A new high affinity technetium-99m-bombesin analogue with low abdominal accumulation
A new high affinity technetium-99m-bombesin analogue with low abdominal accumulation
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DOI：
10.1021/bc049820h
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发表时间：
2005-01-01
影响因子：
4.7
通讯作者：
Wagner, HN
中科院分区：
文献类型：
--
作者：
Lin, KS;Luu, A;Wagner, HN
Tc-99 m标记的蛙皮素类似物已显示出用于非侵入性检测许多表达蛙皮素（BN）/胃泌素释放肽（GRP）受体的肿瘤的前景。然而，由于Tc-99 m螯合物的亲脂性，Tc-99 m标记的肽由于肝胆清除而具有在肝脏和肠中积累的趋势。这使得腹部区域病变的成像变得困难。在本研究中，我们合成了一种新的高亲和力Tc-99 m标记的BN类似物[DTPA（1），Lys（3）（Tc-99 m-Pm-DADT），Tyr（4）]BN，其具有内置的药代动力学修饰剂DTPA，并使用亲水性二胺二硫醇螯合剂（Pm-DADT）用Tc-99 m标记以实现低肝胆清除率。使用人前列腺癌PC-3细胞膜进行的体外结合研究显示，[DTPA（1），Lys（3）（Tc-99-Pm-DADT），Tyr（4）]BN的抑制常数（Ki）为4.1 +/- 1.4 nM。[DTPA（1），Lys（3）（Tc-99 m-Pm-DADT），Tyr（4）]BN在正常小鼠中的生物分布研究显示，肝脏和肠道中的放射性蓄积非常低（分别为1.32 +/- 0.13和4.58 +/- 0.50% ID，注射后4 h）。在表达BN/GRP受体的胰腺中有显著的摄取（7.71 +/-1.37%ID/g，注射后1小时）。BN可阻断胰腺的摄取，神经介肽B可部分阻断，但生长抑素不影响胰腺的摄取，表明体内结合是BN/GRP受体特异性的。闪烁图像显示了SCID小鼠中前列腺癌PC-3异种移植物的特异性高对比度描绘。因此，这种新肽具有很大的潜力，可用于成像BN/GRP受体阳性的癌症，甚至位于腹部。
Tc-99m-labeled bombesin analogues have shown promise for noninvasive detection of many tumors that express bombesin (BN)/gastrin-releasing peptide (GRP) receptors. Tc-99m-labeled peptides, however, have a tendency to accumulate in the liver and intestines due to hepatobiliary clearance as a result of the lipophilicity of the Tc-99m chelates. This makes the imaging of lesions in the abdominal area difficult. In this study, we have synthesized a new high affinity Tc-99m-labeled BN analogue, [DTPA(1), Lys(3)(Tc-99m-Pm-DADT), Tyr(4)]BN, having a built-in pharmacokinetic modifier, DTPA, and labeled with Tc-99m using a hydrophilic diaminedithiol chelator (Pm-DADT) to effect low hepatobiliary clearance. In vitro binding studies using human prostate cancer PC-3 cell membranes showed that the inhibition constant (K-i) for [DTPA(1), Lys(3)(Tc-99-Pm-DADT), Tyr(4)]BN was 4.1 +/- 1.4 nM. Biodistribution studies of [DTPA(1), Lys(3)(Tc-99m-Pm-DADT), Tyr(4)]BN in normal mice showed very low accumulation of radioactivity in the liver and intestines (1.32 +/- 0.13 and 4.58 +/- 0.50% ID, 4 h postinjection, respectively). There was significant uptake (7.71 +/- 1.37% ID/g, 1 h postinjection) in the pancreas which expresses BN/GRP receptors. The uptake in the pancreas could be blocked by BN, partially blocked by neuromedin B, but not affected by somatostatin, indicating that the in vivo binding was BN/GRP receptor specific. Scintigraphic images showed specific, high contrast delineation of prostate cancer PC-3 xenografts in SCID mice. Thus, the new peptide has a great potential for imaging BN/GRP receptor-positive cancers located even in the abdomen.