CN116916972A - 用于核医学诊断和治疗前列腺癌诱发的骨转移瘤的标记前体和放射性示踪剂 - Google Patents
用于核医学诊断和治疗前列腺癌诱发的骨转移瘤的标记前体和放射性示踪剂 Download PDFInfo
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Abstract
用于核医学诊断和治疗诊断的标记前体具有结构(式(I))或(式(II)),所述结构具有第一PSMA特异性靶载体TV1、第二成骨亲和性的靶载体TV2、用于络合放射性同位素的螯合剂Chel以及两个或三个连接基L1、L2和L3。
Description
本发明涉及用于络合放射性同位素的标记前体,包括螯合物Chel和用于PSMA和骨转移瘤的与螯合物Chel共轭的两个靶载体。
提出将本发明的化合物用于成像式核医学诊断和治疗(治疗诊断学)由前列腺癌诱发的骨转移瘤。
放射治疗诊断学
自从约15年前起,在临床实践中,成像式核医学诊断方法如正电子发射断层成像法(PET)和单光子发射计算机断层成像法(single photon emission computedtomography,SPECT)的应用范围越来越大。最近,治疗诊断学方法也变得越来越重要。
在核医学的诊断和疗法中用放射性同位素例如镓-68(68Ga)或镥-177(177镥)标记或照射肿瘤细胞和转移瘤。在此,尤其使用配位结合相应的放射性同位素(68Ga、99mTc、177Lu)并且形成放射性示踪剂的标记前体。标记前体包括螯合剂作为重要的化学组分以便有效且稳定地络合放射性同位素并且包括在肿瘤组织中结合到经限定的目标结构的生物靶载体作为功能组分。一般而言,生物靶载体对跨膜的受体、蛋白质、酶或肿瘤细胞的其他结构具有高亲和性。
在静脉注射到血液循环中之后,用放射性同位素标记的治疗诊断药物或放射性示踪剂在原发肿瘤和转移组织的细胞上或其中富集。目的是在肿瘤中累积杀死组织的辐射剂量。同时,应将施加到健康组织的辐射剂量保持得较低,使得健康组织可以容忍伤害。
通过螯合剂来改变靶载体的构型和化学特性并且一起强烈影响其对肿瘤细胞的亲和性。对应地,在高耗费的试错实验或所谓的生化筛选中对螯合剂与靶载体之间的偶联进行定制。在此,合成了大量的包含螯合剂和靶载体的标记前体并且尤其将其对肿瘤细胞的亲和性定量化。螯合剂和与靶载体的化学偶联对于相应放射治疗诊断药物的生物和核医学潜力而言是重要的。
除了高亲和性之外,标记前体还必须满足其他要求,如
-快速且有效地络合相应的放射性同位素;
-最终的放射治疗诊断药物对肿瘤细胞和转移瘤——尤其骨转移瘤——相对于健康组织的高选择性;
-活体内的稳定性,也就是说最终的放射治疗诊断药物在生理条件下在血清中的生化耐受性。
前列腺癌
对于工业国家的男性而言,前列腺癌是最常见的癌症类型并且是第三常见的致死癌症。在这种疾病中,肿瘤生长仅缓慢进展。在早期阶段中进行诊断的情况下,5年的存活率接近100%。如果在肿瘤已经转移时才发现此种疾病,则存活率大幅度降低。过早且过于激进的针对此种肿瘤的方式进而不必要地影响患者的生活质量。于是例如以手术方式摘除前列腺可能导致失禁和阳痿。关于疾病阶段的安全的诊断和信息对于以较高生活质量成功治疗患者而言是关键的。除了由医师对前列腺进行采样之外,广泛使用的一种诊断手段是确定患者血液中的肿瘤标记物。前列腺癌症的最显著的标记物是血液中前列腺特异抗原(PSA)的浓度。然而,PSA浓度的说服力有待证实,因为具有略微升高的数值的患者通常没有前列腺癌症,然而具有前列腺癌症的患者中的15%没有显示出血液中升高的PSA浓度。
前列腺特异膜抗原(PSMA)
用于诊断前列腺肿瘤的目标结构是前列腺特异膜抗原(PSMA)。与PSA不同,在血液中无法检测PSMA。它是一种具有酶活性的膜结合的糖蛋白质。其任务是从N-乙酰基-天冬氨酰基-谷氨酸盐(NAAG)和叶酸-(聚)-γ-谷氨酸盐切掉C端的谷氨酸盐。PSMA在正常组织中几乎不出现,但是被前列腺癌症细胞大幅度过表达,其中表达紧随肿瘤疾病的阶段而修正。前列腺癌症的淋巴结转移瘤和骨转移瘤的约40%的比例也表达出PSMA。
PSMA分子靶向战略是用抗体结合到PSMA的蛋白质结构上。另一种手段是利用PSMA的已得以良好理解的酶活性。在PSMA的酶结合袋中存在两个结合谷氨酸盐的Zn2+离子。在带有这两个Zn2+离子的中心前方存在芳香族的结合袋。这种蛋白质能够扩展并且适配于结合配对物(诱导契合),使得除了NAAG之外还可以结合叶酸,其中碟啶酸基团停靠在芳香族结合袋中。利用PSMA的酶亲和性,可以与底物的酶裂解无关地实现底物向细胞中的吸收(胞饮)。
因此,尤其PSMA抑制剂良好地适合作为用于成像式诊断和治疗诊断的放射性药物或放射性示踪剂的靶载体。放射性标记的抑制剂结合到酶的活性中心,但是在那里不进行转化。即在抑制剂和放射性标志物之间的结合不会脱离。通过胞饮有助于将抑制剂与放射性标志物吸收到细胞中并且在肿瘤细胞中富集。
对PSMA具有高亲和性的抑制剂(图示1)一般包含谷氨酸盐主题(Motiv)以及不可用酶裂解的结构。高度有效的PSMA抑制剂是2-磷酰基甲基-戊二酸或2-磷酰基甲基-戊烷二酸(2-PMPA),其中谷氨酸盐主题结合到无法由PSMA裂解的膦酸基团。基于脲的抑制剂构成了在临床中相关的放射性拟药PSMA-11(图示2)和PSMA-617(图示3)中使用的另一组PSMA抑制剂。
已经证明为特别有利的是,除了用于谷氨酸盐主题的结合袋之外,还涉及PSMA的芳香族结合袋。例如,在高度有效的放射性拟药PSMA-11中,结合主题L-赖氨酸-脲-L-谷氨酸盐(KuE)通过己基(己基连接基)结合到芳香族的HBED螯合剂(N,N'-双(2-羟基-5-(亚乙基-β-羧基)苄基)亚乙基二胺N,N'-二乙酸盐)。
如果相反将L-赖氨酸-脲-L-谷氨酸盐(KuE)结合到非芳香族的螯合剂DOTA(1,4,7,10-四氮杂环十二碳-1,4,7,10-四乙酸盐),则造成了在肿瘤组织中降低的亲和性和富集。为了仍然能够将DOTA螯合剂用于带有治疗效果的放射性同位素(如177Lu或225Ac)的对PSMA有亲和性的放射性拟药,必须将连接基进行适配。借助于针对性地由不同芳香族结构来取代己基,已经发现了高度有效的放射性拟药PSMA-617(当时的优质标准)。
图示1:PSMA抑制剂
图示2:标记前体PSMA-11
图示3:标记前体PSMA-617
在现有技术中已知许多用于诊断和治疗诊断癌症的带有放射性同位素的标记前体。WO 2015055318 A1公开了用于诊断和治疗诊断(除其他之外)前列腺癌症或上皮癌症的放射性示踪剂,即在图示3中所示的化合物PSMA-617。
骨转移瘤和双膦酸盐
双膦酸盐(BP)在临床实践中用于治疗骨和钙代谢障碍。这包括派杰氏病、骨质输送和对骨肿瘤的常规系统性治疗。双膦酸盐的独特之处在于其富集矿物质型磷酸钙时出色的选择性。这是以双膦酸盐与钙(II)离子形成两齿螯合络合物为基础的。双膦酸盐优选吸附在快速骨重建的区域中。与健康组织相比,在骨转移瘤中发生较高强度的重建。因此,双膦酸盐在骨转移瘤中以增强的幅度富集并且在那里引起了不同的过程。
另一方面,双膦酸盐抑制骨质的矿物质化以及骨分解。这种作用尤其是基于对焦磷酸法尼基合成酶(FPPS)的抑制,这是HMG-CoA还原酶-(甲羟戊酸盐)途径中的一种酶。通过抑制这种酶,防止了产生法尼基(对于将信号蛋白质锚固在细胞膜上而言重要的分子,FPPS)并且引发了细胞的凋亡。于是,双膦酸盐衍生物自身在细胞层面上已经实现了治疗功能。
双膦酸盐在骨表面处的选择性富集有助于成骨性细胞、尤其的破骨细胞的凋亡,破骨细胞在骨基质的脱矿质化时以增大的幅度吸收双膦酸盐。破骨细胞的更多的凋亡进而促成了抗吸收效果。
