CN113583089B - 靶向肿瘤pd-l1的pet显像剂、其标记前体、制法和应用 - Google Patents
靶向肿瘤pd-l1的pet显像剂、其标记前体、制法和应用 Download PDFInfo
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Abstract
本发明公开了靶向肿瘤PD‑L1的PET显像剂、其标记前体、制法和应用,属于放射性药物化学技术领域。本发明的靶向肿瘤PD‑L1的PET显像剂的标记前体的结构如式I所示,靶向肿瘤PD‑L1的PET显像剂结构如式Ⅱ所示。本发明创造性地将双功能螯合剂DOTA与环肽类抑制剂SETSKSF连接在一起,合成了式I所示的靶向肿瘤PD‑L1的PET显像剂的标记前体。本发明的前体化合物用Ga‑68标记后可以得到的式II化合物具有良好的稳定性、药代动力学优良、与肿瘤PD‑L1结合特异性好,且易于合成。
Description
技术领域
本发明涉及放射性药物化学技术领域,具体涉及靶向肿瘤PD-L1的PET显像剂、其标记前体、制法和应用。
背景技术
近年来,肿瘤免疫治疗进展迅速,在肿瘤治疗方面表现出良好的应用前景。程序性细胞死亡蛋白-1(Programmed cell death protein 1,PD-1)及其配体即程序性细胞死亡配体-1(Programmed cell death ligand-1,PD-L1)信号通路是癌细胞用于产生和维持免疫耐受的主要免疫检查点通路,PD-1/PD-L1信号通路已成为肿瘤免疫治疗的一个新靶点。作为B7家族的成员,PD-L1表达于正常非淋巴器官,并在活化的T细胞、抗原呈递细胞和非造血细胞中表达上调。PD-L1在肿瘤细胞中的异常表达会损害机体的抗肿瘤免疫,导致肿瘤细胞的免疫逃避。多种肿瘤细胞PD-L1表达水平增高,包括非小细胞肺癌、乳腺癌、黑色素瘤、脑胶质瘤、淋巴瘤、泌尿生殖系统肿瘤及消化道肿瘤等。抗PD-L1单克隆抗体能够通过与PD-L1结合,阻断PD-1与PD-L1之间的结合从而增强机体抗肿瘤的免疫能力,在一些难治性、复发性肿瘤患者中取得了良好的疗效。目前已有多种抗PD-L1单抗如Atezolizumab(2016年)、Durvalumab(2017年)、Avelumab(2017年)等获得美国食品与药品监督管理局(Food andDrug Administration,FDA)批准成为肿瘤免疫治疗抗体。但多项临床试验发现也有一部分接受抗PD-L1免疫治疗的患者未见临床获益,且抗体治疗还可能导致部分患者产生免疫相关不良反应,如自身免疫性肝炎、肺炎及结肠炎等等。肿瘤PD-L1表达水平高低是判断免疫治疗反应的重要指标,患者在接受抗PD-L1免疫治疗前后,评估肿瘤PD-L1表达水平具有重要意义。通过评估肿瘤PD-L1的表达水平,临床医生能够筛选抗PD-L1免疫治疗的优势人群及评估其疗效,预测哪些患者可以从抗PD-L1免疫治疗中获益,解释不同患者之间的疗效差异及监测疾病进展情况,避免无效的免疫治疗引起的不良反应。对多种肿瘤而言,肿瘤细胞高表达PD-L1的患者往往预后不良,但肿瘤PD-L1高表达的患者对抗PD-L1免疫治疗的疗效更佳。另外,肿瘤PD-L1表达水平高低是判断预后的重要指标。临床试验表明,肿瘤PD-L1的表达水平与肿瘤浸润深度、TNM分期、淋巴结和远处转移密切相关,从而与患者临床分期及预后关系密切。
