Robu Stephanie, Schmidt Alexander, Eiber Matthias, Schottelius Margret, Günther Thomas, Hooshyar Yousefi Behrooz, Schwaiger Markus, Wester Hans-Jürgen
Chair of Pharmaceutical Radiochemistry, Technical University Munich, Walther-Meissner-Strasse 3, 85748, Garching, Germany.
Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675, Munich, Germany.
EJNMMI Res. 2018 Apr 12;8(1):30. doi: 10.1186/s13550-018-0382-8.
Due to its high and consistent expression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) represents an ideal target for molecular imaging and targeted therapy using highly specific radiolabeled PSMA ligands. To address the continuously growing clinical demand for F-labeled PSMA-probes, we developed two novel Glu-urea-Glu-(EuE)-based inhibitors, EuE-k-F-FBOA (1) and EuE-k-β-a-F-FPyl (2), both with optimized linker structure and different F-labeled aromatic moieties. The inhibitors were evaluated in a comparative preclinical study with F-DCFPyl and F-PSMA-1007.
Radiolabeling procedures allowed preparation of (1) and (2) with high radiochemical yields (67 ± 7 and 53 ± 7%, d.c.) and purity (> 98%). When compared with F-DCFPyl (IC = 12.3 ± 1.2 nM) and F-PSMA-1007 (IC = 4.2 ± 0.5 nM), both metabolically stable EuE-based ligands showed commensurable or higher PSMA affinity (IC = 4.2 ± 0.4 nM (1), IC = 1.1 ± 0.2 nM (2)). Moreover, 1.4- and 2.7-fold higher internalization rates were observed for (1) and (2), respectively, resulting in markedly enhanced tumor accumulation in LNCaP-tumor-bearing mice ((1) 12.7 ± 2.0% IA/g, (2) 13.0° ± 1.0% IA/g vs. 7.3 ± 1.0% IA/g (F-DCFPyl), 7.1 ± 1.5% IA/g (F-PSMA-1007), 1 h p.i.). In contrast to (1), (2) showed higher kidney accumulation and delayed clearance kinetics. Due to the high hydrophilicity of both compounds, almost no unspecific uptake in non-target tissue was observed. In contrast, due to the less hydrophilic character (logP = - 1.6) and high plasma protein binding (98%), F-PSMA-1007 showed uptake in non-target tissue and predominantly hepatobiliary excretion, whereas, F-DCFPyl exhibited pharmacokinetics quite similar to those obtained with (1) and (2).
Both F-labeled EuE-based PSMA ligands showed excellent in vitro and in vivo PSMA-targeting characteristics. The substantially higher tumor accumulation in mice compared to recently introduced F-PSMA-1007 and F-DCFPyl suggests their high value for preclinical studies investigating the effects on PSMA-expression. In contrast to (2), (1) seems to be more promising for further investigation, due to the more reliable F-labeling procedure, the faster clearance kinetics with comparable high tumor uptake, resulting therefore in better high-contrast microPET imaging as early as 1 h p.i.
前列腺特异性膜抗原（PSMA）在前列腺癌（PCa）中高度且持续表达，是使用高特异性放射性标记的PSMA配体进行分子成像和靶向治疗的理想靶点。为满足对F标记的PSMA探针不断增长的临床需求，我们开发了两种新型基于Glu-脲-Glu-（EuE）的抑制剂，EuE-k-F-FBOA（1）和EuE-k-β-a-F-FPyl（2），二者均具有优化的连接子结构和不同的F标记芳环部分。在一项与F-DCFPyl和F-PSMA-1007的比较性临床前研究中对这些抑制剂进行了评估。
放射性标记程序能够以高放射化学产率（67±7%和53±7%，放化纯）和高纯度（>98%）制备（1）和（2）。与F-DCFPyl（IC = 十二点三±一点二 nM）和F-PSMA-1007（IC = 四点二±零点五 nM）相比，两种代谢稳定的基于EuE的配体均表现出相当或更高的PSMA亲和力（IC = 四点二±零点四 nM（1），IC = 一点一±零点二 nM（2））。此外，（1）和（2）的内化率分别高1.4倍和2.7倍，导致在荷LNCaP肿瘤小鼠中的肿瘤蓄积显著增强（（1）12.7±2.0% IA/g，（2）13.0°±1.0% IA/g，而F-DCFPyl为7.3±1.0% IA/g，F-PSMA-1007为7.1±1.5% IA/g，注射后1小时）。与（1）相反，（2）显示出更高的肾脏蓄积和延迟的清除动力学。由于两种化合物的亲水性高，在非靶组织中几乎未观察到非特异性摄取。相比之下，由于亲水性较低（logP = -1.6）和血浆蛋白结合率高（98%），F-PSMA-1007在非靶组织中有摄取且主要经肝胆排泄，而F-DCFPyl表现出与（1）和（2）相似的药代动力学。
两种F标记的基于EuE的PSMA配体均表现出优异的体外和体内PSMA靶向特性。与最近推出的F-PSMA-1007和F-DCFPyl相比，在小鼠中显著更高的肿瘤蓄积表明它们在研究对PSMA表达影响的临床前研究中具有很高价值。与（2）相反，（1）似乎更有进一步研究的前景，因为其F标记程序更可靠，清除动力学更快且肿瘤摄取相当高，因此早在注射后1小时就能实现更好的高对比度微型PET成像。