临床相关的双膦酸盐是:氯膦酸盐、羟乙膦酸盐、帕米膦酸盐、利塞膦酸盐和唑来膦酸盐。
唑来膦酸盐(ZOL,具有杂芳香族N单元的羟基双膦酸盐)已经证实为是对于治疗诊断骨转移瘤特别有效的放射性示踪剂。与螯合剂NODAGA和DOTA共轭的唑来膦酸盐(图示4)代表了对于骨转移瘤而言目前最强力的放射性治疗诊断药。
图示4:示踪剂DOTA-唑来膦酸盐(左)和NODAGA唑来膦酸盐(右)
在治疗发展阶段的前列腺癌症和前列腺转移瘤时,目前优选使用带有上述PSMA靶载体KuE的单体型放射性示踪剂。在健康细胞的表面上也表达PSMA。因此,带有PSMA靶载体的单体型放射性示踪剂在相当大的程度上也富集在健康组织中。与之相关的辐射剂量造成了各种毒副作用。特别明显的是在用225Ac(225锕)标记的放射性示踪剂时的副作用,它总体上且不可逆地损伤唾液腺。因此不再使用具有放射性同位素225Ac的治疗形式。
虽然在近几年由于改进的诊断方式患有转移性前列腺癌的病人数量有所回落,但患有前列腺癌转移瘤的患者的数量仍然很多,其中约80%的转移瘤影响倒骨组织。在转移性前列腺癌症的情况下,存活率大幅度降低。对于骨转移瘤尤其如此。另外,骨转移瘤导致了强烈的疼痛并且严重影响生活质量。一般而言,只剩下姑息治疗作为临床选项(Gandaglia,G.,等人,Impact of Metastases on Survival in Patients withMetastatic Prostate Cancer,European Urology,2015,68(2),325-334)。
本发明的目的在于,提供用于温和且有效地治疗转移性前列腺癌的标记前体和放射性示踪剂。
这个目的通过用于络合放射性同位素的标记前体实现,所述标记前体具有以下结构:
TV1-L1-Chel-L2-TV2
或者
其中X=CH或N
其中
-第一靶载体TV1选自包括以下项的PSMA抑制剂的组:
-第二靶载体TV2选自包括以下项的双膦酸盐的组:
-第一连接基L1具有选自以下的结构:
G;
以及
其中G为
或者/>
O1、O2和O3彼此独立地选自包括以下项的组:酰胺残基、羧酸酰胺残基、次膦酸盐/酯残基、烷基残基、三唑残基、硫脲残基、亚乙基残基、马来酰亚胺残基、-(CH2)-、-(CH2CH2O)-、-CH2-CH(COOH)-NH-和-(CH2)qNH-其中q=1、2、3、4、5、6、7、8、9或10;
p1、p2和p3彼此独立地选自量{0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20};
-第二连接基L2具有选自以下的结构:
以及
其中R1、R2和R3彼此独立地选自包括以下项的组:酰胺残基、羧酸酰胺残基、次膦酸盐/酯残基、烷基残基、三唑残基、硫脲残基、亚乙基残基、马来酰亚胺残基、呋喃残基、唑残基、噁唑残基、噻吩残基、噻唑残基、吖嗪残基、噻嗪残基、萘残基、喹啉残基、吡咯残基、咪唑残基、吡唑残基、四唑残基、噻二唑残基、噁二唑残基、吡啶残基、嘧啶残基、三嗪残基、四嗪残基、噻嗪残基、噁嗪残基、萘残基、色烯残基或硫代色烯残基、-(CH2)-、-(CH2CH2O)-、-CH2-CH(COOH)-NH-和-(CH2)qNH-其中q=1、2、3、4、5、6、7、8、9或10;
s1、s2和s3彼此独立地选自量{0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20};
-第三连接基L3具有选自以下的结构:
以及
其中
T1、T2和T3彼此独立地选自包括以下项的组:酰胺残基、羧酸酰胺残基、次膦酸盐/酯残基、烷基残基、三唑残基、硫脲残基、亚乙基残基、马来酰亚胺残基、-(CH2)-、-(CH2CH2O)-、-CH2-CH(COOH)-NH-和-(CH2)VNH-其中v=1、2、3、4、5、6、7、8、9或10;
u1、u2和u3彼此独立地选自量{0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20};
-QS为方酸残基
;以及
-选自包括以下项的组的螯合剂Chel:H4pypa,EDTA(乙二胺四乙酸盐),EDTMP(二亚乙基三胺五(亚甲基膦酸)),DTPA(二亚乙基三胺五乙酸盐)及其衍生物,DOTA(十二碳-1,4,7,10-四胺-四乙酸盐),DOTAGA(2-(1,4,7,10-四氮杂环十二烷-4,7,10)-戊烷二酸)以及其他的DOTA衍生物,TRITA(十三碳-1,4,7,10-四胺-四乙酸盐),TETA(十四碳-1,4,8,11-四胺-四乙酸盐)及其衍生物,NOTA(壬-1,4,7-三胺-三乙酸盐)及其衍生物例如NOTAGA(1,4,7-三氮杂环壬烷,1-戊二酸,4,7-乙酸盐),TRAP(三氮杂环壬烷次膦酸),NOPO(1,4,7-三氮杂环壬烷-1,4-双[亚甲基(羟甲基)次膦酸]-7-[亚甲基(2-羧乙基)次膦酸]),PEPA(十五碳-1,4,7,10,13-五胺五乙酸盐),HEHA(十六碳-1,4,7,10,13,16-六胺-六乙酸盐)及其衍生物,HBED(羟苄基-亚乙基-二胺)及其衍生物,DEDPA及其衍生物如H2DEDPA(1,2-[[6-(羧酸酯)吡啶-2-基]甲基胺]乙烷),DFO(去铁胺)及其衍生物,三羟基吡啶酮(THP)及其衍生物如YM103,TEAP(四氮杂环癸烷次膦酸)及其衍生物,AAZTA(6-氨基-6-甲基全氢-1,4-二氮杂-N,N,N',N'-四乙酸盐)以及衍生物如DATA((6-戊烷酸)-6-(氨基)甲基-1,4-二氮杂/>四乙酸盐);SarAr(1-N-(4-氨基苄基)-3,6,10,13,16,19-六氮杂二环[6.6.6]-二十烷-1,8-二胺)及其盐,(NH2)2SAR(1,8-二氨基-3,6,10,13,16,19-六氮杂二环[6.6.6]二十烷)及其盐和衍生物,氨基硫醇及其衍生物。
本发明的标记前体的便利的实施方式的特征在于以下特征的任意组合,至少这些特征不互相排斥,并且因此:
-所述螯合剂Chel为DOTA;
-所述螯合剂Chel为H4pypa;
-所述螯合剂Chel为DATA;
-所述螯合剂Chel为DOTAGA;
-所述第二连接基L2包括至少一个选自以下项的残基:
-所述第二连接基L2包括至少一个方酸残基
-所述第二连接基L2包括至少一个选自以下项的残基:
-所述连接基L1和L2是相同的(L1=L2);
-所述连接基L1和L3是相同的(L1=L3);
-所述连接基L2和L3是相同的(L2=L3);
-所述连接基L1、L2和L3是相同的(L1=L2=L3);
-所述第二连接基L2包括选自包括以下项的残基的组的残基:吡咯1,2-噁唑/>1,2,3,5-四嗪/>咪唑/>1,2,3-噁二唑/>1,2-噻嗪/>吡唑/>1,3,4-噁二唑/>1,3-噻嗪/>1,2,3-三唑/>1,2,5-噁二唑/>1,4-噻嗪/>1,2,4-三唑/>1,2,4-噁二唑/>1,3-噁嗪/>四唑/>吡啶/>1,4-噁嗪/>噻吩/>吡啶/>萘/>呋喃/>1,2,3-三嗪/>喹啉/>噻唑/>1,2,4-三嗪/>2H-色烯1,2-噻唑/>1,3,5-三嗪/>4H-色烯/>噻二唑1,2,3,4-四嗪/>2H-硫代色烯/>噁唑/>1,2,4,5-四嗪4H-硫代色烯/>以及上述残基的衍生物;
-所述第二连接基L2包括至少一个咪唑残基
-G为
-所述标记前体具有以下结构
下面将借助于附图和实施例详细阐释本发明。在附图中
图1示出放射性示踪剂的功能性组分;
图2示出大鼠的活体PET照片;
图3示出关于SUV时间曲线和骨骺与血液的PET信号比的图表;以及
