Lin Kuo-Shyan, Luu Andrew, Baidoo Kwamena E, Hashemzadeh-Gargari Hossein, Chen Ming-Kai, Pili Roberto, Pomper Martin, Carducci Michael, Wagner Henry N
Department of Environmental Health Sciences, The Johns Hopkins Medical Institutions, 615 North Wolfe Street, Room E6632, Baltimore, Maryland 21205, USA.
Bioconjug Chem. 2004 Nov-Dec;15(6):1416-23. doi: 10.1021/bc0498267.
The bombesin (BN)/gastrin-releasing peptide (GRP) receptor is expressed in high density on the cell surface of a variety of tumors. This makes the receptors accessible as a molecular target for the detection of lesions in which they are expressed. In this study, we describe a high affinity hydrophilic (99m)Tc-labeled BN analogue, [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]BN, having diethylenetriaminepentaacetic acid (DTPA), as a build-in pharmacokinetic modifier, to direct its excretion through the urinary system in order to lower abdominal background activity. In vitro binding studies using [(125)I-Tyr(4)]BN (K(d), 0.1 nM) and human prostate cancer PC-3 cell membranes showed that the inhibition constant (K(i)) of [DTPA(1), Lys(3)((99)Tc-Hx-DADT), Tyr(4)]BN was 19.9 +/- 8.0 nM. Biodistribution studies in normal mice showed fast blood clearance (0.15 +/- 0.01% ID/g, 4 h postinjection), low intestinal accumulation (9.16 +/- 2.35% ID/g, 4 h postinjection), and significant uptake in BN/GRP receptor rich tissues such as the pancreas (21.83 +/- 2.88% ID/g, 15 min postinjection). The pancreas/blood, pancreas/muscle, and pancreas/liver ratios were highest at 2 h postinjection at 23, 74, and 8.4, respectively. The uptake in the pancreas could be blocked by BN (11.96 +/- 1.17 vs 0.65 +/- 0.16% ID/g), partially blocked by neuromedin B (11.96 +/- 1.17 vs 6.66 +/- 0.51% ID/g), but not affected by somatostatin (11.96 +/- 1.17 vs 12.91 +/- 2.53% ID/g), indicating that the binding of [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]BN to the receptors was specific. Scintigraphic imaging of human PC-3 prostate cancer xenografts in SCID mice gave a high target to nontarget ratio on the image. Thus, [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]BN has the potential for imaging BN/GRP receptor-positive lesions.
蛙皮素（BN）/胃泌素释放肽（GRP）受体在多种肿瘤细胞表面高密度表达。这使得这些受体可作为检测其表达的病变的分子靶点。在本研究中，我们描述了一种高亲和力的亲水性（99m）Tc标记的BN类似物，[二乙三胺五乙酸（DTPA）（1），赖氨酸（3）（（99m）Tc-Hx-DADT），酪氨酸（4）]BN，它含有二乙三胺五乙酸（DTPA）作为内置的药代动力学修饰剂，以引导其通过泌尿系统排泄，从而降低腹部背景活性。使用[（125）I-酪氨酸（4）]BN（K（d），0.1 nM）和人前列腺癌PC-3细胞膜进行的体外结合研究表明，[DTPA（1），赖氨酸（3）（（99）Tc-Hx-DADT），酪氨酸（4）]BN的抑制常数（K（i））为19.9±8.0 nM。正常小鼠的生物分布研究表明，血液清除迅速（注射后4小时为0.15±0.01%ID/g），肠道蓄积低（注射后4小时为9.16±2.35%ID/g），并且在富含BN/GRP受体的组织如胰腺中摄取显著（注射后15分钟为21.83±2.88%ID/g）。胰腺/血液、胰腺/肌肉和胰腺/肝脏的比值在注射后2小时最高，分别为23、74和8.4。胰腺中的摄取可被BN阻断（11.96±1.17对0.65±0.16%ID/g），被神经介素B部分阻断（11.96±1.17对6.66±0.51%ID/g），但不受生长抑素影响（11.96±1.17对12.91±2.53%ID/g），表明[DTPA（1），赖氨酸（3）（（99m）Tc-Hx-DADT），酪氨酸（4）]BN与受体的结合具有特异性。对SCID小鼠中人PC-3前列腺癌异种移植瘤的闪烁成像在图像上给出了高的靶与非靶比值。因此，[DTPA（1），赖氨酸（3）（（99m）Tc-Hx-DADT），酪氨酸（4）]BN具有对BN/GRP受体阳性病变进行成像的潜力。
