CN117545513A - 用于神经内分泌治疗诊断的前体和放射性示踪剂 - Google Patents
用于神经内分泌治疗诊断的前体和放射性示踪剂 Download PDFInfo
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Abstract
命名为DAZTA5‑PPA2的新型前体,用于具有放射性同位素68Ga和177Lu的SSR活动性病变的PET/CT诊断和核治疗,提供了改善的亲和力、特异性和小转移瘤的成像。
Description
发明内容
本发明涉及被命名为DAZTA5-PPA2的前体或其盐,其用于放射性标记和靶向生长抑素受体2(SSR2),生长抑素受体2包括螯合剂DAZTA5及与其缀合的肽配体PPA2,其中
DAZTA5=
1,4-双(羧甲基)-6-[甲基-羧甲基-氨基]-6-[戊酸]-1,4-二氮杂环己烷
或
1,4-双(羧甲基)-6-[双(羧甲基)-氨基]-6-[戊酸]-1,4-二氮杂环己烷;
和
PPA2=Cpa-环[DCys-Pal-DAph(Cbm)-Lys-Thr-Cys]DTyr-NH2其中
Cpa=4-氯-苯丙氨酸,DAph(Cbm)=D-4-氨基-氨甲酰基-苯丙氨酸和
Pal=吡啶基丙氨酸。
发明背景
神经内分泌肿瘤的核诊断
正电子发射断层扫描(PET)与使用镓-68(Ga-68或68Ga)的计算机断层扫描(CT)相结合,现已成为临床上公认的核诊断技术。美国食品和药物管理局以及欧洲药品管理局已批准68Ga标记的1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(68Ga-DOTA-奥曲肽或68Ga-DOTA-TATE)和68Ga-DOTA-d-Phe(1)-Tyr(3)-奥曲肽(68Ga-DOTA-TOC)用于定位成人和儿童患者(美国)和有高分化胃肠胰神经内分泌肿瘤(GEP-NET)指征的成年患者(欧盟)的生长抑素受体(SSR)阳性的神经内分泌肿瘤(NET)。DOTA-TOC和DOTA-TATE由DOTA-螯合剂与8种氨基酸环肽缀合而成,这些肽对生长抑素受体2(SSR2)具有高亲和力,它们充当生长抑素受体2(SSR2)的激动剂。
PET/CT的诊断价值取决于灵敏度、特异性和准确性。灵敏度衡量被正确识别的阳性的比例(真阳性除以真阳性和假阴性之和)。特异性衡量被正确识别的阴性的比例(真阴性除以真阴性和假阳性之和)。诊断准确性与测试区分目标条件和健康状况的能力有关。这种区分能力可以通过测量灵敏度与特异性、靶本底比值或对象操作特征曲线(ROC曲线)下面积来定量。
通过增加PET示踪剂对目标SSR的亲和力或通过扩大结合谱以涵盖SSR3和SSR5以及SSR2,可以潜在地增强SSR成像灵敏度。后者的方法可以在SSR阳性靶组织中产生更高的示踪剂摄取,但也可以增加脱靶摄取,从而导致肿瘤背景比值降低和较差的图像对比度。
现有技术还报道了用于PET/CT的生长抑素受体配体,其产生改进的诊断准确性和其他优点,其中包括SSR激动剂如对SSR2、SSR3和SSR5具有高亲和力的DOTA-NOC(DOTA-1-Nal(3)-奥曲肽)或HA-DOTA-TATE(DOTA-碘-Tyr3-奥曲肽)。
DOTA-ST8951(DOTA-(4-氨基)-D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2)对SSR2和SSR5具有亲和力,但肝脏摄取增加会影响靶本底比值。F-18标记的SSR配体如18F-FET-βAG-TOCA被报道具有较差的成像性能。
SSR激动剂与拮抗剂
