Assessment of an 18F-labeled phosphoramidate peptidomimetic as a new prostate-specific membrane antigen-targeted imaging agent for prostate cancer.
Assessment of an 18F-labeled phosphoramidate peptidomimetic as a new prostate-specific membrane antigen-targeted imaging agent for prostate cancer.
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DOI：
10.2967/jnumed.109.066589
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Jones EF
中科院分区：
文献类型：
--
作者：
Lapi SE;Wahnishe H;Pham D;Wu LY;Nedrow-Byers JR;Liu T;Vejdani K;VanBrocklin HF;Berkman CE;Jones EF
前列腺特异性膜抗原（PSMA）是一种常见于晚期和转移性前列腺癌表面的跨膜蛋白，也是一种众所周知的用于分期和监测治疗的成像生物标志物。尽管111 In标记caprop-umab pendetide是唯一获批用于PSMA成像的药物，但其临床应用受到限制，因为其分布和清除缓慢，导致图像判读困难。使用放射性标记的基于脲的PSMA抑制剂作为成像剂的小分子方法已经显示出前列腺癌成像的前景。这项工作的动机是探索氨基磷酸酯作为一类新的有效的PSMA抑制剂，以开发具有改善的特异性和清除特性的更有效的前列腺癌成像剂。将N-琥珀酰亚胺基-4-18F-氟苯甲酸酯（18F-SFB）缀合至S-2-（（2-（S-4-氨基-4-羧基丁酰氨基）-S-2-羧基乙氧基）-羟基磷酰基氨基）-戊二酸（氨基磷酸酯（1）），产生S-2-（（2-（S-4-（4- 18F-氟苯甲酰氨基）-4-羧基丁酰氨基）-S-2-羧基乙氧基）羟基磷酰基氨基）-戊二酸（3）。在携带LNCaP（PSMA阳性）或PC-3（PSMA阴性）肿瘤的小鼠中进行体内研究。PET图像采集在1和2小时或不预先注射的非放射性版本的氟磷酰胺。在2小时成像结束时进行组织分布研究。氨基磷酸酯（1）及其氟苯甲酰氨基缀合物（2）是PSMA的强效抑制剂（抑制浓度分别为50% [IC 50]、14和0.68 nM）。在LNCaP与PC-3肿瘤异种移植物中观察到PSMA介导的肿瘤蓄积。LNCaP肿瘤摄取也在成像研究前通过给予非放射性物质阻断（2）。除肾脏外，2 h时肿瘤与组织和肿瘤与血液的比值均大于5：1。强的肾摄取可能是由于小鼠肾中已知的PSMA表达，因为在注射（2）的小鼠中观察到肾活性的显著降低（>6倍）。18F标记的氨基磷酸酯（3）是一类新的PSMA靶向肽模拟物分子的代表，其显示出作为检测PSMA+前列腺肿瘤的成像剂的巨大前景。
Prostate-specific membrane antigen (PSMA) is a transmembrane protein commonly found on the surface of late-stage and metastatic prostate cancer and a well-known imaging biomarker for staging and monitoring therapy. Although 111In-labeled caprop-mab pendetide is the only approved agent available for PSMA imaging, its clinical use is limited because of its slow distribution and clearance that leads to challenging image interpretation. A small-molecule approach using radiolabeled urea-based PSMA inhibitors as imaging agents has shown promise for prostate cancer imaging. The motivation of this work is to explore phosphoramidates as a new class of potent PSMA inhibitors to develop more effective prostate cancer imaging agents with improved specificity and clearance properties. N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) was conjugated to S-2-((2-(S-4-amino-4-carboxybutanamido)-S-2-carboxyethoxy)-hydroxyphosphorylamino)-pentanedioic acid (Phosphoramidate (1)), yielding S-2-((2-(S-4-(4-18F-fluorobenzamido)-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (3). In vivo studies were conducted in mice bearing either LNCaP (PSMA-positive) or PC-3 (PSMA-negative) tumors. PET images were acquired at 1 and 2 h with or without a preinjection of a nonradioactive version of the fluorophosphoramidate. Tissue distribution studies were performed at the end of the 2 h imaging sessions. Phosphoramidate (1) and its fluorobenzamido conjugate (2) were potent inhibitors of PSMA (inhibitory concentration of 50% [IC50], 14 and 0.68 nM, respectively). PSMA-mediated tumor accumulation was noted in the LNCaP versus the PC-3 tumor xenografts. The LNCaP tumor uptake was also blocked by the administration of nonradioactive (2) prior to imaging studies. With the exception of the kidneys, tumor-to-tissue and tumor-to-blood ratios were greater than 5:1 at 2 h. The strong kidney uptake may be due to the known PSMA expression in the mouse kidney, because significant reduction (>6-fold) in kidney activity was seen in mice injected with (2). 18F-labeled phosphoramidate (3) is a representative of a new class of PSMA targeting peptidomimetic molecules that shows great promise as imaging agents for detecting PSMA+ prostate tumors.
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