目前临床评估肿瘤PD-L1表达水平的方法主要是取肿瘤组织标本进行免疫组织化学(immunohistochemistry,IHC)检测。FDA已经批准将Dako22C3、Dako28-8、VentanaSP14等抗体用于肿瘤组织PD-L1表达水平的IHC检测,在此基础上对即将接受抗PD-L1免疫治疗的患者进行筛选。已有临床试验结果表明IHC检测结果与患者的治疗反应相关。但也有研究发现该方法并不能十分精准地预测患者疗效,例如,一项临床试验表明对纳入的经IHC检测为PD-L1高表达的晚期黑色素瘤患者中,只有39%的患者对抗PD-L1免疫治疗有效,并且也有13%PD-L1阴性的患者对抗PD-L1免疫治疗产生了疗效。另外,IHC检测方法在实际临床应用中也有诸多限制:IHC属于有创性检查,肿瘤PD-L1表达水平在治疗过程中会发生动态变化,难以实现在治疗过程中多次取样对肿瘤PD-L1表达水平进行动态监测;肿瘤不同部位、不同转移灶及疾病不同时期都会导致肿瘤在空间及时间上的异质性,活组织检查的肿瘤组织只是肿瘤整体的一部分,无法反映出全部肿瘤PD-L1的表达情况,尤其对于有多发转移灶的患者;在进行放化疗后肿瘤组织可能会出现免疫抗原的释放而改变免疫状态,影响PD-L1检测结果;各个临床实验室中所使用的抗体种类、染色方法及尚不统一的PD-L1临界值标准也会影响肿瘤PD-L1检测结果。近期研发出可用于定量分析非小细胞肺癌细胞和免疫细胞亚型样本PD-L1表达量的OncoTect肺试剂,相对于IHC,OncoTect/>肺试剂盒可提供高度可重复结果及扩展信息,但也面临通过有创操作获取肿瘤组织等问题。
近年来,随着PET、SPECT等无创影像技术的发展,核医学在肿瘤分子显像基础研究及临床转化方面均取得了突破性进展。PD-L1靶向核素探针免疫显像可以减少穿刺等有创检查,避免肿瘤异质性的影响,提供原发灶、转移灶及全身PD-L1表达情况,有望成为一种更精准的筛选免疫治疗受益患者的检查方法。同时,核医学分子影像可以在治疗过程中多次重复、定量地对肿瘤原发灶及转移灶的PD-L1表达水平进行监测,在治疗过程中实时监测PD-L1的表达变化,监测疾病进展及评估免疫治疗疗效,为及时调整免疫治疗方案提供更多影像学依据。由于单克隆抗体对靶点具有高度亲和力和选择性,目前,很多研究者利用中、长半衰期的放射性核素如111In、64Cu、89Zr等标记大分子抗体及抗体片段研发出靶向PD-L1的抗体类示踪剂。该类探针具有亲和力强、特异性高、稳定性好等优点,是当前研发的靶向肿瘤PD-L1主要的示踪显像剂。这些探针已被证实在多种肿瘤中均可精确检测PD-L1的表达,如黑色素瘤、乳腺癌、非小细胞肺癌等。然而,由于单克隆抗体药代动力学缓慢,抗体作为示踪剂需要使用具有长半衰期的核素进行标记,这造成了对正常组织、器官的高辐射剂量。考虑到抗体分子量大、组织渗透性差及药代动力学缓慢等缺点,一些研究者使用放射性核素标记分子量更小的配体(如亲和体分子、内连接蛋白、单域抗体)用于评估肿瘤PD-L1表达水平。然而,繁锁的制备流程限制了这些配体的广泛应用。为了避免放射性核素直接标记抗体类显像剂分子量大、体内循环时间长、对正常组织器官辐射损伤大等缺点,我们课题组也曾研发出基于单克隆抗体的预定位策略分子探针(Atezolizumab-TCO/99mTc-HYNIC-PEG11-Tz)用于评估肿瘤PD-L1表达水平,但该类预定位分子探针也存在制备流程复杂,TCO及Tz体内稳定性差等缺点,难以进行临床转化。因此,有必要寻求新的分子探针来弥补上述显像剂在评估肿瘤PD-L1表达水平上的不足,为临床PD-L1免疫治疗筛选优势人群及评估其疗效,提供精准、个体化诊疗模式。