在核诊断中,SSR激动剂由SSR拮抗剂补充,SSR拮抗剂针对靶细胞上的多个结合位点。这是由于大多数SSR以非活性形式存在,因此只适应拮抗剂结合。因此,与SSR2激动剂放射性示踪剂相比,互补SSR2拮抗剂放射性示踪剂如68Ga-DOTA-JR11和68Ga-NODAGA-LM3(JR11=Cpa-环[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH2;NODAGA=1,4,7-三氮杂环壬烷,l-戊二酸-4,7-乙酸;LM3=Cpa-环[D-Cys-Tyr-D-4-氨基-Phe(氨甲酰基)-Lys-Thr-Cys]D-Tyr-NH2)在临床前和临床环境中显示出更高的摄取率,即使它们的SSR2亲和力没有明显更高。在头对头的比较中,68Ga-DOTA-JR11在检测肝转移方面优于68Ga-DOTA-TATE,但对骨转移的敏感性要低得多。这一发现强调了图像对比度对PET/CT诊断的重要性。
为了提高图像对比度,即特异性,要求PET/CT示踪剂对脱靶组织和疾病无关受体具有低亲和力。扩大与受体亚型SSR1、SSR3、SSR4和SSR5的结合谱可以增加脱靶摄取并降低特异性和图像对比度。
此外,选择适当的特定疾病所特有的或是高度过度表达的靶点对诊断结果有很大影响。例如,最常用的PET示踪剂是放射性标记的葡萄糖类似物18F-2-氟-2-脱氧-D-葡萄糖(18F-FDG),它被各种组织吸收,并且在非恶性疾病的情况下,在全身性葡萄糖消耗增加的组织中吸收。
临床批准的包括68Ga-DOTA-TATE和177Lu-DOTA-TATE的治疗双联体极大地促进了受NET困扰的患者的治疗,并集中体现了核医学对抗癌方面的益处。为NET患者提供改进的治疗工具的其他研究表明,无论是在临床前水平还是在体内,放射性标记的SSR2拮抗剂均比其激动剂相应物具有明显优势。与放射激动剂不同,SSR2放射拮抗剂不会通过胞吞作用内化到靶细胞中。然而,它们仍表现出了优越的药代动力学,结合了SSR2阳性肿瘤病变中更高和更长的保留时间,以及从健康组织中更快的清除。后者还涉及生理上表达SSR2的健康器官,如胃和胰腺。分子和细胞水平的研究表明,放射拮抗剂在靶细胞膜上占据了更大的SSR2群体,包括活性和非活性受体,而激动剂在被内化之前只与细胞膜上的活性SSR2亚群结合。
近年来,已经开发了几种类型的SSR2拮抗剂,并与各种螯合剂缀合,用于二价和三价放射性金属的络合,用于NET诊断和治疗。特别是DOTA-LM3(DOTA=1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸;LM3=H-DPhe-环[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH2;DAPH(CBM)4=D-4-氨基-氨甲酰基-苯丙氨酸,参见方案1)示出了NET诊断和分级的前景(参见R.P.Baum,J.Zhang,C.Schuchardt,D.Mueller,H.Maecke;First-in-human study ofnovel SSTR antagonist 177Lu-DOTA-LM3 for peptide receptor radionuclide therapyin patients with metastatic neuroendocrine neoplasms:dosimetry,safety andefficacy;Journal of Nuclear Medicine March 2021,jnumed.120.258889;DOI:https://doi.org/10.2967/jnumed.120.258889)。
用于络合金属放射性同位素的螯合剂
根据本领域的现有技术知识:
-螯合剂和放射性同位素对SSR放射性示踪剂的亲和力和药代动力学有很大影响;
-DOTA可以严重影响SSR配体亲和力;
-螯合剂、放射性同位素和SSR配体以协同或拮抗的方式不可预测地相互作用。
例如,螯合剂DOTA不太适合络合相对较小的(放射性)金属镓,并且需要升高的反应温度,这对许多抗体和热敏生物分子是不利的。络合后,68Ga-DOTA螯合物在静脉注射前需要冷却时间,因此由于68Ga的半衰期较短,为67.7分钟,限制了其临床使用。
