Assessment of PSMA targeting ligands bearing novel chelates with application to theranostics: Stability and complexation kinetics of 68Ga3+, 111In3+, 177Lu3+., and 225AC3+
Assessment of PSMA targeting ligands bearing novel chelates with application to theranostics: Stability and complexation kinetics of 68Ga3+, 111In3+, 177Lu3+., and 225AC3+
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DOI：
10.1016/j.nucmedbio.2017.10.001
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发表时间：
2017-12-01
影响因子：
3.1
通讯作者：
Babich, John W.
中科院分区：
文献类型：
--
作者：
Kelly, James M.;Amor-Coarasa, Alejandro;Babich, John W.
介绍：最近通过全身性腔内放射疗法治疗转移性去势抵抗性前列腺癌（mCRPCa）的成功引发了对开发靶向前列腺特异性膜抗原（PSMA）的小分子配体和能够稳定络合金属放射性核素用于成像和治疗的螯合剂的新兴趣。由于用于成像的金属（如Ga-68（3+））和用于靶向治疗的金属（如Lu-177（3+）和Ac-225（3+））的尺寸和配位数基本上不同，因此它们可能显示出对不同齿度的大环的偏好。我们已经准备了三个简单的共轭物，目标PSMA和形成放射性金属配合物，通过协调由八，十，或十二齿四氮杂环十二烷螯合剂。在两个相关温度下测定这些构建体的复合物形成和金属离子选择性，在体外检查复合物稳定性，并在临床前PCa模型中证明肿瘤靶向，以期鉴定具有作为用于mCRPCa的成像和治疗的治疗诊断剂的潜在价值的候选物。三种具有高齿度的双功能螯合物，包括八齿螯合物DOTA、十齿3 p-C-DEPA和DEPA的新型十二齿类似物，合成并缀合至谷氨酸-脲-赖氨酸（EuK）药效团（分别为EuK-DOTA、EuK-107和EuK-106）以能够靶向PSMA。通过在25 ℃和95 ℃下与三价放射性金属Ga-68（3+）、In-111（3+）、Lu-177（3+）和Ac-225（3+）一起温育来测定每种构建体的金属离子选择性。通过使用LNCaP细胞的竞争性结合来确定PSMA结合亲和力，同时通过正电子发射断层扫描（PET）在携带LNCaP异种移植肿瘤的小鼠中检查Ga-68标记的构建体的体内肿瘤靶向。PMSA亲和力（IC 50值）对于EuK-DOTA为133 +/- 0.9 nM，对于EuK-107为18.0 +/- 3.7 nM，并且对于EuK-106为42.6 +/- 6.6 nM。EuK-107和EuK-DOTA证明在95 ℃下快速且接近定量地络合Ga-68（3+）、In-111（3+）、Lu-177（3+）和Ac-225（3+），其中EuK-107还在25 ℃下快速络合In-111（3+）和Lu-177（3+）。EuK-106不能螯合Lu-177（3+）和Ac-225（3+），这表明对于螯合较大的放射性金属，大环的空腔大小可能比供体基团的数量更关键。在体内，Ca-68-EuK-107被证明在PSMA阳性异种移植肿瘤模型中具有与Ga-68-DKEZ-PSMA-617（目前在临床评估中的治疗诊断配体）相似的摄取。宽的金属离子选择性、对PSMA的良好体外亲和力和良好的体内肿瘤靶向表明EuK-107与3 β-C-DEPA螯合剂，作为前列腺癌治疗诊断学构建物值得进一步评估。(C)2017由Elsevier Inc.出版
Introduction: Recent successes in the treatment of metastatic castration-resistant prostate cancer (mCRPCa) by systemic endoradiotherapy has sparked renewed interest in developing small molecule ligands targeting prostate specific membrane antigen (PSMA) and chelators capable of stable complexation of metal radionuclides for imaging and therapy. As the size and coordination number of metals for imaging, such as Ga-68(3+), and for targeted therapy, such as Lu-177(3+) and Ac-225(3+), are substantially different, they may show a preference for macrocycles of different denticity. We have prepared three simple conjugates that target PSMA and form radiometal complexes through coordination by either octa-, deca-, or dodecadentate tetraazacyclododecane chelators. The complex formation and metal ion selectivity of these constructs were determined at two relevant temperatures, complex stability was examined in vitro, and tumor targeting was demonstrated in predinical PCa models with a view towards identifying a candidate with potential value as a theranostic agent for the imaging and therapy of mCRPCa.Methods: Three bifunctional chelates with high denticity, including the octadentate chelate DOTA, the decadentate 3p-C-DEPA and a novel dodecadentate analogue of DEPA, were synthesized and conjugated to a glutamate-urea-lysine (EuK) pharmacophore (EuK-DOTA, EuK-107 and EuK-106, respectively) to enable targeting of PSMA. The metal ion selectivity for each construct was determined by incubation at 25 degrees C and 95 degrees C with the trivalent radiometals Ga-68(3+), In-111(3+), Lu-177(3+) and Ac-225(3+). PSMA binding affinity was determined by competitive binding using LNCaP cells, while in vivo tumor targeting of the Ga-68-labeled constructs was examined by positron emission tomography (PET) in LNCaP xenograft tumor-bearing mice.Results: PMSA affinities (IC50 values) were 133 +/- 0.9 nM for EuK-DOTA, 18.0 +/- 3.7 nM for EuK-107 and 42.6 +/- 6.6 nM for EuK-106. EuK-107 and EuK-DOTA proved to rapidly and near quantitatively complex Ga-68(3+), In-111(3+), Lu-177(3+) and Ac-225(3+) at 95 degrees C, with EuK-107 also rapidly complexing In-111(3+) and Lu-177(3+) at 25 degrees C. The inability of EuK-106 to chelate Lu-177(3+) and Ac-225(3+) suggests that size of the cavity of the macrocylic ring may be more critical than the number of donor groups for the chelation of larger radiometals. In vivo, Ca-68-EuK-107 proved to have similar uptake to Ga-68-DKEZ-PSMA-617, a theranostic ligand currently in clinical evaluation, in a PSMA positive xenograft tumor model.Conclusions: The broad metal ion selectivity, good in vitro affinity for PSMA and good in vivo tumor targeting suggest that EuK-107, with the 3p-C-DEPA chelator, merits further evaluation as a theranostics construct in prostate cancer. (C) 2017 Published by Elsevier Inc.