图4示出PSMA结合袋的停靠模拟;
图5示出标记前体的标记物动力学;
图6在生理环境中放射性示踪剂的稳定性;
图7对羟基磷灰石的接合亲和性;
图8在没有和带有PSMA封阻的情况下的离体器官富集。
酰胺偶联的实施例
在本发明中优选借助于酰胺偶联反应将螯合剂Chel、靶载体TV1、TV2以及连接基L1、L2共轭化。在医学化学中,形成蛋白质骨架的酰胺偶联是最常用的反应。酰胺偶联的属类实例在图示5中示出。
图示5:酰胺偶联
由于实际上无限的组成而容易获得的羧酸衍生物和酰胺衍生物,酰胺偶联策略开创了用于合成新型化合物的简单途径。本领域技术人员已知大量的酰胺偶联试剂和实验方案。最常用的酰胺偶联策略是基于羧酸与胺的缩合。为此通常将羧酸活化。在活化之前对其余的官能团进行保护。这个反应在两个步骤中在一种反应介质中(一锅)在使经活化的羧酸直接反应的情况下进行,或者在两个步骤中在将经活化的“被捕捉”的羧酸分离并且与胺反应的情况下进行。
在此,羧酸酯与偶联试剂反应,从而形成反应性中间产物,可以将其分离或使其直接与胺反应。大量的试剂可用于活化羧酸,如酸卤化物(氯化物、氟化物)、叠氮化物、酸酐或碳二亚胺。另外,作为反应性中间产物可以形成酯,如五氟苯基酰亚胺基酯或羟基琥珀酰亚胺基酯。由酰氯或叠氮化物衍生的中间产物具有高反应活性。但是,严苛的反应条件和高反应活性通常阻碍使用敏感的底物或氨基酸。相对而言,使用碳二亚胺如DCC(二环己基碳二亚胺)或DIC(二异丙基碳二亚胺)的酰胺偶联策略打开了宽广的应用范围。通常、尤其在固相合成中使用添加剂来改进反应效率。铵盐是具有较短反应时间和最低消旋的高效肽偶联试剂。用若干添加剂例如HOBt甚至可以完全避免消旋。铵试剂与羧酸等摩尔使用,以防止与肽的游离胺的过量反应。鏻盐与羧酸酯反应,这一般需要两当量的碱,例如DIEA。鏻盐相对于亚胺离子试剂的重要优点是鏻不与胺组分的游离氨基反应。这使得可能以等摩尔的酸和胺之比进行偶联,并且帮助避免直链肽的分子内成环以及昂贵的胺组分的过量使用。
酰胺偶联的反应策略和试剂的全面总结见于以下综述文章:
-Analysis of Past and Present Synthetic Methodologies on MedicinalChemistry:Where Have All the New Reactions Gone?;D.G.Brown,J.J.Med.Chem.2016,59(10),4443-4458;
-Peptide Coupling Reagents,More than a Letter Soup;A.El-Faham,F.Albericio;Chem.Rev.2011,111(11),6557-6602;
-Rethinking amide bond synthesis;V.R.Pattabiraman,J.W.Bode;Nature,Vol.480(2011)471-479;
-Amide bond formation:beyond the myth of coupling reagents;E.Valeur,M.Bradley;Chem.Soc.Rev.,2009,38,606-631。
根据本发明使用的螯合剂中的许多(尤其如DOTA)具有一个或多个羧基或酰胺基。对应地,这些螯合剂借助于现有技术中已知的酰胺耦联策略以简单的方式与连接基L1、L2共轭化。图示6和7示出连接基-靶载体单元L1-TV1与螯合剂Chel的偶联实例,图示8-10示出L2-TV2与螯合剂Chel的偶联实例。
图示6:在加入有机碱的有机溶剂中借助于HATU和HOBt将连接基L1酰胺偶联到螯合剂Chel。
图示7:在pH值为9的情况下在水性缓冲液中借助于方酸乙酯在连接基L1与螯合剂Chel之间形成酰胺键。
图示8:在加入有机碱的有机溶剂中借助于HATU和HOBt将连接基L2酰胺偶联到螯合剂Chel。
图示9:在水性、略碱性溶液中螯合剂Chel的NHS偶联。
图示10:在水性、略碱性溶液中螯合剂Chel的NCS偶联。
用于带有放射性同位素的标记物的螯合剂Chel
螯合剂Chel被设置为用于以选自包括以下项的组的放射性同位素来标记根据本发明的标记前体:44Sc,47Sc,55Co,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,89Zr,86Y,90Y,89Zr,90Nb,99mTc,111In,135Sm,140Pr,159Gd,149Tb,160Tb,161Tb,165Er,166Dy,166Ho,175Yb,177Lu,186Re,188Re,211At,212Pb,213Bi,225Ac和232Th。在现有技术中已知许多用于络合上述放射性同位素的螯合剂。在图示11中展示了根据本发明使用的螯合剂的例子。
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DTPA的稳定化的衍生物
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图示11:根据本发明使用的螯合剂
根据本发明优选的是很好地适合于络合68Ga还有177Lu的螯合剂DOTA。尤其还使用螯合剂H2pypa来络合177Lu。H2pypa的合成在图示12中示出。
(i)DCC,叔丁醇,DCM,RT,12小时,50%;(ii)NaBH4,干燥MeOH,RT,3-4小时,72%;(iii)SeO2,1,4-二噁烷,100℃,12小时,56%;(iv)1.干燥MeOH,RT,1小时;2.NaBH3CN,干燥MeOH,3小时,70%;(v)NaBH4,干燥MeOH,RT,12小时,92%;(vi)PBr3,干燥CHCl3/ACN,60℃,18小时,70%;(vii)K2CO3,干燥ACN,60℃,24小时,70%;(viii)TFA/DCM,RT,12小时,70%。
图示12:用于络合177Lu的螯合剂H4pypa的合成。
放射性同位素
尤其将放射性同位素68Ga或177Lu用于核医学治疗诊断(诊断和治疗)。
本发明还提出使用选自包括以下项的组的放射性同位素:44Sc,47Sc,55Co,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,89Zr,86Y,90Y,89Zr,90Nb,99mTc,111In,135Sm,159Gd,149Tb,160Tb,161Tb,165Er,166Dy,166Ho,175Yb,177Lu,186Re,188Re,211At,212Pb,213Bi,225Ac和232Th。
下面对本发明标记前体的结构式进行详述:
图示13:Pam.SA.DOTAGA.KuE-617
图示14:Pam.SA.DOTAGA.SA.KuE
图示15:Zol.DOTAGA.KuE-617
图示16:Zol.DOTAGA.SA.KuE
图示17:DOTA.L-Lys(SA.Pam)KuE-617
图示18:DOTA.Glu(Zol)KuE-617
图示19:Zol.DOTAGA.I&T
图示20:PAM.SA.DOTAGA.I&T
图示21:Zol.NCS.DOTAGA.KuE-617
图示22:Zol.NCS.DOTAGA.I&T
实施例1:方酸作为用于双膦酸盐的亲和性促进剂
发明人已经出人意料地发现,方酸作为双膦酸盐靶载体的组成成分提高了对骨组织中羟基磷灰石的亲和性。这种有利的效果通过螯合剂NODAGA与方酸-帕米膦酸盐(NODAGA.QS.Pam)和NODAGA与唑来膦酸盐(NODAGA.Zol)的共轭物的吸附热(Adsorptionsthermen)而表现出来。为此,根据Langmuir和Freundlich的方法来确定吸附热。
