CN114394930A - 一种靶向cbr受体的pet示踪剂及其制备方法和用途 - Google Patents
一种靶向cbr受体的pet示踪剂及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种靶向CBR受体的PET示踪剂及其制备方法和应用，所述PET示踪剂为18F‑SQKJ‑1，结构如下式，所述示踪剂能够靶向CB1受体，即对CB1受体具有选择性，可高质量成像于CB1受体，因此该化合物可作为特异性的PET示踪剂用于PET影像学方面，由于CB1受体在精神类疾病有密切的相关性。因此，本发明18F‑PET示踪剂有望应用于PET/CT或PET/MR等影像学方面，用于精神类疾病的诊断。
Description
技术领域
本发明属于放射性药物及核医学技术领域，具体涉及一种靶向CBR受体的 PET示踪剂及其制备方法和用途。
背景技术
正电子发射断层显像(Positron Emission Tomography，PET)是目前惟一可 在活体上显示生物分子代谢、受体及神经介质活动的新型影像技术，现已广泛用 于多种疾病的诊断与鉴别诊断、疗效评价、脏器功能研究和新药开发等方面。PET 成像技术灵敏度高，特异性高，穿透性强，而且其可以全身显像，一次性全身显 像检查便可获得全身各个区域的图像。PET是一种反映分子代谢的显像，当疾病 早期处于分子水平变化阶段，病变区的形态结构尚未呈现异常，MRI、CT检查 还不能明确诊断时，PET检查即可发现病灶所在，并可获得三维影像，还能进行 定量分析，实现早期诊断，这是目前其它影像检查所无法比拟的。
PET示踪剂也称为PET显影剂，是被可发射正电子的核素标记后的示踪剂 引入体内后能进行脏器、组织或分子显像的放射性药物。放射性药物引入体内后， 能聚于靶器官或组织中，通过显像仪器对其发射的射线进行探测，从而获得药物 在体内的分布图像，用以诊断多种疾病。PET探针中主要用于临床研究的葡萄糖 类，如18-氟-脱氧葡萄糖(18F-FDG)为最常见的正电子显像剂，在肿瘤诊断和 治疗中得到了深入的研究。但是，PET成像也具有其内在的不足，其具有较低的 空间分辨率，无法准确定位病变部位。
虽然18-氟-脱氧葡萄糖(18F-FDG)、18F-NaF在癌症中的应用日益得到推广， 但18-氟-脱氧葡萄糖(18F-FDG)、18F-NaF等现阶段临床应用的多为非特异性示 踪剂，难以对特定区域或组织进行特异性成像。本发明提供一种可以对外周、脑 等组织中大麻素受体相结合的特异性PET示踪剂，示踪剂的分布情况可反映了 生物体内某种细胞或分子的分布，有望应用于炎症、精神类疾病等的早期诊断和 治疗。因此，该造影剂可弥补特异性PET示踪剂的技术空缺。
发明内容
本发明的目的在于针对现有技术的不足，提供一种可靶向CBR受体的PET 示踪剂及其制备方法和用途。
本发明采用的技术方案如下：
一种化合物，所述化合物为SQKJ-1,结构如下：
所述的化合物的制备方法，包括如下：
1)化合物9和化合物10在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺催化下， 缩合反应合成化合物11。
2)化合物11与化合物12在碳酸铯催化下反应得化合物13。
3)化合物13与化合物NaF以N,N-二甲基甲酰胺为溶剂，发生取代反应后， 纯化，洗脱，即得SQKJ-1。
以上述SQKJ-1为标准品，本发明还提供一种放射性化合物，所述化合物为 18F-SQKJ-1，结构如下：
进一步的，所述放射性化合物可以作为示踪剂，尤其可作为PET示踪剂， 且所述示踪剂可靶向CB1受体。
更进一步的，所述放射性化合物用于制备在精神类疾病诊断中应用的示踪剂，也可以加上药学上可接受的辅料制备成所述示踪剂；所述精神疾病包括抑郁症、偏 执等。
