Radiopharmaceutical Chemistry, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
EJNMMI Res. 2012 Jun 6;2(1):23. doi: 10.1186/2191-219X-2-23.
Alternative positron-emission tomography (PET) probes like labeled inhibitors of the prostate-specific membrane antigen (PSMA) are of emerging clinical impact as they show the ability to image small lesions of recurrent prostate cancer. Here, the dimerization of the pharmacophore Glu-ureido-Lys via the 68Ga chelator N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) was investigated to further improve the binding characteristics and pharmacokinetics.
The peptidomimetic structures were synthesized by solid-phase chemistry, and the resulting products were coupled with the respective 2,3,5,6-tetrafluorophenol esters of HBED-CC to form the monomeric reference and the dimeric Glu-ureido-Lys derivative. The binding properties were analyzed in competitive binding, internalization, and cell surface retention experiments. PET images and biodistribution data were obtained 1 h after injection in BALB/c nu/nu mice bearing LNCaP tumor xenografts.
Cell binding data revealed significant better binding properties of the dimer (IC50 = 3.9 ± 1.8 nM; IC50 (monomer) = 12.1 ± 2.1 nM). The inhibition potency investigated by the enzyme-based NAALADase assay confirmed these results. Specific internalization in LNCaP cells was demonstrated for both, the monomer and dimer. As shown by efflux measurements, the dimeric compound was more effectively retained on the cell surface, resulting in advanced in vivo properties (T/BMonomer = 9.2; T/BDimer = 26.5).
The dimeric [68Ga]7 is a promising imaging agent for PSMA-expressing tumors as it shows higher tumor uptake while observing more favorable background clearance. As compared to the respective monomer, the higher affinity and prolonged tumor retention additionally represent promising features and warrant further evaluation regarding 68Ga-PET imaging of PSMA expression.
类似前列腺特异性膜抗原（PSMA）的标记抑制剂的替代正电子发射断层扫描（PET）探针具有新兴的临床影响，因为它们显示出能够对复发性前列腺癌的小病灶进行成像的能力。在这里，通过 68Ga 螯合剂 N,N'-双[2-羟基-5-（羧乙基）苄基]乙二胺-N,N'-二乙酸（HBED-CC）对药效团 Glu-脲基-Lys 进行二聚化，以进一步改善结合特性和药代动力学。
通过固相化学合成肽模拟结构，并将所得产物与各自的 HBED-CC 的 2,3,5,6-四氟苯酚酯偶联，形成单体参考物和 Glu-脲基-Lys 二聚体衍生物。在竞争结合、内化和细胞表面保留实验中分析结合特性。在荷有 LNCaP 肿瘤异种移植物的 BALB/c nu/nu 小鼠中，在注射后 1 小时获得 PET 图像和生物分布数据。
细胞结合数据显示二聚体（IC50=3.9±1.8 nM；IC50（单体）=12.1±2.1 nM）具有显著更好的结合特性。基于酶的 NAALADase 测定的抑制效力证实了这些结果。单体和二聚体都在 LNCaP 细胞中表现出特异性内化。如流出测量所示，二聚化合物在细胞表面更有效地保留，导致体内特性得到改善（T/BMonomer=9.2；T/BDimer=26.5）。
二聚体 [68Ga]7 是一种有前途的 PSMA 表达肿瘤成像剂，因为它显示出更高的肿瘤摄取量，同时观察到更有利的背景清除。与相应的单体相比，更高的亲和力和延长的肿瘤保留另外代表了有前途的特征，并需要进一步评估其用于 PSMA 表达的 68Ga-PET 成像。