为了对比,图示23和24示出螯合剂NODAGA与方酸-帕米膦酸盐(NODAGA.QS.Pam)和NODAGA与唑来膦酸盐(NODAGA.Zol)的共轭物以及根据Langmuir和Freundlich方法测量的相应的吸附系数KLF。
KLF=34.8±15.9ml/μmol
图示23:NODAGA.QS.Pam
KLF=11.9±13.3ml/μmol
图示24:NODAGA.Zol
共轭物NODAGA.QS.Pam的吸附系数KLF约为NODAGA.Zol(其包含咪唑残基而非方酸基)的吸附系数的三倍。由此可以直接看出,方酸明显提高了双膦酸盐基团对骨组织的亲和性。
另外,用放射性示踪剂[68Ga]Ga-NODAGA.QS.Pam(参见图2)对年轻健康的大鼠体内PET(正电子发射断层成像法)研究显示出在骨骺中的高度富集,其特征在于在年轻动物中——类似于骨转移瘤——骨组织的快速更新和重构。
与对于SUV骨骺=17.4的PET放射性标记物[68Ga]Ga-DOTA.Zol公开的SUV(标准化摄取值,https://de.wikipedia.org/wiki/SUV_(Nuklearmedizin))相比,用[68Ga]NODAGA.QS.Pam可以实现显著提高的SUV骨骺=22.9(参见图3)。
另外,[68Ga]NODAGA.QS.Pam的肾沉积(%ID肾=40±4,60min p.i.)比[68Ga]Ga-DOTA.Zol(%ID肾=33±17,60min p.i.)更快。对于[68Ga]NODAGA.QS.Pam由此得到——如图3中所示——299.1的更高的骨骺-血液比,相比之下对于[68Ga]Ga-DOTA.Zol为30.3,并且对应地得到了更好的PET成像对比度(或信噪比)。
实施例2:KuE单元的合成
作为用于PSMA的靶载体,例如借助于根据等人的已知方法(LinkerModification Strategies To Control the Prostate-Specific Membrane Antigen(PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMAInhibitors;J Med Chem,2016,59(5),1761-1775)来合成PSMA抑制剂L-赖氨酸-脲-L-谷氨酸盐(KuE)(参见图示25)。在此将固相、尤其结合了聚合物树脂并且用叔丁氧基羰基(叔丁基)保护的赖氨酸与用叔丁基两次保护的谷氨酸进行反应。在通过三光气活化被保护的谷氨酸以及偶联到固相结合的赖氨酸之后,借助于TFA将L-赖氨酸-脲-L-谷氨酸盐(KuE)断开并且同时完全脱保护。随后可以借助于游离赖氨酸的半制备型HPLC以71%的产率分离产物。
图示25:PSMA抑制剂KuE的固相合成;(a)DIPEA,三光气,DCM 0℃,4小时;(b)H-Lys(tBoc)-2CT-聚苯乙烯固相,DCM,RT,16小时;(c)TFA,RT,71%。
然后可以借助于作为偶联试剂的方酸二乙酯将PSMA-抑制剂KuE(1)偶联到标记前体。KuE(1)对方酸二酯的偶联在0.5M磷酸盐缓冲液中在pH 7的pH值下进行。在加入这两种反应物之后,必须用苛性钠(1M)后续调节pH值,因为磷酸盐缓冲液的缓冲能力不足。在pH 7下,酸的简单的酰胺化(图示26)在室温下以较短的反应时间快速进行。在HPLC纯化之后以16%的总产率获得了KuE-QS(2)。
图示26:KuE对方酸的偶联;(d)0.5M磷酸盐缓冲液pH 7,RT,16小时,23%。
如此获得的KuE方酸单酯是可储存的并且可以用作其他合成的构造单元。
实施例3:KuE单元和PSMA-617连接基的基于固相的合成
根据等人(Linker Modification Strategies To Control theProstate-Specific Membrane Antigen(PSMA)-Targeting and PharmacokineticProperties of DOTA-Conjugated PSMA Inhibitors;JMed Chem,2016,59(5),1761-1775)说明的固相肽合成来进行谷氨酸盐-脲-赖氨酸结合主题KuE与芳香族连接基单元的共轭化。略微更改/>等人给出的合成方式(参见图示27)。
图示27.1:KuE单元的合成以及对芳香族连接基的偶联;
(a)三光气,DIPEA,DCM;
图示27.2:KuE单元的合成以及对芳香族连接基的偶联;
(b)DMF中50%的哌啶;(c)DCM中的化合物(I);
图示27.3:KuE单元的合成以及对芳香族连接基的偶联;
(d)DCM中的四(三苯基)钯和吗啉;
(e)DMF中的Fmoc-3-(2-萘基)-L-丙氨酸、HBTU和DIPEA;
图示27.4:KuE单元的合成以及对芳香族连接基的偶联;
(f)DMF中50%的哌啶,DMF中的Fmoc-4-Amc-OH、HBTU和DIPEA;
(g)DMF中50%的哌啶。
实施例4:标记前体Pam.QS.DOTAGA.KuE-617的合成
首先合成DOTAGA子结构。产率为74%。
图示28:能够偶联的DOTAGA螯合剂的合成。
由可商购的DO2A(tBu)-GABz出发来进行合成,其在仲胺上用Boc保护的氨基官能化。
以还原方式去除DOTAGA(COOtBu)3(NHBoc)-GABz(4)的戊二酸侧链的苄基保护剂,以便能够偶联到靶载体上。
随后借助于酰胺偶联使PSMA-617连接基偶联到螯合剂(5)。
图示29:螯合剂(5)对连接基PSMA-617.KuE单元的偶联。
螯合剂(5)对KuE结合的连接基的偶联在图示29中描述。通过酰胺偶联获得的被保护的PSMA-617衍生物(6)借助于三氟乙酸(TFA)被脱保护并且被固相溶解。在HPLC纯化后,两步合成的总产率为6%。
在最后一步中合成帕米膦酸盐-方酸单元并将其偶联至化合物(7)(图示30)。从β-丙氨酸出发,首先制备帕米膦酸盐(8)并且在pH为7的水性磷酸盐缓冲液中偶联到方酸二酯。帕米膦酸盐-方酸基团(9)与DOTAGA.KuE-617(7)的共轭化在pH为9的水性磷酸盐缓冲液中进行(参见图示30)。在HPLC纯化之后,以49%的产率获得了根据本发明的标记前体Pam.QS.DOTAGA.KuE-617(10)。
图示30:Pam.QS.DOTAGA.KuE-617的合成
实施例5:标记前体DOTA.L-Lys(SA.Pam)KuE-617的合成
图示17中所示的标记前体DOTA.L-Lys(SA.Pam)KuE-617的合成在图示31中示出。首先以如图示27所示的相同方式合成被结合到固相上的第一靶载体KuE以及与之共轭的芳香族连接基(图示31中的结构(11))。然后将邻位受保护的赖氨酸作为桥接单元X共轭到连接基。在Fmoc脱保护之后(结构(12))用DOTA-三(叔丁酯)进行偶联,其中分别使用HATU作为形成酰胺的试剂并且获得根据结构式(13)的化合物。接下来将化合物(13)在TFA/DCM中完全脱保护并且与固相解除偶联,以获得化合物(14)。最后使由帕米膦酸盐和方酸组成的第二靶载体(9)与化合物(14)共轭化。第二靶载体以与图示30中相同的方式预先合成。
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图示31:DOTA.L-Lys(SA.Pam)KuE-617的合成
实施例6:化合物NH2.DOTAGA.KuE-617、NH2.DOTAGA.QS.KuE和Pam.SA.DOTAGA.KuE-
617的体内研究
