 1.7, 3.2, 3.1, and 5.8, respectively ( Fig. 3 ).
由實驗結果可知,這些類似物在正常小鼠中的親脂性及全腦攝取均顯著高於[18F]T807本身。綜上所述,這些[18F]T807類似物的顯影能力顯著提升,因此可作為比[18F]T807更佳之PHF-Tau蛋白造影劑。 From the experimental results, the lipophilicity and whole brain uptake of these analogs in normal mice were significantly higher than that of [ 18 F]T807 itself. In summary, the development ability of these [ 18 F]T807 analogs is significantly improved, so it can be used as a better PHF-Tau protein contrast agent than [ 18 F]T807.
一個熟知此領域技藝者能很快體會到本發明可很容易達成目標,並獲得所提到之結果及優點,以及那些存在於其中的東西。本發明中之化合物、組合物、其製造程序與方法及其用途乃較佳實施例的代表,其為示範性且不僅侷限於本發明領域。熟知此技藝者將會想到其中可修改之處及其他用途。這些修改都蘊含在本發明的精神中,並在申請專利範圍中界定。 A person skilled in the art will readily appreciate that the present invention can be easily accomplished with the results and advantages and those present in the present invention. The compounds, compositions, processes and methods of making the same, and uses thereof, are representative of the preferred embodiments, which are exemplary and not limited to the field of the invention. Those skilled in the art will be aware of the modifications and other uses therein. These modifications are intended to be within the spirit of the invention and are defined in the scope of the claims.
本發明的內容敘述與實施例均揭示詳細,得使任何熟習此技藝者能夠製造及使用本發明,即使其中有各種不同的改變、修飾、及進步之處,仍應視為不脫離本發明之精神及範圍。 The present invention has been described in detail with reference to the embodiments of the present invention, and the invention may be Spirit and scope.
說明書中提及之所有專利及出版品,都以和發明有關領域之一般技藝為準,且其全部內容係藉由引用在此併入本文中。所有專利和出版品都在此被納入相同的參考程度,就如同每一個個別出版品都被具體且個別地指出納入參考。 All of the patents and publications mentioned in the specification are subject to the ordinary skill in the art to which the invention pertains, and the entire contents of which are incorporated herein by reference. All patents and publications are hereby incorporated by reference to the same extent as if each individual publication is specifically and individually indicated.
在此所適當地舉例說明之發明,可能得以在缺乏任何要件,或許多要件、限制條件或並非特定為本文中所揭示的限制情況下實施。所使用的名詞及表達是作為說明書之描述而非限制,同時並無意圖使用這類排除任何等同於所示及說明之特點或其部份之名詞及表達,但需認清的是,在本發明的專利申請範圍內有可能出現各種不同的改變。因此,應了解到雖然已根據較佳實施例及任意的特點來具體揭示本發明,但是熟知此技藝者仍會修改和改變其中所揭示的內容,諸如此類的修改和變化仍在本發明之申請專利範圍內。 The invention as exemplified herein may be practiced in the absence of any element, or a plurality of elements, limitations, or limitations. The nouns and expressions used are as a description and not a limitation of the description, and are not intended to be used to exclude any nouns and expressions that are equivalent to the features or parts thereof shown and described, but Various changes are possible within the scope of the patent application of the invention. Therefore, it is to be understood that the present invention has been disclosed and described herein in accordance with the preferred embodiments and the features of the present invention. Within the scope.
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