EP 2801582 A1(第102、109段;表12)公开了具有结构DOTA-Cpa-环[DCys-Pal-DAph(Cbm)-Lys-Thr-Cys]DTyr-NH2的放射性标记前体,其明显用作在HEK293-SSR2肿瘤细胞中没有可定量摄取的参考实例。
DATA作为“混合型”螯合剂
最近开发的DATA型螯合剂(参见方案2)表现出环状、非环状和中间体性质,并且与已有的螯合剂相比,具有标记68Ga的有利性质。特别是,它们可以在环境温度和宽pH范围内使用68Ga进行快速定量放射性标记。此外,68Ga-DATA螯合物对反式螯合(DTPA和脱铁转铁蛋白)和反式金属化(FeIII)具有免疫力。
下面的方案2显示了本发明DAZTA5螯合剂,其具有核心二氮杂环庚烷环的分别为(1,4-双(羧甲基)-6-[甲基-羧甲基-氨基]-1,4-二氮杂环己烷和1,4-双(羧甲基)-6-[双(羧甲基)-氨基]-1,4-二氮杂环己烷)。
具体实施方式
本发明的目的是改进以生长抑素受体(SSR)表达升高为特征的疾病,特别是神经内分泌癌的核治疗诊断。
该目的是通过命名为DAZTA5-PPA2并具有以下结构的前体或其盐实现的。
其中
并且
本发明前体DAZTA5-PPA2的有利实施方案的特征在于:
本发明的另一目的是提供用于与SSR表达升高相关的疾病,特别是神经内分泌癌的核成像的放射性药物。该目的是通过放射性示踪剂68Ga-DAZTA5-PPA2实现的,该示踪剂由的前体DAZTA5-PPA2和与之络合的放射性同位素68Ga组成。
本发明的另一目的是提供用于与SSR表达升高相关的疾病,特别是神经内分泌癌的核治疗的放射性药物。这一目的是通过放射性示踪剂177Lu-DAZTA5-PPA2实现的,该示踪剂由的前体DAZTA5-PPA2和与之络合的放射性同位素177Lu组成。
本发明的其他的有利的实施方案涉及:
-放射性药物试剂盒,其包括的前体DAZTA5-PPA2或其盐;
-放射性药物试剂盒,其包括的前体DAZTA5-PPA2或其盐;
-放射性药物试剂盒,其包括的前体DAZTA5-PPA2或其盐和溶剂,溶剂选自水、0.45%的NaCl水溶液、0.9%的NaCl水溶液、林格氏液(乳酸林格氏液)、5%的葡萄糖水溶液和酒精水溶液;
-放射性药物试剂盒,其包括的前体DAZTA5-PPA2或其盐和溶剂,该溶剂选自水、0.45%的NaCl水溶液、0.9%的NaCl水溶液、林格氏液(乳酸林格氏液)、5%的葡萄糖水溶液和酒精水溶液;
-放射性药物试剂盒,其包括
-第一小瓶,其包括的前体DAZTA5-PPA2或其盐,和
-第二小瓶,其包括的前体DAZTA5-PPA2或其盐。
-放射性药物试剂盒,其包括
-第一小瓶,其包括的前体DAZTA5-PPA2或其盐,
-第二小瓶,其包括的前体DAZTA5-PPA2或其盐,
-第三小瓶,其包括选自水、0.45%的NaCl水溶液、0.9%的NaCl水溶液、林格氏液(乳酸林格氏液)、5%的葡萄糖水溶液和酒精水溶液的溶剂,和
-任选地第四小瓶,其包括选自水、0.45%的NaCl水溶液、0.9%的NaCl水溶液、林格氏液(乳酸林格氏液)、5%的葡萄糖水溶液和酒精水溶液的溶剂。
本发明提供了在使用68Ga-DOTA-TOC或68Ga-DOTA-TATE的PET/CT成像提供低标准化摄取值(SUV)或在尽管生长抑素受体阳性神经内分泌肿瘤的临床指征难以解释结果的情况下,通过68Ga-PET/CT检测生长抑素受体的表达。
可以预期X=CH3或X=CH2COOH的前体DAZTA5-PPA2与放射性同位素68Ga或44Sc络合以用于诊断用途或与177Lu、90Y或161Tb络合以用于治疗用途。指定为68Ga-DAZTA5-PPA2、44Sc-DAZTA5-PPA2、177Lu-DAZTA5-PPA2、90Y-DAZTA5-PPA2和161Tb-DAZTA5-PPA2的相应放射性示踪剂表现出卓越的的靶本底比值,即在肿瘤病变中优先摄取和在健康组织特别是肝和脾组织摄取较低。因此,本发明的放射性示踪剂为诊断和治疗与生长抑素受体表达升高相关的疾病提供了高图像对比度、灵敏度和选择性。
