Lapi Suzanne E, Wahnishe Hilla, Pham David, Wu Lisa Y, Nedrow-Byers Jessie R, Liu Tiancheng, Vejdani Kaveh, VanBrocklin Henry F, Berkman Clifford E, Jones Ella F
Department of Radiology and Biomedical Imaging, Center for Molecular and Functional Imaging, University of California, San Francisco, California 94107, USA.
J Nucl Med. 2009 Dec;50(12):2042-8. doi: 10.2967/jnumed.109.066589. Epub 2009 Nov 12.
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 (111)In-labeled capropmab 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-(18)F-fluorobenzoate ((18)F-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-(18)F-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% [IC(50)], 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).
(18)F-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.
前列腺特异性膜抗原（PSMA）是一种跨膜蛋白，常见于晚期和转移性前列腺癌表面，是用于分期和监测治疗的著名成像生物标志物。尽管（111）铟标记的卡波单抗喷地肽是唯一获批用于PSMA成像的药物，但其临床应用有限，因为其分布和清除缓慢，导致图像解读具有挑战性。使用放射性标记的基于尿素的PSMA抑制剂作为成像剂的小分子方法已显示出在前列腺癌成像方面的前景。这项工作的目的是探索磷酰胺作为一类新型强效PSMA抑制剂，以开发具有更高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-（18）F-氟苯甲酸酯（（18）F-SFB）与S-2-（（2-（S-4-氨基-4-羧基丁酰胺基）-S-2-羧基乙氧基）羟基磷酰氨基）-戊二酸（磷酰胺（1））偶联，得到S-2-（（2-（S-4-（4-（18）F-氟苯甲酰胺基）-4-羧基丁酰胺基）-S-2-羧基乙氧基）羟基磷酰氨基）-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。在注射或不注射非放射性氟磷酰胺的情况下，于1小时和2小时采集PET图像。在2小时成像期结束时进行组织分布研究。
磷酰胺（1）及其氟苯甲酰胺偶联物（2）是PSMA的强效抑制剂（半数抑制浓度[IC（50）]分别为14和0.68 nM）。在LNCaP与PC-3肿瘤异种移植模型中观察到PSMA介导的肿瘤蓄积。在成像研究前给予非放射性的（2）也可阻断LNCaP肿瘤摄取。除肾脏外，2小时时肿瘤与组织及肿瘤与血液的比率均大于5:1。肾脏摄取强烈可能是由于小鼠肾脏中已知的PSMA表达，因为在注射（2）的小鼠中肾脏活性显著降低（>6倍）。
（18）F标记的磷酰胺（3）是一类新型靶向PSMA的拟肽分子的代表，作为检测PSMA阳性前列腺肿瘤的成像剂显示出巨大前景。