借助于基于细胞的分析,利用化合物NH2.DOTAGA.KUE-617和NH2.DOTAGA.QS.KuE(图示32中的结构式(8)和(10))研究了KuE靶载体与亲脂连接基——类似于PSMA-617——以及与方酸连接基的亲和性。
图示32:NH2.DOTAGA.KuE-617(7)和NH2.DOTAGA.QS.KuE(16)
为了进行分析,用滴管将LNCaP细胞滴入多孔板(Merck MilliporeMultiscreenTM)中。待分析的化合物以逐渐升高的浓度分别与具有已知Kd值的经限定的量或浓度的参比化合物68Ga[Ga]PSMA-10混合并且在孔中与LNCaP细胞一起培养45分钟时间。在多次清洗之后确定了细胞结合的亲和性。通过所获得的抑制曲线计算了表1中展示的IC50值和Ki值。
表1:IC50值
化合物 | IC50值(nM) |
PSMA-617 | 15.1±3.8 |
PSMA-11 | 26.1±1.2 |
NH2.DOTAGA.KuE-617 | 20.6±3.4 |
NH2.DOTAGA.Qs.KuE | 20.2±3.5 |
Pam.SA.DOTAGA.KuE-617 | 49.8±10 |
为了确定非特异性结合,还将所有化合物与过量的PSMA抑制剂2-PMPA(2-(磷酰基甲基)-戊二酸)混合并且经受与上文所述的相同的LNCaP分析。
含方酸化合物NH2.DOTAGA.QS.KuE(16)和NH2.DOTAGA.KuE-617(7)的亲和性实际上是大小相同的并且大致对应于成熟的化合物PSMA-617和PSMA-11的亲和性。
图4展示了QS.KuE基团与PSMA结合袋的相互作用。与其他化合物相比,用于合成含方酸化合物NH2.DOTAGA.QS.KuE(10)的耗费显著更低。使用方酸作为靶载体KuE与螯合剂之间的连接基还开创了简单地定量合成具有两个彼此不同的靶载体——在当前情况下为KuE和双膦酸盐——的复杂标记前体的可能性。
另外,确定了最终的标记前体Pam.SA.DOTAGA.KuE-617(10)的PSMA亲和性。IC50值为49.8±10nM。
实施例7:[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617的放射化学分析
在95℃的温度下在1mL的乙酸铵缓冲水溶液中(1M,pH 5.5)中用177Lu对标记前体DOTA.L-Lys(SA.Pam)KuE-617(见图示17以及图示31中的结构式(15))进行标记。图5中展示了作为包含于乙酸铵缓冲溶液中的标记前体量(5,10和30nmol)的函数的放射化学产率(RCY)。对于≥10nmol的标记前体量实现了在5分钟之后≥90%的放射化学产率(RCY)值。与之相对,在5nmol标记前体量下,5分钟之后的产率仅为75%并且在继续进行之后实现了85%的平台值。借助于放射薄层色谱法(radio-TLC)和放射高压液相色谱法(radio-HPLC)来确定放射化学产率和纯度。对于放射性示踪剂[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617,放射薄层色谱法提供了0.0的Rf值。相对于此,对于作为流动相的柠檬酸盐缓冲液中未结合的[177Lu]Lu3+产生了0.8至1.0的Rf值。在分析型放射高压液相色谱法中,对于放射性示踪剂测得9.8分钟的保留时间tR。
在图6中展示了关于放射性示踪剂[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617在磷酸盐缓冲盐溶液(PBS)、等渗食盐溶液(NaCl)和人类血清(HS)中的稳定性的测量值。在PBS和等渗食盐溶液(NaCl)中即使在14天之后,≥98%的放射性示踪剂[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617以经络合的形式存在。在人类血清(HS)中,在9天之后稳定性略低,为93%,其中在14天之后稳定性仍为93%。
通过确定化合物在正辛醇和PBS混合物中的分配平衡来确定[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617的亲脂性。表2中展示了[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617和[117Lu]Lu-PSMA-617的LogD7,4系数的测量值。结果显示,[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617实际上具有与PSMA-617相同的亲脂性。
表2:放射性示踪剂亲脂性
实施例8:对羟基磷灰石(HAP)的亲和性
含钙的晶体羟基磷灰石是哺乳动物骨骼的重要组成成分并且适合作为体外研究健康骨组织以及骨转移瘤中双膦酸盐富集的模型底物。图7示出在普通的HAP以及用帕米膦酸盐预处理或封阻的HAP上[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617、[117Lu]Lu-PSMA-617和[117Lu]Lu3+的富集度的测量值,其中游离的[117Lu]Lu3+已知具有对HAP的高亲和性并且用作参比。结合到HAP上的放射性示踪剂[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617的比例为98.2%并且略微低于对于游离[117Lu]Lu3+测量的99.9%的值。与之相比,对于[117Lu]Lu-PSMA-617仅仅得到了1.2%的在HAP上富集的比例。为了确定选择性,还测量在先前用过量帕米膦酸盐处理的HAP上的富集度。在此对于[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617获得了7.3%的值并且对于被证明对于HAP具有高选择性的游离[117Lu]Lu3+获得了4.9%的值。
实施例9:对PSMA的体外亲和性
借助于对比用放射性配体分析,对于放射性示踪剂或标记前体DOTA.L-Lys(SA.Pam)KuE-617和参比结构来确定对PSMA的结合亲和性。抑制常数Ki的对应测量值在表3中展示。[natLu]Lu-DOTA.L-Lys(SA.Pam)KuE-617的Ki值大致对应于标记前体DOTA.L-Lys(SA.Pam)KuE-617的值。由此可以看出,用镥络合不会不利地影响对PSMA的结合亲和性。然而,与DOTA.L-Lys.KuE-617——对应于图示31中的结构式(14)相比,[natLu]DOTA.L-Lys(SA.Pam)KuE-617的Ki值大约2倍。由此可以看出,方酸-帕米膦酸盐基团降低了对PSMA的亲和性。
表3:对PSMA的亲和性
实施例10:离体研究
对于放射性示踪剂[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617,用诱导的LNCaP肿瘤研究了Balb/c小鼠中的器官富集度。结果展现在图8中。放射性示踪剂[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617在肿瘤和股骨中的富集度相当,分别具有4.2±0.7%ID/g和3.4±0.4%ID/g的值。与肿瘤相反,骨骼中的富集无法通过配给PSMA抑制剂PMPA(2-(磷酰基甲基)-戊烷二酸)来阻碍。由此可以看出,骨骼中的吸收不是通过PSMA造成的,因为没有进行PSMA的表达。以17±2%ID/g的值,肾显示出较高的[117Lu]Lu-DOTA.L-Lys(SA.Pam)KuE-617富集度,这同样可以通过PMPA的给药而大幅度降低。相比之下,在肝脏和脾脏中的富集不是PSMA特异的。在肿瘤和血液中的富集度之比具有210或170的异常高的值并且指示较少的血液学副作用。