因此,本发明包括以下放射性示踪剂:
-68Ga-DAZTA5-PPA2(X=CH3),即68Ga-DATA5m-PPA2;
-44Sc-DAZTA5-PPA2(X=CH3),即44Sc-DATA5m-PPA2;
-68Ga-DAZTA5-PPA2(X=CH2COOH),即68Ga-AAZTA-PPA2;
-44Sc-DAZTA5-PPA2(X=CH2COOH),即44Sc-AAZTA-PPA2;
-177Lu-DAZTA5-PPA2(X=CH2COOH),即177Lu-AAZTA-PPA2;
-90Y-DAZTA5-PPA2(X=CH2COOH),即90Y-AAZTA-PPA2;
-111In-DAZTA5-PPA2(X=CH2COOH),即111In-AAZTA-PPA2;
-161Tb-DAZTA5-PPA2(X=CH2COOH),即161Tb-AAZTA-PPA2;和
-225Ac-DAZTA5-PPA2(X=CH2COOH),即225Ac-AAZTA-PPA2。
DAZTA5-PPA2可以很容易地以冻干形式提供,并与佐剂如pH缓冲剂、防止辐射分解的抗氧化自由基清除剂和冷冻干燥填充剂一起包装为使用点试剂盒。包含X=CH3或X=CH2COOH的DAZTA5-PPA2的试剂盒可用于在室温下仅需摇动试剂混合物即可加入分别含有68GaCl3、44ScCl3或177LuCl3的符合欧洲药典的盐酸溶液来制备本发明的放射性示踪剂68Ga-DAZTA5-PPA2、44Sc-DAZTA5-PPA2或177Ga-DAZTA5-PPA2。不需要带有加热室的自动化模块。
实施例
合成策略
叔丁基保护且羧化的DAZTA5-PPA2前螯合剂的合成如下文方案4和方案5所述。
方案3中所示的SSR2肽配体PPA2是使用Fmoc作为保护基结合去保护/偶联循环(方案6)的普通固相肽合成(SPPS)制备的,并通过反相色谱法纯化,然后进行HPLC和MS表征。
试剂与分析
试剂购自或/>且无需进一步纯化即可使用。/>水通过Millipore滤膜(0.54μm)过滤。反应进程使用二氧化硅TLC板(二氧化硅60F2544.5×4.5cm,Merck)和在波长254nm处的UV吸光度和/或KMnO4滴定来监测。柱色谱法使用硅胶60(Fisher/>0.04nm至0.063nm)进行。
合成的化合物的化学特性通过除DAZTA5-PPA2缀合物外的1H-、13C-NMR和HRMS证实,其通过HPLC和HRMS表征。1H-、13C-NMR和HRMS数据以S.I.单位表示。
NMR谱(1H-、13C、HSQC、HRMS)在Avance III HD 400光谱仪(Bruker,美国)上记录。化学位移以ppm给出。MS(ESI)使用Thermo Quest Navigator仪器(Thermo Electron)进行。质谱结果以m/z形式给出,单位为克/摩尔。HPLC使用配备四元泵、AS-50自动进样器、UV/Vis检测器和自动馏分收集器AFC-3000的无金属Dionex ICS-5000系统进行。
DAZTA5(X=CH3)前螯合剂合成
5-(1,4-二苄基-6-硝基-[1,4]二氮杂-6-基)-戊酸甲酯(1)
将2-硝基环己酮(0.608g,4.3毫摩尔)加入Amberlyst A21(1.216g,2质量当量)的EtOH中,并在氩气下在于60℃下搅拌2h。添加N,N'-二苄基-乙二胺(1.020g,4.3毫摩尔)和多聚甲醛(0.446g,14.9毫摩尔)并将反应混合物于60℃下搅拌过夜。将混合物通过过滤,并在减压下去除溶剂。将所得残余物重新溶解于CHCl3(40mL)中并连续用K2CO3水溶液(2×30mL,0.1M)和H2O(30mL)洗涤,经MgSO4干燥,过滤并在减压下去除溶剂。通过硅胶柱色谱法(DCM)纯化,得到黄色油状目标化合物(1.607g,85%)。Rf=0.80(DCM)。
5-(1,4-二苄基-6-硝基-[1,4]二氮杂-6-基)-戊酸甲酯(2)
