Development of 99mTc-labeled asymmetric urea derivatives that target prostate-specific membrane antigen for single-photon emission computed tomography imaging
Development of 99mTc-labeled asymmetric urea derivatives that target prostate-specific membrane antigen for single-photon emission computed tomography imaging
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DOI：
10.1016/j.bmc.2016.03.051
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发表时间：
2016-05-15
影响因子：
3.5
通讯作者：
Saji, Hideo
中科院分区：
文献类型：
--
作者：
Kimura, Hiroyuki;Sampei, Sotaro;Saji, Hideo
前列腺特异性膜抗原(PSMA)在前列腺癌中有很强的表达，因此是一个有吸引力的诊断和放射免疫治疗靶点。与以往PMSA靶向阳离子或不带电荷的~(99)T-三甲基络合物的报道不同，阴离子~(99)M-三甲基络合物未见报道。值得注意的是，阳离子和阴离子电荷赋予的亲水性导致快速的肝胆清除，而相对于阳离子电荷，阴离子电荷可能更好地增强肾脏清除。因此，使用阳离子或阴离子电荷，特别是阴离子电荷，有望改善快速清除。在这项研究中，我们设计并合成了一种新型的阴离子~(99m)Tc-TMCE，并评价了其作为单光子发射计算机断层扫描(SPECT)成像探针检测PSMA的性能。以亚氨基二乙酸二甲酯为原料，采用微波一锅法直接合成了对PSMA具有重要作用的不对称尿素和琥珀酰亚胺基团。尽管前驱体含有复杂的生物活性部分，但仍能成功地形成络合物。[TC-99m]TMCE的放化产率为12-17%，放化纯度经高效液相纯化后大于98%。[TC-99m]TMCE在体外具有较高的亲和力，在LNCaP肿瘤中有较高的蓄积，在生物分布和SPECT/CT研究中肝滞留较低。这些发现为进一步评价[TC-99m]TMCE作为显像剂提供了依据，并支持了这一策略对其他PSMA成像探针设计的益处。(C)2016爱思唯尔有限公司。保留所有权利。
Prostate-specific membrane antigen (PSMA) is expressed strongly in prostate cancers and is, therefore, an attractive diagnostic and radioimmunotherapeutic target. In contrast to previous reports of PMSA-targeting Tc-99m-tricarbonyl complexes that are cationic or lack a charge, no anionic Tc-99m-tricarbonyl complexes have been reported. Notably, the hydrophilicity conferred by both cationic and anionic charges leads to rapid hepatobiliary clearance, whereas an anionic charge might better enhance renal clearance relative to a cationic charge. Therefore, an improvement in rapid clearance would be expected with either cationic or anionic charges, particularly anionic charges. In this study, we designed and synthesized a novel anionic Tc-99m-tricarbonyl complex ([Tc-99m] TMCE) and evaluated its use as a single-photon emission computed tomography (SPECT) imaging probe for PSMA detection. Direct synthesis of [Tc-99m] TMCE from dimethyl iminodiacetate, which contains both the asymmetric urea and succinimidyl moiety important for PSMA binding, was performed using our microwave-assisted one-pot procedure. The chelate formation was successfully achieved even though the precursor included a complicated bioactive moiety. The radiochemical yield of [Tc-99m] TMCE was 12-17%, with a radiochemical purity greater than 98% after HPLC purification. [Tc-99m] TMCE showed high affinity in vitro, with high accumulation in LNCaP tumors and low hepatic retention in biodistribution and SPECT/CT studies. These findings warrant further evaluation of [Tc-99m] TMCE as an imaging agent and support the benefit of this strategy for the design of other PSMA imaging probes. (C) 2016 Elsevier Ltd. All rights reserved.