方法和材料
概述
所有化学品购自Sigma-Aldrich、Merck、Fluka、AlfaAesar、VWR、AcrosOrganics、TCI、Iris Biotech或Fisher Scientific并且在没有额外纯化的情况下使用。干燥的溶剂购自Merck和VWR,用于氘的NMR谱的氘化溶剂。PSMA-617由Hycultec出售。Merck的用硅胶60F254涂覆的铝板来进行薄层色谱法。通过λ=254nm下的荧光消光法以及用高锰酸钾染色来进行分析。用Raytest的CR-35Bio Test Imager和软件AIDA(Raytest)来分析放射性TLC。在Bruker的Bruker Avance III HD 300光谱仪(300MHz,具有z梯度的5mm BBFO样品头以及ATM和BACS 60样品切换器)、Bruker Avance II 400光谱仪(400MHz,具有z梯度的5mm BBFO样品头,ATM和SampleXPress 60样品切换器)以及Avance III 600光谱仪(600MHz,具有z梯度的5mm TCI CryoProbe样品头以及ATM和SampleXPress Lite 16样品切换器)上进行1H和13C-NMR测量。在Agilent Technologies 1220Infinity LC系统上进行LC/MS测量,将其与Agilent Technologies 6130B Single Quadrupole LC/MS系统耦合。在Hitachi LaChrom的系列7000以及分别提及的条件和柱上进行半制备型HPLC纯化。对于放射性标记实验,使用由ITM Garching提供的0.04M HCl中的[177Lu]LuCl3。
有机合成
PSMA配体的固相合成(聚苯乙烯树脂上的KuE-617)
依照根据等人(/>M.;/>M.;Bauder-Wüst,U.;Afshar-Oromieh,A.;Kratochwil,C.;Mier,W.;Haberkorn,U.;Kopka,K.;Eder,M.Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor withOptimized Linker Moiety for Imaging and Endoradiotherapy of ProstateCancer.J.Nucl.Med.2015,56(6),914-920;/>M.;Bauder-Wüst,U.;/>M.;Klika,K.D.;Mier,W.;Haberkorn,U.;Kopka,K.;Eder,M.Linker ModificationStrategies to Control the Prostate-Specific Membrane Antigen(PSMA)-Targetingand Pharmacokinetic Properties of DOTA-Conjugated PSMAInhibitors.J.Med.Chem.2016,59(5),1761-1775.)说明且略微适配的方法的成熟的固相肽化学来制备谷氨酸盐-脲-赖氨酸结合主题KuE和KuE-617配体的连接基。将双(叔丁基)-L-谷氨酸盐-氯化氢(4.5g,15.21mmol)和DIPEA(7.98g,10.5ml,61.74mmol)溶解在干燥的二氯甲烷(200ml)中并且冷却到0℃。将二氯甲烷中(30ml)的三光气(1.56g,5.26mmol)在4.5小时的时间段内逐滴加入。在完全加入之后将溶液再搅拌一小时。去除Fmoc-L-赖氨酸(Alloc)-Wang树脂(1.65g,1.5mMol,0.9mMol/g)的Fmoc保护基团,其方式为将其在哌啶/DMF溶液(1:1)中搅拌15分钟,随后是用二氯甲烷的清洗步骤。将脱保护的L-赖氨酸(Alloc)-Wang树脂加入先前制备的溶液并且在室温下搅拌过夜。用二氯甲烷(15ml)清洗树脂并且在没有进一步纯化的情况下使用。
将四(三苯基膦)钯(516mg,0.45mmol)和吗啉(3.92g,3.92mL,45mmol)溶解在二氯甲烷(12mL)中并加入。将溶液在遮光情况下搅拌24小时。然后用二氯甲烷(15ml)、DMF中1%的DIPEA溶液(3x 13ml)和DMF中二乙基二硫代氨基甲酸钠三水合物(15mg/ml)溶液(9x10.5ml x 5分钟)清洗,以获得树脂结合的且Alloc脱保护的谷氨酸盐-脲-赖氨酸共轭物。将Fmoc-3-(2-萘基)-L-丙氨酸(1.75g,4.00mmol)、HATU(1.52g,4.00mmol)、HOBt(540mg,4mmol)和DIPEA(780mg,1.02ml,6.03mmol)溶解在干燥DMF(10ml)中并且加入树脂中。将溶液搅拌过夜并且随后用DMF(10ml)和二氯甲烷(10ml)清洗。为了去除Fmoc基团,将树脂在哌啶/DMF溶液(1:1,3x 11ml)分别搅拌10分钟并且用DMF(10ml)和二氯甲烷(10ml)清洗。将Fmoc-4-Amc-OH(1.52g,4mmol)、HATU(1.52g,4mmol)、HOBt(540mg,4mmol)和DIPEA(780mg,1.02ml,6.03mmol)在干燥DMF(10ml)中加入树脂中。将溶液搅拌两天并且然后用DMF(10ml)和二氯甲烷(10ml)清洗。为了去除Fmoc基团,将反应溶液分别在哌啶/DMF溶液(1:1,11ml)搅拌10分钟时间并且用DMF(10ml)和二氯甲烷(10ml)清洗,以获得树脂结合的KuE-617配体。
帕米膦酸盐合成
将β-丙氨酸(1.5g,0.017Mol)和磷酸(2.76g,0.034Mol)溶解在环丁砜(5.5ml)中并且冷却到0℃。逐滴加入三氯化磷(4.62g,2.95ml,0.034mmol)。将溶液在75℃下搅拌3小时。加入水(15ml)并且在100℃下搅拌12小时。最后加入乙醇(15ml)并且在0℃结晶3天之后作为黄色固体获得帕米膦酸盐(1.48g,0.006mol,37%)。
1H-NMR(300MHz,D2O):δ[ppm]=3.34(t,J=7.1Hz,2H),2.31(tt,J=13.7,7.1Hz,2H)。
13C-NMR(400MHz,D2O):δ[ppm]=72.58;36.14;30.54。
31P-NMR(121.5MHz,D2O):δ[ppm]=17.58(s,2P)。
MS(ESI+):236.0[M+H]+,对于C3H11NO7P2计算的:235.07[M]+。
帕米膦酸盐-方酸乙酯的合成
帕米膦酸盐(500mg,2.13mmol)溶解在磷酸盐缓冲液(0.5M,pH 7,5ml)中。加入3,4-二乙氧基环丁-3-烯-1,2-二酮(方酸二乙酯,SADE,542mg,468μl,3.2mmol)并且将混合物在室温下搅拌2天。为了结晶,加入乙醇(3ml)。将混合物在冰柜中静置3天,以完成结晶。用冷乙醇清洗白色沉淀并且作为白色固体获得帕米膦酸盐-方酸乙酯产物(0.58g,1.62mol,76%)。
1H-NMR(400MHz,D2O):δ[ppm]=4.79-4.62(m,2H),3.31(t,J=6.6Hz,2H),2.32-2.15(m,2H)1.42(dt,J=11.7,7.2Hz,3H)。
31P-NMR(162MHz,D2O):δ[ppm]=17.92(s),2.26(s)。