将催化量的Pd(OH)2/C和乙酸(50μL,0.87毫摩尔)加入甲醇保护的三胺1(0.10g,0.29毫摩尔),并在氢气的标准大气压下搅拌该混合物3h(1atm H2)。TLC(DCM)用于确认硝基的完全还原和苄基N-取代基的裂解。使用过滤器去除Pd(OH)2/C。在减压下去除溶剂,得到黄色油状物(0.065g,97%)。
5-[1,4-双-叔丁氧基羰基甲基-6-(叔丁氧基羰基甲基-氨基)-[1,4]二氮杂-6-基]-戊酸甲酯(3)
将溴乙酸叔丁酯(0.567g,2.91毫摩尔)加入含2(0.208g,0.91毫摩尔)和K2CO3(0.377g,2.73毫摩尔)的MeCN(25mL)溶液中,并将混合物在氩标准大气压下在于368K搅拌24h。通过TLC(己烷/乙酸乙酯;1:1)监测反应是否形成四烷基化衍生物。在减压下去除溶剂,将所得油状物重新溶解于CHCl3(25mL)中并连续用K2CO3水溶液(2×25mL,0.1M)和H2O(25mL)洗涤,经MgSO4干燥,过滤并在减压下去除溶剂。通过硅胶柱色谱法(己烷/乙酸乙酯,2:1→1:1)纯化,得到黄色油状物(0.229g,44%)。Rf=0.35(己烷/乙酸乙酯;2:1)。
5-[1,4-双-叔丁氧基羰基甲基-6-(叔丁氧基羰基甲基-甲基-氨基)-[1,4]二氮杂-6-基]-戊酸甲酯(4)
将碘甲烷(0.023g,0.16毫摩尔)加入在冰浴中冷却的含3(0.104g,0.18毫摩尔)和K2CO3(0.025g,0.18毫摩尔)的DCM/MeCN(3:1)中。将反应混合物加热至室温,然后放置过夜。在减压下去除溶剂,将所得油状物重新溶解于CHCl3(20mL)中,过滤并连续用K2CO3水溶液(2×20mL,0.1M)和H2O(20mL)洗涤,经MgSO4干燥,过滤并在减压下去除溶剂。通过硅胶柱色谱法(己烷/乙酸乙酯,3:1→2:1)纯化,得到黄色油状物(0.043g,46%)。Rf=0.38(己烷/乙酸乙酯;2:1)。
5-[1,4-双-叔丁氧基羰基甲基-6-(叔丁氧基羰基甲基-甲基-氨基)-[1,4]二氮杂-6-基]-戊酸(5)
将LiOH(0.009g,0.039毫摩尔)溶解于H2O(0.5mL)中,加入4(0.010g,0.023毫摩尔)的THF(0.5mL)溶液,并于298K下搅拌。使用LC-ESIMS监测该反应的酯裂解情况。一旦完成,通过冷冻干燥去除溶剂。加入H2O(5mL)并通过冷冻干燥去除,并重复该过程两次。所得固体用冰冷的DCM(0.5mL)洗涤,并在真空中干燥以得到蜡状黄色固体(0.009g,70%)。
方案4:3tBu保护的DAZTA5(X=CH3)前螯合剂的合成(i)Amberlyst-21,EtOH;(ii)CH2O,EtOH;(iii)CH3COOH,Pd(OH)2/C,H2,EtOH;(iv)BrCH2COOtBu,K2CO3,MeCN;(v)CH3I,K2CO3,DCM:MeCN;(vi)LiOH,THF:H2O
DAZTA5(X=CH2COOH)前螯合剂合成
前螯合剂DAZTA5(X=CH2COOH),通常也称为AAZTA,可以通过Manzoni等人描述的方法制备(L.Manzoni,L.Belvisi,D.Arosio,M.P.Bartolomeo,A.Bianchi,C.Brioschi,F.Buonsanti,C.Cabella,C.Casagrande,M.Civera,M.De Matteo,L.Fugazza,L.Lattuada,F.Maisano,L.Miragoli,C.Neira,M.Pilkington-Miksa,C.Scolastico;Synthesis of Gdand 68Ga Complexes in Conjugation with a Conformationally Optimized RGDSequence as Potential MRI and PET Tumour-Imaging Probes;ChemMedChem 2012,7,1084-1093)如方案5所示。