本发明的有益效果是：
18F核素探针是临床使用最广的一种核素显像剂，其半衰期为109.8min，非 常适合用于临床疾病诊断研究。将本发明中8F核素标记的化合物具有PET成像 能力，利用其极高的灵敏度和极强的穿透力，可对人体进行成像分析，尤其是本 发明中的放射性化合物可靶向CB1受体，即对CB1受体具有选择性，可高质量 成像于CB1受体，该化合物可作为特异性的PET示踪剂用于PET影像学方面， 有望弥补精神类疾病和炎症类疾病诊断的技术空缺，改变在精神类疾病和炎症类 疾病诊断上的PET示踪剂缺乏的局面。
附图说明
图1为非放射性标准品SQKJ-1的HPLC图谱；在放射性检测器下无信号， 在紫外检测器下有信号。
图2为本发明PET示踪剂18F-SQKJ-1的HPLC图谱；在放射性检测器下有 信号，在紫外检测器下有信号。
图3非放射性标准品SQKJ-1与本发明PET示踪剂18F-SQKJ-1混合进样后 的HPLC图谱；在放射性检测器下有信号，在紫外检测器下有信号。
图4为以雄性Sprague-Dawley大鼠作为PET扫描示例注入PET示踪剂18F -SQKJ-1后的PET图像数据。
具体实施方式
下面结合附图和具体实例对本发明技术方案做进一步的说明。本发明使用的 原料、设备若未经特别说明，则均为已知产品，可通过市售产品获得。
化合物SQKJ-1及PET示踪剂18F-SQKJ-1的一种制备方法如下：
1)化合物9和化合物10以乙腈为溶剂，在1-乙基-(3-二甲基氨基丙基)碳酰 二亚胺催化下，于50℃缩合反应4小时，过滤，浓缩后合成化合物11。
2)化合物11与化合物12以N,N-二甲基甲酰胺为溶剂，碳酸铯催化下，20℃ 反应为2.5小时，过滤，浓缩得化合物13。化合物13核磁共振氢谱为：1H NMR (400MHz,Chloroform-d)δ8.43(d,J＝1.6Hz,1H),7.88(dd,J＝7.5,1.4Hz,1H), 7.76–7.68(m,2H),7.39(dq,J＝7.6,0.8Hz,2H),7.34–7.24(m,4H),7.13–7.02 (m,3H),6.85(td,J＝1.5,0.6Hz,1H),4.47–4.20(m,4H),4.13(dp,J＝8.6,6.9Hz, 1H),3.58–3.48(m,1H),3.17–3.00(m,2H),2.43(t,J＝0.7Hz,3H),1.56(s,3H), 1.51(s,3H),1.20(d,J＝6.8Hz,3H).
3)化合物13与化合物Na18F以N,N-二甲基甲酰胺为溶剂置于PET热合成 模块中，发生取代反应后，纯化，洗脱，即得18F-SQKJ-1。
化合物13与化合物NaF以N,N-二甲基甲酰胺为溶剂，发生取代反应后，纯 化，洗脱，即得SQKJ-1。其核磁共振氢谱1H NMR(400MHz,Chloroform-d)δ8.40 (d,J＝1.5Hz,1H),7.89(dd,J＝7.5,1.5Hz,1H),7.33–7.26(m,4H),7.11(dt,J＝
7.5,1.1Hz,2H),7.05(d,J＝7.5Hz,1H),6.85(td,J＝1.5,0.6Hz,1H),4.81(dt,J＝ 12.3,7.0Hz,1H),4.65(ddt,J＝31.9,12.4,7.2Hz,1H),4.49(dt,J＝12.3,7.0Hz, 1H),4.41–4.06(m,3H),3.58–3.48(m,1H),3.11(ddt,J＝12.4,7.0,1.0Hz,1H), 3.02(ddt,J＝12.3,7.0,1.0Hz,1H),1.56(s,3H),1.51(s,3H),1.20(d,J＝6.9Hz, 3H).