MS(ESI+):360.0[M+H]+,720.0 2[M+H]+,763.0 2[M+Na]+,对于C9H15NO10P2计算的:359.16[M]+。
Fmoc-L-Lys(Boc)-KuE-617树脂
将Fmoc-L-丙氨酸(Boc)-OH(506mg,0.0011mmol)、HATU(415mg,0.0011mmol)、HOBt(146mg,0.0011mmol)和DIPEA(277μl,211mg,0.00162mmol)溶解在乙腈(4ml)中并且搅拌30分钟。加入KuE-617树脂(300mg,0.0027mmol,0.09mmol/g)并且在室温下将混合物搅拌一天。将树脂与乙腈(10ml)和二氯甲烷(10ml)混合物并且预先放置用于后续的合成步骤。
L-Lys(Boc)-KuE-617树脂
将Fmoc-L-Lys(Boc)-KuE-617树脂在由DMF和哌啶形成的混合物(1:1,6ml)中搅拌一小时时间。将由Fmoc脱保护的树脂用DMF(10ml)和二氯甲烷(10ml)清洗并且在没有另外的纯化的情况下用在下一个步骤中。
DOTA(tBu)3-L-Lys(Boc)-KuE-617树脂
将DOTA-三(叔丁酯)(310mg,0.54μmol)、HATU(308mg,0.00081mmol)、HOBt(110mg,0.00081mmol)和DIPEA(184μl,140mg,0.0011mmol)溶解在乙腈(4ml)中并且搅拌30分钟。加入L-Lys(Boc)-KuE-617树脂(461mg,0.00027mMol,0.9mMol/g)并且在室温下将混合物搅拌一天。将树脂用乙腈(10ml)和二氯甲烷(10ml)清洗并且在没有另外的纯化的情况下用在下一个步骤中。
DOTA-L-Lys-KuE-617
将DOTA(tBu)3-L-Lys(Boc)-KuE-617树脂(536mg,0.00027mmol,0.9mmol/g)在由TFA和二氯甲烷形成的溶液(1:1,4ml)中搅拌2小时时间。在减压下将TFA/二氯甲烷溶液蒸发浓缩并且在半制备HPLC纯化之后作为无色粉末获得产物(10.6mg,0.0091mmol,4%)(柱:LiChrospher 100RP18 EC(250x 10mm)5μ,流速:5mL/min,H2O/MeCN+0.1%TFA,25%MeCN等浓度,tR=10.3分钟)。
MS(ESI+):1172.5[M+2H]+,585.9 1/2[M+2H]+,391.0 1/3[M+2H]+,对于C55H83N11O17计算的:1170.33[M]+。
DOTA-L-Lys(SA.Pam)-KuE-617
将来自图示31(10mg,0.0085mmol)的化合物(14)和帕米膦酸盐-方酸乙酯(16mg,0.043mmol)溶解在磷酸盐缓冲液(0.5M,pH 9,1ml)中并且搅拌2天。在半制备HPLC纯化之后作为无色粉末获得产物DOTA-L-Lys(SA.Pam)-KuE-617(10.56mg,0.0071mmol,84%)(柱:LiChrospher 100RP18 EC(250x 10mm)5μ,流速:5mL/min,H2O/MeCN+0.1%TFA,20分钟内23%至28%MeCN,tR=8.2分钟)。
MS(ESI+):511.3 1/3[M+H+2Na]+,520.0[1/3M+2K]+,781.01/2[M+2K]+,对于C62H92N12O26P2计算的:1483.42[M]+。
带有镥-177的DOTA-L-Lys(SA.Pam)-KuE-617放射性标记物
为了进行放射性标记,使用0.04M HCl中的[177Lu]LuCl3(德国Garching,ITG)。在1ml 1M乙酸铵缓冲液中在pH 5.5下进行放射性标记。用不同的前驱体量(5、10和30nmol)并且在95℃用40-50MBq n.c.a.镥-177来进行反应。为了控制反应,采用放射性薄层色谱法(Merck的TLC硅胶60F254)以及作为流动性的柠檬酸盐缓冲液(pH 4)以及在使用分析仪器HPLC 7000Hitachi LaChrom的情况下的高压液相色谱(柱:MerckRP-18e,10分钟内5-95%MeCN(+0.1%TFA)/95-5%Wasser(+0.1%TFA))。用Elysia-Raytest(德国Straubenhardt)的TLC Imager CR-35Bio Test-Imager以AIDA软件来测量并分析放射性薄层色谱法样品。
体外稳定性研究
在人类血清(HS,人类男性AB血浆,来自美国,Sigma-Aldrich)和磷酸盐缓冲的食盐溶液中用177Lu标记的化合物的稳定性研究。在0.5ml的介质中将5MBq的放射性化合物培养14天。在不同的时间点(1小时,2小时,5小时,1天,2天,5天,7天,9天和14天)取出等分试样,以便确定放射化学稳定性。每个测试进行三次。
亲脂性的测定
通过正辛醇和PBS中的分配系数来确定相应化合物的LogD7.4值。将标记物溶液设置为pH 7.4,并且将5MBq稀释成700μl正辛醇和700μl PBS。在1500转/分钟下振动2分钟时间并且随后离心。将400μl的正辛醇相和400μl的PBS相分别转移到新的Eppendorf小管中。将3-6μl用滴管滴加到TLC板上并且借助于磷成像器分析。按照两个相的活性比来计算LogD7.4值。另外,用更高活性的样品将对每一个相的测量再重复两次,从而可以获得三个LogD7.4值并且可以计算平均值。
177Lu标记的化合物的羟基磷灰石亲和性的测量
在食盐溶液(1ml)中将羟基磷灰石(20mg)培养24小时。加入50μl的放射性示踪剂[177Lu]Lu-DOTA-L-Lys(SA.Pam)-KuE-617(5MBq)或[177Lu]Lu-PSMA-617(5MBq)。用涡流混合器将每种悬浮液搅拌20秒并且在室温下培养1小时。随后将每种悬浮液引导穿过过滤器(Xtra PTFE-45/13)并且用水(500μl)清洗上清液。分别用居里计(Aktivimeter Isomed 2010MED Nuklear-Medizintechnik Dresden GmbH)测量所获得的液体和含HAP的上清液的放射性。作为被吸收在HAP上的活性的百分比来确定[177Lu]Lu-DOTA-L-Lys(SA.Pam)-KuE-617和[177Lu]Lu-PSMA-617的结合。作为参比,以类似方式测量游离Lu-177的HAP结合。以类似方式进行对被保护的羟基磷灰石的对比测量。为此在食盐溶液(1ml)中用帕米膦酸盐(100mg)培养HAP(20mg)并且分别确定[177Lu]Lu-DOTA-L-Lys(SA.Pam)-KuE-617以及游离Lu-177的活性。
PSMA结合亲和性的体外研究
通过在1M乙酸铵缓冲液中在95℃振动包含标记前体DOTA-L-Lys(SA.Pam)-KuE-617的溶液(371μl,1mg/ml,250nmol)与LuCl3(129μl,1mg/ml,375nmol,金属与标记前体之比1.5:1)2小时来制备非活性的(冷的)[natLu]Lu络合物。借助于ESI-LC/MS来监测络合物形成。