目前研发的靶向PD-L1的分子探针主要是利用中、长半衰期核素标记的生物大分子,尤其是单克隆抗体,该类显像剂分子量大,体内循环时间长,辐射剂量大;富血供器官显影明显,靶/本底比值低。少数研究机构利用亲和体分子、内连接蛋白等配体研发的显像剂也存在制备流程繁锁、难以临床推广等问题。那么,目前是否有易于制备的靶向PD-L1的小分子或肽类药物,能否使用短半衰期的核素进行标记制备显像剂用于肿瘤PD-L1表达水平的评估,克服目前已研发探针的不足?近年来,为了避免抗体类PD-L1免疫抑制剂制备成本高、给药途径不便、体内药代动力学缓慢、组织通透性差及容易引起免疫相关副作用等缺陷,许多研究机构及制药公司已经研发出靶向肿瘤PD-L1的小分子及肽类抑制剂(包括线性肽及环肽),其中一些抑制剂生物化学性质优良、对靶点亲和力及特异性高且体内稳定性好,相对于大分子单克隆抗体,这些小分子及肽类抑制剂具有易于制备、口服生物利用度高、膜通透性好、易于到达靶点部位且不会引起免疫反应等优势。一些小分子及肽类PD-L1抑制剂(如BMS-986189、CA-170及CA-327)已经进入临床I期临床实验用于晚期实体瘤及淋巴瘤的治疗,并显示出较好的疗效及应用前景。对肽类PD-L1抑制剂修饰添加双功能螯合剂(如DOTA)用于标记放射性核素易于操作,修饰后对肽类药物的结构影响小,因此不易改变其与PD-L1靶点的亲和力及特异性,也不易改变其稳定性及其在体内的药代动力学。近几年来,核医学临床成功转化的放射性药物主要是肽类放射性药物,如68Ga-RGD、68Ga-PSMA、68Ga-DOTATATE等。相对于抗体类示踪显像剂,肽类分子探针易于制备,分子量小、体内循环时间短,可用于标记短半衰期放射性核素,对正常组织器官造成的辐射剂量小。另外,添加修饰的螯合剂DOTA既能用于标记诊断性核素又能用于标记治疗性核素,通过标记诊断性核素如68Ga制备的示踪显像剂能够用于评估肿瘤PD-L1表达水平高低,评估患者抗PD-L1免疫治疗疗效;而标记治疗性核素如177Lu能够用于对PD-L1高表达的肿瘤患者进行放射性核素靶向治疗。目前,肿瘤的临床治疗方法主要包括外科手术治疗、局部消融、化放疗及靶向治疗等。外科手术治疗被认为是早期肿瘤最有效的治疗方法,但术后复发,转移率高,且不适用于中晚期初诊患者;消融、放疗只能局限于病灶局部,且治疗后癌灶周围往往仍有肿瘤细胞存活;化疗对中晚期肿瘤患者疗效差,且副作用大;近年来,针对肿瘤分子靶点,涌现出许多分子靶向药物,但分子靶向药物的有效率一直不高,且一些免疫治疗药物容易产生免疫相关副作用。对肿瘤进行单一治疗往往效果不佳,有必要寻求多学科联合治疗,核素治疗也在临床应用中备受关注。使用治疗性核素标记靶向肽类抑制剂进行治疗,即肽受体放射性核素靶向治疗(Peptide receptor radionuclide therapy,PRRT),通过肽受体的介导可实现对肿瘤细胞进行靶向特异性的内照射治疗。目前,临床上已有177Lu标记肽类成功转化用于针对肿瘤特异性分子靶点的靶向治疗药物,例如,靶向前列腺特异性膜抗原的177Lu-PSMA-617以及靶向神经内分泌肿瘤生长抑素受体的177Lu-DOTATATE。包括非小细胞肺癌、乳腺癌、黑色素瘤等在内的多种临床常见的肿瘤PD-L1表达水平增高,研发针对肿瘤PD-L1的核素标记治疗药物能够对多种肿瘤进行放射性核素靶向治疗,目前尚无针对肿瘤PD-L1靶点的核素治疗药物报道。
发明内容