化合物6
将N,N′-二苄基乙二胺二乙酸酯(14.67g;40.7毫摩尔)悬浮于EtOH(50mL)中并将混合物在50℃下加热直至得到澄清溶液。加入多聚甲醛(3.67g;122.1毫摩尔),并将混悬液于80℃下加热1.5h以得到深橙色澄清溶液。逐滴加入含6-硝基己酸甲酯(R.Ballini,M.Petrini,V.Polzonetti Synthesis 1992,355-357)(7.13g;40.7毫摩尔)的EtOH(10mL)溶液。将所得溶液冷却至室温,在室温下搅拌18h,然后于50℃下搅拌4.5h。蒸发混合物,将残余物溶解在EtOAc(100mL)中,并将溶液用Na2CO3水溶液和盐水洗涤。分离水相并用EtOAc(1×50mL;1×30mL)萃取。收集有机相,干燥(Na2SO4),过滤并蒸发。通过快速液相色谱法(硅胶柱,90∶10石油醚/EtOAc)纯化粗产物,得到浅黄色油状物23(10.8g;24.6毫摩尔)。(60%)。
1H-NMR(CDCl3,400MHz):δ0.80(m,2H),1.32(m,2H),1.58(m,2H),2.12(t,2H,J=7.5Hz),2.62(m,4H),2.96(d,2H,J=14.2Hz),3.52(d,2H,J=14.2Hz),3.59(d,2H,J=13Hz),3.66(s,3H),3.75(d,2H,J=13Hz),7.28(m,10H).13C-NMR(CDCl3,100.6MHz):δ174.0,139.5,129.5,128.7,127.6,95.2,64.4,62.0,59.2,51.9,36.9,33.9,25.0,23.0.MS(ESI+)m/z:(M+H+),440.5。
化合物7
将10%Pd/C(1.5g)加入含化合物23(10g;22.8毫摩尔)的MeOH(400mL)溶液中,并将混悬液在氢气标准大气压下于40℃下搅拌5h。过滤(过滤器FT 0.45μm)混悬液并蒸发溶液。将残余物溶解在MeCN(100mL)中并加入新研磨的K2CO3(16.8g;122毫摩尔)和Na2SO4(3g;21毫摩尔)。加入溴乙酸叔丁酯(20.8g;107毫摩尔),搅拌橙色混合物并在80℃下加热7h。过滤混合物,加入更多的K2CO3(16.8g;122毫摩尔)、Na2SO4(3g;21毫摩尔)和溴乙酸叔丁酯(0.88g;4.5毫摩尔),并将新混合物于80℃下加热9.5h。过滤混合物,蒸发并通过色谱法(硅胶柱,3∶2正己烷/EtOAc)纯化残余物,得到浅黄色油状物24(7.8g;11.4毫摩尔)。(50%)。
1H-NMR(CDCl3,400MHz):δ1.46(s,36H),1.62-1.48(br,6H),2.33(t,2H,J=7.5Hz),2.65(d,2H,J=14.2Hz),2.83(m,4H),3.00(d,2H,J=14.2Hz),3.24(s,4H),3.62(s,4H),3.67(s,3H).13C-NMR(CDCl3,400MHz):δ173.1,171.2,81.1,80.6,65.5,63.4,62.9,60.8,52.3,51.8,37.6,34.5,28.5,26.1,22.1.MS(ESI+)m/z:(M+H+),686.5,(M+Na+),708.5。
DAZTA5(X=CH3COOH)/AAZTA (8)
将1M LiOH溶液(95.4mL;95.4毫摩尔)滴加至冷却至0℃的含化合物24(8.17g;11.9毫摩尔)的THF(200mL)溶液中。然后将溶液在室温下搅拌28h。通过添加AcOH(4mL)将溶液的pH调节至pH为7。加入水(50mL)并蒸发THF。用EtOAc(3×75mL)萃取含水残余物。收集有机相,干燥(Na28O4),过滤并蒸发。通过快速液相色谱法(硅胶柱,3:2正己烷/EtOAc)纯化粗产物,得到浅黄色油状物4(3.76g;5.6毫摩尔)。(47%)。
