Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer
Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer
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DOI：
10.2967/jnumed.114.147413
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发表时间：
2015-06-01
影响因子：
9.3
通讯作者：
Eder, Matthias
中科院分区：
文献类型：
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作者：
Benesova, Martina;Schaefer, Martin;Eder, Matthias
尽管在过去几年中取得了许多进展，但转移性前列腺癌的治疗仍然具有挑战性。近年来，前列腺特异性膜抗原（PSMA）抑制剂被广泛研究，以开发用于PET或SPECT成像前列腺癌病变的低分子量配体。然而，这些化合物的内放射性使用需要关于放射性核素螯合剂和螯合剂与药效团之间的接头部分的优化，这影响所得放射性配体的总体药代动力学性质。为了实现前列腺癌的检测和最佳治疗，已经开发了定制的新型含萘基DOTA缀合的PSMA抑制剂。研究方法：通过固相肽化学合成肽模拟物结构，并使用反相高效液相色谱和基质辅助激光解吸/电离质谱进行表征。随后的Ga-67/68和Lu-177标记分别导致大于97%或大于99%的放射化学产率。使用PSMA阳性LNCaP细胞系进行竞争性结合和内化实验。在携带LNCaP异种移植物的BALB/c nu/nu小鼠中研究了体内生物分布和动态小动物PET成像研究。结果：化学修饰的PSMA抑制剂PSMA-617表现出至少72 h的高辐解稳定性。证明了高抑制效力（对LNCaP的平衡解离常数[K-i] = 2.34 +/- 2.94 nM;酶促测定的K-i = 0.37 +/- 0.21 nM）和高效内化到LNCaP细胞中。小动物PET测量显示早在注射后1小时肿瘤与背景对比度就很高。器官分布显示在LNCaP肿瘤和注射后1小时在肾脏中的特异性摄取。关于治疗用途，该化合物显示出从肾脏的快速清除率，从1小时的113.3 +/-24.4%注射剂量/g至24小时的2.13 +/-1.36%注射剂量/g。该分子的有利药代动力学导致注射后24小时的肿瘤与背景比分别为1，058（肿瘤与血液）和529（肿瘤与肌肉）。结论：本文介绍的定制DOTA结合的PSMA抑制剂PSMA-617通过对连接区进行系统的化学修饰，在肿瘤靶向和药代动力学特性方面进行了可持续的改进和改进。因此，这种放射性示踪剂适用于首次在人体治疗诊断应用，并可能有助于改善前列腺癌的临床管理在未来。
Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-containing DOTA-conjugated PSMA inhibitor has been developed. Methods: The peptidomimetic structure was synthesized by solid-phase peptide chemistry and characterized using reversed-phase high-performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent Ga-67/68 and Lu-177 labeling resulted in radiochemical yields of greater than 97% or greater than 99%, respectively. Competitive binding and internalization experiments were performed using the PSMA-positive LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts. Results: The chemically modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equilibrium dissociation constant [K-i] = 2.34 +/- 2.94 nM on LNCaP; K-i = 0.37 +/- 0.21 nM enzymatically determined) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-to-background contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compound exhibited a rapid clearance from the kidneys from 113.3 +/- 24.4 at 1 h to 2.13 +/- 1.36 percentage injected dose per gram at 24 h. The favorable pharmacokinetics of the molecule led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), respectively, 24 h after injection. Conclusion: The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chemical modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clinical management of prostate cancer in the future.