本发明的目的之一在于,提供如式I所示的靶向肿瘤PD-L1的PET显像剂的标记前体,其可以与诊断性核素或/和治疗性核素合成,用于PD-L1高表达肿瘤的诊疗。
本发明的目的之二在于,提供如式II所示的靶向肿瘤PD-L1的PET显像剂。
本发明的目的之三在于,提供式I所示的靶向肿瘤PD-L1的PET显像剂的标记前体的制备方法。
本发明的目的之四在于,提供如式II所示的靶向肿瘤PD-L1的PET显像剂的制备方法。
本发明的目的之五在于,提供式I所示的靶向肿瘤PD-L1的PET显像剂的标记前体的应用。
本发明的目的之六在于,提供如式II所示的靶向肿瘤PD-L1的PET显像剂的应用。
为实现上述目的,本发明采用以下技术方案:
本发明所述的一种靶向肿瘤PD-L1的PET显像剂的标记前体,其结构如式I所示:
本发明所述的一种靶向肿瘤PD-L1的PET显像剂,其结构如式Ⅱ所示:
申请人经过大量试验,付出了创造性的劳动后,筛选出了针对肿瘤PD-L1的环肽类抑制剂SETSKSF(结构简式:DOTA-Ser-Cyclo(Glu-Thr-Ser-Lys)-Ser-Phe-NH2;化学名:68Ga标记2,2',2'-(10-(2-((S)-1-((3S,6S,9S,18S)-18-((S)-1-((S)-1-氨基-1-氧代-3-苯基丙烷-2-基氨基)-3-羟基-1-氧代丙烷-2-基氨甲酰基)-6-((R)-1-羟乙基)-3-(羟甲基)-2,5,8,12-四氧代-1,4,7,13-四氮杂环十八烷-9-基氨基)-3-羟基-1-氧代丙烷-2-基氨基)-2-氧代乙基)-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸),SETSKSF由7个氨基酸残基构成,其中赖氨酸和谷氨酸残基内酰胺化构成模拟环。申请人将双功能螯合剂DOTA连接在氮端丝氨酸残基处,成功合成了前体化合物DOTA-SETSKSF。
本发明所述的一种靶向肿瘤PD-L1的PET显像剂的标记前体的合成方法,以SETSKSF所需氨基酸、DOTA为原料,采用多肽Fmoc合成法合成。
本发明所述的一种靶向肿瘤PD-L1的PET显像剂的合成方法,式I化合物与68Ga的盐反应,生成式Ⅱ化合物,其反应式为:
本发明的部分实施方案中,反应体系的pH值为2~7,反应温度为60~95℃,反应时间为5~30min,进行最佳标记条件筛选。
本发明的部分实施方案中,反应体系的pH值为4,反应温度为80℃,反应时间为10min。
本发明的部分实施方案中,在反应体系添加缓冲溶液以调节pH值,所述缓冲溶液选自醋酸钠/醋酸体系、醋酸铵/醋酸体系、醋酸钠/盐酸体系、HEPES体系、或Tris体系。
本发明的部分实施方案中,还包括纯化步骤,将反应完成后的反应液采用C18柱进行纯化。
本发明所述的靶向肿瘤PD-L1的PET显像剂的标记前体在制备标记诊断性核素或/和治疗性核素的诊断试剂/药物、或/和治疗药物中的应用。
本发明所述的一种靶向肿瘤PD-L1的PET显像剂在制备PD-L1高表达肿瘤的诊断试剂/药物、或/和治疗药物中的应用;优选地,所述PD-L1高表达肿瘤包括非小细胞肺癌、黑色素瘤、乳腺癌中的任意一种或几种。
与现有技术相比,本发明具有以下有益效果:
本发明设计科学,构思巧妙。本发明创造性地将双功能螯合剂DOTA与环肽类抑制剂SETSKSF连接在一起,合成了式I所示的靶向肿瘤PD-L1的PET显像剂的标记前体。该前体化合物,用Ga-68标记后可以得到的式II化合物具有良好的稳定性、药代动力学优良、与肿瘤PD-L1结合特异性好,且易于合成。