1H-NMR(CDCl3,400MHz):δ1.48(s,36H),1.66-1.57(br,6H),2.38(t,2H,J=7.5Hz),2.79-2.67(br,6H),3.03(d,2H,J=14.2Hz),3.05(s,4H),3.63(s,S-44H).13C-NMR(CDCl3,100.6MHz):δ178.8,173.1,171.0,81.3,80.8,65.4,63.3,62.7,59.4,37.4,34.4,28.4,28.3,22.1.MS(ESI+)m/z:(M+H+),672.6。
PPA2肽合成
PPA2肽可以通过经典的溶液合成或优选地通过方案6中描述的和美国专利第7,019,109号和第5,874,227号中描述的已建立的固相技术来制备,其内容通过引用整体并入本文。本领域已知的侧链保护基团包括作为具有特别反应性侧链的任何氨基酸的一部分,并且可任选地用于其他氨基酸如Trp的情况,其中这样的氨基酸偶联到建立在树脂上的链上。这种合成提供了完全受保护的中间体肽树脂。保护基团通常被剥离,并且在氧化之前将肽从树脂载体上裂解,以在Cys侧链之间形成二硫键。
或者,肽PPA2可以从各种商业供应商处获得,如Peptide SpecialtyLaboratories GmbH(https://www.peptid.de/)。
PET/CT成像技术的现有技术
图1示出了使用已建立的放射性示踪剂68Ga-NODAGA-LM3(图1a)和68Ga-DOTA-TATE(图1b和图1c)对患有肝癌的患者进行的PET/CT图像。68Ga-NODAGA-LM3提供了改进的转移瘤可视化。
使用68Ga-DAZTA5-PPA2(X=CH3)的PET/CT成像分级
图2示出了使用本发明的X=CH3的放射性示踪剂68Ga-DAZTA5-PPA2(即68Ga-DATA5m-PPA2)在不同时间通过PET/CT获取的患者的五幅图像,其特点是肝转移瘤的高灵敏度可视化、鲜明的对比度以及小转移瘤和受影响的淋巴结的检测。
使用68Ga-DAZTA5-PPA2(X=CH3)对骨转移瘤进行PET/CT成像
图3示出了患有多发性骨转移瘤的患者的PET/CT图像,由于没有成骨细胞变化,因此在CT扫描中无法检测到。图3a和图3b分别示出了CT图像及其与PET图像的融合。
使用68Ga-DAZTA5-PPA2(X=CH3)对淋巴结进行PET/CT成像
图4显示了CT扫描(图4b)无法发现的直径小于6mm的源自神经内分泌癌的腹部小淋巴结转移瘤的PET/CT图像(图4a)。使用68Ga-NODAGA-LM3和68Ga-DAZTA5-PPA2(X=CH3)进行PET/CT成像
图5示出了使用X=CH3的放射性示踪剂68Ga-NODAGA-LM3和68Ga-DAZTA5-PPA2(即68Ga-DATA5m-PPA2)对患有肝癌的患者进行的PET/CT图像。68Ga-DATA5m-PPA2与来自健康肝脏和脾组织的明显降低的背景信号结合提供了更好的转移瘤可视化。
使用68Ga-DAZTA5-PPA2(X=CH3)对乳腺转移瘤进行PET/CT成像
图6示出了在磁共振成像(MRI)和CT检查时,分别使用X=CH3的68Ga-DAZTA5-PPA2(即68Ga-DATA5m-PPA2)对没有病变迹象的患者进行的常规CT和PET/CT采集的图像(a)和图像(b)的比较。与MRI和CT成像不同,使用68Ga-DAZTA5-PPA2 PET/CT能够检测直径小至2mm的转移瘤。
细胞摄取和结合
图7示出了使用细胞系HEK293-SSR2对激动剂放射性示踪剂68Ga-DATA5m-TOC与X=CH3的拮抗剂放射性示踪剂68Ga-DAZTA5-PPA2(即68Ga-DATA5m-PPA2)进行体外细胞摄取比较的结果。本发明的放射性示踪剂68Ga-DATA5m-PPA2表现出优异的总体摄取率和膜结合与细胞掺入(胞吞作用)的高比率。
68Ga-DAZTA5-PPA2(X=CH3)放射性标记动力学