其中化合物9可以采用如下方式获得：
步骤a：化合物1与化合物2以甲苯为溶剂，反应温度100℃，在三-(二亚 苄基丙酮)二钯、戴夫福斯试剂催化下，发生取代反应合成化合物3；
步骤b：化合物3与对氯氯苄以二氯甲烷为溶剂发生取代反应合成化合物4；
步骤c：化合物4以四氢呋喃为溶剂，反应温度-60℃，与三叔丁基硼氢化 锂反应12小时，发生还原反应合成化合物5；
步骤d：在0℃下，化合物5的甲苯溶液中加入三乙胺和甲磺酰氯，搅拌5 分钟后，过滤，滤液用碳酸氢钠水溶液洗涤后，浓缩得到化合物6。
步骤e：化合物6中加入N,N-二甲基甲酰胺溶液中并加入叠氮化钠，在 70℃下加热7小时。反应混合物用乙酸异丙酯溶解并用碳酸氢钠水溶液和水洗 涤，浓缩后用体积比90:10正己烷/乙酸乙酯柱层析得化合物7。
步骤f：向化合物8的乙酸异丙酯溶液中加入林德拉催化剂，并将混合物加 入在0.28MPa,45℃下氢化24小时，过滤，浓缩，加入氯化氢乙酸异丙酯溶液后 浓缩得化合物8。
步骤g：化合物8以甲醇为溶剂在钯碳催化下，氢气0.25MPa，25℃氢化4 小时，过滤，浓缩得化合物9。
以上仅为化合物9的一种可行的制备方案，对于本领域技术人员而言可通过 分析设计其他任意可行制备路径，在本发明中不做限定。
本发明制得的18F-SQKJ-1的效果验证：
以雄性Sprague-Dawley大鼠作为PET扫描示例，通过尾静脉注射一定剂量 的18F-SQKJ-1，在注射60分钟后，通过microPET获取静态扫描15分钟的PET 图像数据，PET图像同磁共振图像进行整合进行分析处理。
根据PET图像数据分析，该探针在SD大鼠的全脑区有明显的摄取，其中探 针在尾壳核和丘脑的探针摄取最高，而皮层、脑桥、杏仁核的探针摄取最低，小 脑、海马摄取居中。这些区域同CB1R的分布基本吻合。结果如图4所示。同时， 设置CB1R阻断对比实验，对同一只SD大鼠重复试验时，在PET示踪剂注射 30分钟前，按照3mg/kg的剂量注射CB1R特异性阻断剂利莫那班，再通过同样 的条件进行PET扫描。观察到探针在大脑的摄取减少62％，特别是尾壳核、丘 脑、海马摄取探针降低尤其明显，进一步证明该探针同CB1R的特异性结合。
Claims (9)
1.一种化合物，其特征在于：所述化合物为SQKJ-1,结构如下：
2.如权利要求1所述的化合物的制备方法，其特征在于，包括如下：
1)化合物9和化合物10在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺催化下缩合反应，合成化合物11；
2)化合物11与化合物12在碳酸铯催化下反应得化合物13；
3)化合物13与化合物NaF以N,N-二甲基甲酰胺为溶剂，发生取代反应后，纯化，洗脱，即得SQKJ-1；
3.一种放射性化合物，其特征在于，以SQKJ-1为标准品，所述化合物为18F-SQKJ-1，结构如下：
4.权利要求3所述放射性化合物的应用，其特征在于，所述化合物用于作为示踪剂。
5.权利要求3所述放射性化合物的应用，其特征在于，所述化合物用于作为PET示踪剂，且所述示踪剂靶向CB1受体。
6.权利要求3所述放射性化合物的应用，其特征在于，用于制备在精神类疾病诊断中应用的示踪剂。
7.根据权利要求6所述的应用，其特征在于：所述精神类疾病包括抑郁症、偏执。
8.一种示踪剂，其特征在于，由如权利要求3所述的化合物，加上药学上可接受的辅料制备而成。
9.如权利要求8所述的示踪剂，其特征在于：所述示踪剂化合物具有PET成像能力，利用其极高的灵敏度和极强的穿透力，所述示踪剂作为特异性的PET示踪剂靶向CB1受体，用于PET影像学方面。
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