附图说明
附图1为实施例1制得的式I化合物的质谱图;
附图2为实施例2的Radio-HPLC检测结果图;其中上图为放射性探测仪结果,出峰时间Rt=13.6min处为68Ga-DOTA-SETSKSF的放射峰;下图为紫外探测仪结果,出峰时间Rt=14.5min处为过量非标记前体DOTA-SETSKSF的紫外峰,探测波长为220nm。
附图3为实施例4的药代动力学实验结果图;
附图4为68Ga-DOTA-SETSKSF在B16-F10 C57BL/6小黑鼠模型体内分布情况图;
附图5为68Ga-DOTA-SETSKSF在H1975裸鼠模型体内分布情况图;
附图6为荷黑色素瘤B16-F10模型C57BL/6小黑鼠注射150μCi68Ga-DOTA-SETSKSF后分别于30min、1h、2h及3h后全身Micro-PET/CT MIP显像图。
附图7为荷H1975肿瘤模型鼠注射150μCi 68Ga-DOTA-SETSKSF后分别于1h、2h及3h分钟后全身Micro-PET/CT MPI显像图。
具体实施方式
实施例1
DOTA-SETSKSF的合成
该制备方法为常规多肽Fmoc合成法,通过酰胺键链接DOTA。DOTA-SETSKSF质谱检测图如附图1所示。
实施例2
本实施例公开了式II化合物68Ga-DOTA-SETSKSF的合成,具体为:
将25μg溶于100μL蒸馏水的式I化合物DOTA-SETSKSF放入反应瓶,向反应瓶中加入750μL 0.25M的醋酸钠及3mL新鲜淋洗的68Ga淋洗液(68Ga淋洗在0.05M的盐酸溶液中),反应液pH值约为4.0,混匀后80℃反应10min,反应完成后使用C18柱进行纯化,经radio-HPLC检测产物放射化学纯度大于99%。放射性标记反应方程式如下:
Radio-HPLC检测结果如附图2所示,其中,上图为放射性探测仪结果,出峰时间Rt=13.6min处为68Ga-DOTA-SETSKSF的放射峰;下图为紫外探测仪结果,出峰时间Rt=14.5min处为过量非标记前体DOTA-SETSKSF的紫外峰,探测波长为220nm。
实施例3
本实施例公开了本发明的式II化合物68Ga-DOTA-SETSKSF的体外稳定性实验,具体为:
以实施例2所得的68Ga-DOTA-SETSKSF约100μCi分别置于100μL 0.9%生理盐水及0.1%BSA中,充分混匀后37℃下存放。分别在30min、1h、2h及4h取样,使用分析型Radio-HPLC检验其放射化学纯度变化。结果表明68Ga-DOTA-SETSKSF 4h后放射化学纯度超过98%,稳定性好,几乎没有分解。
实施例4
本实施例公开了本发明的式II化合物68Ga-DOTA-SETSKSF的药代动力学实验,具体为:
以实施例2所得的式II化合物68Ga-DOTA-SETSKSF约150μCi尾静脉注射5只8周雄性裸鼠体内,分别于注射后不同时间点(1、3、5、10、20、30、45、60min)断尾,用毛细血管取约为5μL血样,置于计数管底部,测其计数,绘制其血药浓度-时间曲线。结果如附图3所示,结果表明68Ga-DOTA-SETSKSF静脉注射后迅速分布进入各组织器官,然后从排泄器官(泌尿体统)排出体外,血药浓度低。
实施例5
本实施例公开了本发明的式II化合物68Ga-DOTA-SETSKSF的生物分布实验,具体为:
取荷黑色素瘤B16-F10模型C57BL/6小黑鼠或荷非小细胞肺癌H1975模型裸鼠18只(雌雄各9只),随机分为3组,每组6只(雌雄各3只),以实施例2所得的式II化合物68Ga-DOTA-SETSKSF经尾静脉注射150uCi,按组分别于30min、60min、120min时断头处死,取心、肝、脾、肺、肾、胃、肠、骨骼、肌肉、血液、皮肤、脑等器官测量其放射性,随后立即称重,最后计算每克组织注射剂量百分率(%ID/g)。68Ga-DOTA-SETSKSF在B16-F10 C57BL/6小黑鼠模型体内分布情况如附图4所示,68Ga-DOTA-SETSKSF在H1975裸鼠模型体内分布情况如附图5所示。表明式II化合物在肿瘤中呈高分布。
实施例6
本实施例公开了本发明的式II化合物68Ga-DOTA-SETSKSF的动态活体显像试验:
1.荷黑色素瘤B16-F10模型C57BL/6小黑鼠Micro-PETCT显像
将B16-F10模型鼠置于Micro PET床板上,异氟烷吸入麻醉,胶带固定。床前经尾静脉注射150uCi 0.1mL 68Ga-DOTA-SETSKSF的生理盐水溶液后分别于30min、1h、2h及3h进行静态小动物PET/CT采集,显像结果附图6所示,注射150μCi 68Ga-DOTA-SETSKSF后分别于30min、1h、2h及3h后全身micro-PET/CT MIP显像,肿瘤显影清晰。
2.荷非小细胞肺癌H1975模型裸鼠Micro-PET/CT显像
荷非小细胞肺癌H1975模型裸鼠2只(雌雄各1只),称重后,按小鼠体重经尾静脉注射0.1ml/10g 4%水合氯醛溶液,待小白鼠麻醉后经尾静脉注射68Ga-DOTA-SETSKSF溶液(1.8MBq,0.1ml),以俯卧位使用胶带固定于小动物PET/CT床板上,分别于1h、2h及3h进行静态小动物PET/CT采集,采集图像,如附图7所示。注射150μCi 68Ga-DOTA-SETSKSF后分别于30min、1h、2h及3h后全身micro-PET/CT MIP显像,H1975肿瘤显示清晰。
最后应说明的是:以上各实施例仅仅为本发明的较优实施例用以说明本发明的技术方案,而非对其限制,当然更不是限制本发明的专利范围;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围;也就是说,但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色,其所解决的技术问题仍然与本发明一致的,均应当包含在本发明的保护范围之内;另外,将本发明的技术方案直接或间接的运用在其他相关的技术领域,均同理包括在本发明的专利保护范围内。
Claims (3)
1.一种靶向肿瘤PD-L1的PET显像剂,其特征在于,其结构如式Ⅱ所示:
式Ⅱ;
所述的一种靶向肿瘤PD-L1的PET显像剂的合成方法为显像剂的标记前体与68Ga的盐反应,生成式Ⅱ化合物,其反应式为:
;
所述的显像剂的标记前体结构如式I所示:
式I;
所述的显像剂的标记前体的合成方法为经由SETSKSF所需氨基酸、DOTA为原料,采用多肽Fmoc合成法合成。
2.如权利要求1所述的靶向肿瘤PD-L1的PET显像剂的标记前体在制备标记诊断性核素68Ga的诊断试剂或/和药物中的应用。
3.如权利要求1所述的一种靶向肿瘤PD-L1的PET显像剂在制备PD-L1高表达肿瘤的诊断试剂或/和药物中的应用;
所述PD-L1高表达肿瘤为非小细胞肺癌、黑色素瘤、乳腺癌中的任意一种或几种。
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