根据等人(/>M.;/>M.;Bauder-Wüst,U.;Afshar-Oromieh,A.;Kratochwil,C.;Mier,W.;Haberkorn,U.;Kopka,K.;Eder,M.PreclinicalEvaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with OptimizedLinker Moiety for Imaging and Endoradiotherapy of ProstateCancer.J.Nucl.Med.2015,56(6),914-920.)说明的竞争性放射配体分析来确定PSMA结合亲和性。为此,在RPMI 1640(Thermo Fisher Scientific)中在37℃在5%的CO2中培养用10%胎牛血清(Thermo Fisher Scientific)、100μg/ml链霉素和100单位/ml的青霉素补充的PSMA阳性的LNCaP细胞。在存在0.75nM[68Ga]Ga-PSMA-10存在的情况下,用提高浓度的包含标记前体的溶液培养LNCaP细胞45分钟。通过多个清洗步骤用以冰冷却的PBS去除游离的放射性。所获得的样品在γ-计数器(2480WIZARD2自动伽玛计数器,PerkinElmer)中进行测量。测量数据在GraphPad Prism 9中借助于非线性回归进行分析。
离体研究
所有动物实验都由莱茵兰-普法尔茨州立伦理委员会(根据§8部分1动物保护法,州立研究办公室)授权并且根据相关的联邦法律和研究院政策指南来进行(授权号23 177-07/G 21-1-022)。用5x106LNCaP细胞以200μl 1:1(v/v)Matrigel/PBS对6至8周大的男性BALB/cAnNRj(Janvier Labs)进行皮下接种。在肿瘤已经达到约100cm3的体积之后进行测量。在静脉注射0.5nmol的[177Lu]Lu-DOTA-L-Lys(SA.Pam)-KuE-617之前用2%的异氟烷麻醉带有LNCaP肿瘤的小鼠。比活性为约3MBq/nmol。通过对每个小鼠共注射1.5mmol PMPA来研究PSMA选择性。注射后(p.i.)24小时将动物杀死。收集器官并称重。测量放射性并且作为每克组织质量的注射剂量的经衰减修正的百分比%ID/g来计算。/>
Claims (9)
1.用于络合放射性同位素的标记前体,所述标记前体具有以下结构:
TV1-L1-Chel-L2-TV2
或者
其中X=CH或N
其中
-第一靶载体TV1选自包括以下项的PSMA抑制剂的组:
-第二靶载体TV2选自包括以下项的双膦酸根的组:
-第一连接基L1具有选自以下的结构:
G;
以及
其中G为
或者/>;
O1、O2和O3彼此独立地选自包括以下项的组:酰胺残基、羧酸酰胺残基、次膦酸酯残基、烷基残基、三唑残基、硫脲残基、亚乙基残基、马来酰亚胺残基、-(CH2)-、-(CH2CH2O)-、-CH2-CH(COOH)-NH-和-(CH2)qNH-其中q=1、2、3、4、5、6、7、8、9或10;
p1、p2和p3彼此独立地选自量{0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20};
-第二连接基L2具有选自以下的结构:
以及
其中R1、R2和R3彼此独立地选自包括以下项的组:酰胺残基、羧酸酰胺残基、次膦酸酯残基、烷基残基、三唑残基、硫脲残基、亚乙基残基、马来酰亚胺残基、呋喃残基、唑残基、噁唑残基、噻吩残基、噻唑残基、吖嗪残基、噻嗪残基、萘残基、喹啉残基、吡咯残基、咪唑残基、吡唑残基、四唑残基、噻二唑残基、噁二唑残基、吡啶残基、嘧啶残基、三嗪残基、四嗪残基、噻嗪残基、噁嗪残基、萘残基、色烯残基或硫代色烯残基、-(CH2)-、-(CH2CH2O)-、-CH2-CH(COOH)-NH-和-(CH2)qNH-其中q=1、2、3、4、5、6、7、8、9或10;
s1、s2和s3彼此独立地选自量{0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20};
-第三连接基L3具有选自以下的结构:
以及
其中
T1、T2和T3彼此独立地选自包括以下项的组:酰胺残基、羧酸酰胺残基、次膦酸酯残基、烷基残基、三唑残基、硫脲残基、亚乙基残基、马来酰亚胺残基、-(CH2)-、-(CH2CH2O)-、-CH2-CH(COOH)-NH-和-(CH2)VNH-其中v=1、2、3、4、5、6、7、8、9或10;
u1、u2和u3彼此独立地选自量{0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20};
-QS为方酸残基
;
以及
-选自包括以下项的组的螯合剂Chel:H4pypa,EDTA(乙二胺四乙酸盐),EDTMP(二亚乙基三胺五(亚甲基膦酸)),DTPA(二亚乙基三胺五乙酸盐)及其衍生物,DOTA(十二碳-1,4,7,10-四胺-四乙酸盐),DOTAGA(2-(1,4,7,10-四氮杂环十二烷-4,7,10)-戊烷二酸)以及其他的DOTA衍生物,TRITA(十三碳-l,4,7,10-四胺-四乙酸盐),TETA(十四碳-l,4,8,11-四胺-四乙酸盐)及其衍生物,NOTA(壬-1,4,7-三胺-三乙酸盐)及其衍生物例如NOTAGA(l,4,7-三氮杂环壬烷,1-戊二酸,4,7-乙酸盐),TRAP(三氮杂环壬烷次膦酸),NOPO(1,4,7-三氮杂环壬烷-1,4-双[亚甲基(羟甲基)次膦酸]-7-[亚甲基(2-羧乙基)次膦酸]),PEPA(十五碳-1,4,7,10,13-五胺五乙酸盐),HEHA(十六碳-1,4,7,10,13,16-六胺-六乙酸盐)及其衍生物,HBED(羟苄基-亚乙基-二胺)及其衍生物,DEDPA及其衍生物如H2DEDPA(l,2-[[6-(羧酸酯)吡啶-2-基]甲基胺]乙烷),DFO(去铁胺)及其衍生物,三羟基吡啶酮(THP)及其衍生物如YM103,TEAP(四氮杂环癸烷次膦酸)及其衍生物,AAZTA(6-氨基-6-甲基全氢-l,4-二氮杂-N,N,N',N'-四乙酸盐)以及衍生物如DATA((6-戊烷酸)-6-(氨基)甲基-1,4-二氮杂/>四乙酸盐);SarAr(1-N-(4-氨基苄基)-3,6,10,13,16,19-六氮杂二环[6.6.6]-二十烷-1,8-二胺)及其盐,(NH2)2SAR(1,8-二氨基-3,6,10,13,16,19-六氮杂二环[6.6.6]二十烷)及其盐和衍生物,氨基硫醇及其衍生物。
2.根据权利要求1所述的标记前体,其特征在于,所述螯合剂Chel为DOTA、H4pypa、DATA或DOTAGA。
3.根据权利要求1或2所述的标记前体,其特征在于,所述第二连接基L2包括至少一个选自以下项的残基:
4.根据权利要求3所述的标记前体,其特征在于,所述第二连接基L2包括至少一个方酸残基
5.根据权利要求3所述的标记前体,其特征在于,所述第二连接基L2包括至少一个选自以下项的残基:
6.根据权利要求1至5中一项或多项所述的标记前体,其特征在于,所述第二连接基L2包括至少一个咪唑残基
7.根据权利要求1至6中一项或多项所述的标记前体,其特征在于,所述连接基L1、L2和L3中的两者或三者是相同的。
8.放射性示踪剂,包括根据权利要求1至7中任一项所述的标记前体以及选自包括以下项的组的放射性同位素:44Sc,47Sc,55Co,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,89Zr,86Y,90Y,89Zr,90Nb,99mTc,111In,135Sm,140Pr,159Gd,149Tb,160Tb,161Tb,165Er,166Dy,166Ho,175Yb,177Lu,186Re,188Re,211At,212Pb,213Bi,225Ac和232Th。
9.根据权利要求8所述的放射性示踪剂,其特征在于,所述放射性同位素为68Ga、177Lu或225Ac。
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