在室温(RT)和95℃下,将50μg本发明的X=CH3的前螯合剂DAZTA5-PPA2(即DATA5M-PPA2)加入500μL溶解有68Ga的醋酸钠缓冲液(pH 4.5)中。在5分钟至10分钟以内获得超过95%的放射化学产率(RCY)(参照图8)。
体外稳定性
图9示出了68Ga-DAZTA5-PPA2的体外稳定性。本发明的X=CH3的放射性示踪剂DAZTA5-PPA2(即DATA5m-PPA2)于37℃下悬浮在每种人血清、磷酸盐缓冲盐水(PBS)和生理NaCl溶液中120分钟。在2h内没有检测到可测量的降解。
亲和力测定
表1描述了基于在HEK293-SST2R细胞膜上用[125I][Leu8,DTrp22,I-Tyr25]SS28([125I]I-[LTT]SS28)的置换测定的非金属化的、Ga-、In-络合的和Lu-络合的前体DATA5m-PPA2和AAZTA-PPA2的比较结合分析的相对IC50值(于22℃下1h)。图10a和图10b示出了相应的测量曲线。
化合物 | DATA5m-pPA2 | AAZTA-PPA2 |
非金属化的 | 1.24±0.20 | 1.69±0.47 |
Ga | 1.61±0.32 | n.a. |
In | n.a. | 0.45±0.05 |
Lu | n.a. | 0.55±0.37 |
表1:相对IC50值
表1数据的相应P值为:DATA5-PPA2与Ga-DATA5-PPA2和In-AAZTA-PPA2与Lu-AAZTA-PPA2的P值为P>0.05;AAZTA-PPA2与In-AAZTA-PPA2或与Lu-AAZTA-PPA2的P值为P<0.01。
离体器官分布
图11示出了[68Ga]Ga-DAZTA5-PPA2在HEK293-SST2R阳性(+)荷瘤雄性SCID小鼠中的离体器官分布。注射后1h和4h取出器官。此外,通过在注射后4h施用100μg奥曲肽(TATE)进行阻断来分析肿瘤特异性。
图12描绘了与[111In]In-DOTA-LM3相比,[111In]In-AAZTA-PPA2在HEK293-SST2R阳性(+)和阴性(-)荷瘤雄性SCID小鼠中的离体器官分布。注射后4h和24h取出器官。
Claims (11)
1.一种用于神经内分泌治疗诊断的前体DAZTA5-PPA2或其盐,其具有以下结构
其中
并且
2.根据权利要求1所述的放射性示踪剂68Ga-DAZTA5-PPA2,其由的前体DAZTA5-PPA2和与之络合的放射性同位素68Ga组成。
3.根据权利要求1所述的放射性示踪剂177Lu-DAZTA5-PPA2,其由的前体DAZTA5-PPA2和与之络合的放射性同位素177Lu组成。
4.根据权利要求1所述的放射性药物试剂盒,其包括的前体DAZTA5-PPA2或其盐。
5.根据权利要求1所述的放射性药物试剂盒,其包括的前体DAZTA5-PPA2或其盐。
6.根据权利要求4或5所述的放射性药物试剂盒,其包括溶剂,所述溶剂选自水、0.45%的NaCl水溶液、0.9%的NaCl水溶液、林格氏液(乳酸林格氏液)、5%的葡萄糖水溶液和酒精水溶液。
7.根据权利要求1所述的放射性药物试剂盒,其包括:
-第一小瓶,其包括的前体DAZTA5-PPA2或其盐,和
-第二小瓶,其包括的前体DAZTA5-PPA2或其盐。
8.根据权利要求7所述的放射性药物试剂盒,其包括一种或两种溶剂,所述溶剂彼此独立地选自水、0.45%的NaCl水溶液、0.9%的NaCl水溶液、林格氏液(乳酸林格氏液)、5%的葡萄糖水溶液和酒精水溶液。
9.根据权利要求1所述的前体用于生长抑素表达组织的PET成像、SPECT成像或内放射治疗的用途。
10.根据权利要求2或3所述的放射性示踪剂用于生长抑素表达组织的PET成像、SPECT成像或内放射治疗的用途。
11.根据权利要求4至8中任一项所述的放射性药物试剂盒用于生长抑素表达组织的PET成像、SPECT成像或内放射治疗的用途。
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