Linder Karen E, Metcalfe Edmund, Arunachalam Thangavel, Chen Jianqing, Eaton Stephen M, Feng Weiwei, Fan Hong, Raju Natarajan, Cagnolini Aldo, Lantry Laura E, Nunn Adrian D, Swenson Rolf E
Bracco Research USA Inc., 305 College Road East, Princeton, New Jersey 08540, USA.
Bioconjug Chem. 2009 Jun;20(6):1171-8. doi: 10.1021/bc9000189.
The metabolism of (177)Lu-AMBA (AMBA = DO3A-CH(2)CO-G-(4-aminobenzoyl)-QWAVGHLM-NH(2)), a radiotherapeutic compound in clinical development that binds to GRP and NMB receptors, was studied in vitro (mouse, rat and human plasma, mouse kidney homogenate) and in vivo (by analysis of mouse and rat plasma and urine following IV injection of (177)Lu-AMBA). The primary metabolites were Lu-DO3A-CH(2)CO-G-Abz4-R, where R = -Q-OH (A), -QW-OH (B), and -QWAVGH-OH (C). Minor amounts of (D) where R = -QWAVGHLM-OH and (E) -QWAVGHL-OH were also observed. Clearance of (177)Lu-AMBA and of radioactivity from mouse and rat blood was rapid in vivo. In mouse and rat urine, only metabolites Lu-A and Lu-B were found-no parent drug was excreted. Unmetalated ligands and (nat)Lu and (177)Lu complexes for Lu-AMBA metabolites A-E were synthesized, characterized by HPLC and MS, and used to perform in vitro competition and direct binding studies on GRP receptor-positive PC-3 (human prostate) cancer cells. Biodistribution studies with (177)Lu-labeled metabolites A-E were performed in PC-3 tumor-bearing mice and the results compared with intact (177)Lu-AMBA. IC(50) values for unmetalated metabolite ligands A-E were >400 nM in PC-3 cells in competition binding studies against (177)Lu-AMBA. No direct binding to PC-3 cells was observed with (177)Lu-labeled A-C, confirming IC(50) results. (177)Lu-labeled metabolites A-E showed no uptake in GRP-receptor positive tumor or pancreas in PC-3 tumor bearing mice. All metabolites were rapidly excreted via the renal route (approximately 78-87%) within 1 h. These results demonstrate that the tumor uptake observed with (177)Lu-AMBA is due to parent drug and not due to any of its identified metabolites.
（177）Lu-AMBA（AMBA = DO3A-CH(2)CO-G-(4-氨基苯甲酰基)-QWAVGHLM-NH(2)）是一种处于临床开发阶段的放射治疗化合物，可与GRP和NMB受体结合。本文对其在体外（小鼠、大鼠和人血浆、小鼠肾匀浆）和体内（静脉注射（177）Lu-AMBA后，分析小鼠和大鼠的血浆及尿液）的代谢情况进行了研究。主要代谢产物为Lu-DO3A-CH(2)CO-G-Abz4-R，其中R = -Q-OH（A）、-QW-OH（B）和 -QWAVGH-OH（C）。还观察到少量R = -QWAVGHLM-OH的（D）和 -QWAVGHL-OH的（E）。在体内，（177）Lu-AMBA以及小鼠和大鼠血液中的放射性清除迅速。在小鼠和大鼠尿液中，仅发现代谢产物Lu-A和Lu-B，未排出母体药物。合成了未金属化配体以及Lu-AMBA代谢产物A - E的（天然）Lu和（177）Lu配合物，通过HPLC和MS进行表征，并用于对GRP受体阳性的PC-3（人前列腺）癌细胞进行体外竞争和直接结合研究。用（177）Lu标记的代谢产物A - E在荷PC-3肿瘤小鼠中进行了生物分布研究，并将结果与完整的（177）Lu-AMBA进行比较。在针对（177）Lu-AMBA的PC-3细胞竞争结合研究中，未金属化代谢产物配体A - E的IC(50)值>400 nM。用（177）Lu标记的A - C未观察到与PC-3细胞的直接结合，证实了IC(50)结果。（177）Lu标记的代谢产物A - E在荷PC-3肿瘤小鼠的GRP受体阳性肿瘤或胰腺中未显示摄取。所有代谢产物在1小时内通过肾脏途径迅速排泄（约78 - 87%）。这些结果表明，（177）Lu-AMBA观察到的肿瘤摄取是由于母体药物，而非其任何已鉴定的代谢产物。
